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WO2022254426A1 - Compositions pour le traitement de tumeurs cérébrales - Google Patents

Compositions pour le traitement de tumeurs cérébrales Download PDF

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Publication number
WO2022254426A1
WO2022254426A1 PCT/IL2022/050570 IL2022050570W WO2022254426A1 WO 2022254426 A1 WO2022254426 A1 WO 2022254426A1 IL 2022050570 W IL2022050570 W IL 2022050570W WO 2022254426 A1 WO2022254426 A1 WO 2022254426A1
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WO
WIPO (PCT)
Prior art keywords
bicalutamide
pharmaceutical composition
antagonist
formulation
composition
Prior art date
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Ceased
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PCT/IL2022/050570
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English (en)
Inventor
Iris Lavon
Shlomo Magdassi
Liraz Larush
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hadasit Medical Research Services and Development Co
Yissum Research Development Co of Hebrew University of Jerusalem
Original Assignee
Hadasit Medical Research Services and Development Co
Yissum Research Development Co of Hebrew University of Jerusalem
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Publication of WO2022254426A1 publication Critical patent/WO2022254426A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the field of cancer therapy, specifically to improved compositions for the treatment of cerebral tumors. More specifically, provided are pharmaceutical formulations comprising androgen receptor (AR) antagonists, having improved therapeutic properties.
  • AR androgen receptor
  • Androgen blockade by drugs that prevent the production of androgens (androgen deprivation therapy) and/or block the action of the androgen receptor (AR antagonists), is routinely used to inhibit prostate cancer growth.
  • AR antagonists have been developed and are mainly used in the treatment of prostate cancer, and include, for example, flutamide, nilutamide, bicalutamide and enzalutamide.
  • Compositions and methods of manufacturing and using AR antagonists are disclosed, for example, in U.S. 2014/100256, U.S. 2007/004753, U.S. 2015/239848, and U.S. 2015/210649.
  • Bicalutamide (Casodex) is indicated as a means of androgen deprivation therapy for the treatment of stage D2 metastatic prostate cancer in combination with castration (pharmacological with a GnRH analogue or surgical with an orchiectomy) or at a higher dosage as a monotherapy.
  • Various forms, enantiomers and esters of bicalutamide are disclosed, for example, in WO 2011/002184, WO 2006/090129, WO 2004/029021, WO 2004/074350, and U.S. 2004/0063782.
  • 2008/0045600 discloses pharmaceutical compositions comprising bicalutamide or its pharmaceutically acceptable salts, solvates, single isomers, enantiomers or mixtures thereof, and a hydrophilic excipient, processes for preparing the compositions and finished dosage forms containing them, and methods of use and treatment.
  • bicalutamide or its pharmaceutically acceptable salts, solvates, single isomers, enantiomers or mixtures thereof, and a hydrophilic excipient
  • processes for preparing the compositions and finished dosage forms containing them and methods of use and treatment.
  • an intimate mixture comprising bicalutamide and a hypromellose.
  • the pharmaceutical compositions are disclosed as being useful in the treatment of conditions including prostate cancer. Additional bicalutamide compositions are described, for example, in WO 2006/069098 and WO 2002/067893.
  • AR is amplified in glioblastomas at the DNA, RNA and protein levels, and that 30% of the glioblastomas also expressed a constitutively active AR- splice- variant (AR- V7/AR3) lacking the Ligand-Binding-Domain.
  • AR antagonists including bicalutamide and enzalutamide induced concentration-dependent death in glioblastoma and glioma-initiating cell lines, and silencing of AR expression by siRNA induced cell death in the tested glioblastoma lines.
  • enzalutamide given orally to nude mice bearing subcutaneous human glioma xenografts resulted in a 72% reduction in tumor volume.
  • WO 2018/015958 to some of the present inventors and coworkers relates to the use of endocrine modulators and drug combinations in providing improved therapy for patients afflicted with brain tumors such as glioblastomas.
  • GBM glioblastoma multiforme
  • grade IV astrocytoma glioblastoma multiforme
  • WO 2008/032327 discloses redispersible powder and aqueous dispersions comprising nanoparticles of water-insoluble organic compounds.
  • WO '327 further provides methods for preparing the redispersible powder and the aqueous dispersion, wherein the methods comprise preparation of an oil-in-water microemulsion and solvent removal.
  • WO 2011/092690 to some of the present inventors and coworkers relates to compositions and methods for prevention, treatment or management of pulmonary hypertension using piperidine, pyrrolidine, or azepane derivatives.
  • WO '690 further provides a water dispersible powder comprising nanoparticles comprising said derivatives, as well as pharmaceutical compositions thereof and methods of use.
  • the invention relates to the field of cancer therapy, specifically to compositions and methods for the treatment of brain tumors and androgen receptor (AR) expressing tumors. More specifically, the invention provides novel formulations comprising AR antagonists, having improved therapeutic properties. According to embodiments of the invention, provided are pharmaceutical compositions characterized by enhanced water solubility of the active ingredient, in particular bicalutamide.
  • the invention is based, in part, on the development of novel formulations of AR antagonists exhibiting remarkable properties.
  • the formulations of the invention prepared with a unique combination of ingredients according to a specialized manufacturing process, exhibited superior pharmacokinetic properties and significantly enhanced efficacy in vivo against glial tumors, compared to commercially available and hitherto known formulations.
  • the formulation exhibited remarkable enhancement in oral bioavailability and particularly in brain penetration compared to the control formulation.
  • the results indicate that given similar systemic exposure, the formulation in accordance with the principles of the invention is unexpectedly more effective in delivering bicalutamide specifically to the brain than hitherto known formulations.
  • compositions for delivering AR antagonists to AR-expressing tumors are provided.
  • formulations comprising an AR antagonist, and amphiphilic surface- active agents such as surfactants and emulsifiers.
  • formulations according to embodiments of the invention are especially useful for delivering nonsteroidal anilide AR antagonists such as bicalutamide to brain tumors.
  • the formulations of the invention may be readily dispersed or advantageously dissolved in water, while providing an increased concentration of the active ingredient, compared to the concentration obtained when dissolving the active ingredient alone. Further, the formulations of the invention advantageously provide for enhanced oral bioavailability and/or delivery to brain tumors.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising by dry weight: (i) 5-25% w/w of an androgen receptor (AR) antagonist selected from the group consisting of bicalutamide, and isomers and mixtures thereof, (ii) 35-50% w/w glycyrrhizic acid or a salt thereof, and (iii) 35-50% w/w of a phospholipid surfactant.
  • AR androgen receptor
  • the composition comprises 35-50% w/w ammonium glycyrrhizinate.
  • the surfactant is a phosphatidylcholine-containing phospholipid surfactant.
  • said surfactant comprises soybean phosphatidylcholine.
  • said composition comprises at least 45% w/w (e.g. 45-60% w/w) soybean phosphatidylcholine.
  • said phospholipid surfactant is a soybean lecithin.
  • the composition comprises 35-50% w/w soybean lecithin (e.g. as disclosed hereinbelow).
  • the AR antagonist is bicalutamide.
  • the composition is characterized in that, upon reconstitution at 1% w/w in triple distilled water (TDW), said composition provides an aqueous solution retaining a clear liquid form for at least four hours at 20°C. In another embodiment, the aqueous solution retains a clear liquid form for at least 1-4 days at 20°C.
  • the surfactant and the glycyrrhizic acid or salt thereof are present at a weight ratio of about 1 : 1.
  • the composition comprises soybean lecithin and ammonium glycyrrhizinate at a weight ratio of about 1 : 1 and at a total amount of 80-90% by weight of the composition.
  • said composition is substantially devoid of polysaccharides. In another embodiment, said composition is substantially devoid of polymers.
  • said surfactant is a soybean lecithin comprising a phosphatidylcholine content of 65-80% w/w. In another embodiment, said soybean lecithin is further characterized as comprising 7-30% non-phosphatidylcholine soybean phospholipids comprising lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidic acid. Each possibility represents a separate embodiment of the invention.
  • the composition consists essentially of the AR antagonist, the glycyrrhizic acid or salt thereof, and the surfactant.
  • said composition consists essentially of bicalutamide, ammonium glycyrrhizinate, and soybean lecithin.
  • said composition consists essentially of 5-25% w/w bicalutamide, 35-50% w/w ammonium glycyrrhizinate, and 35-50% w/w soybean lecithin, which may be at a weight ratio of e.g. 1:2:2, 1:3:3, 1:4:4 or 1:4.5:4.5, including any values or ranges in between.
  • Each possibility represents a separate embodiment of the invention.
  • the composition comprises 5-35 mg bicalutamide in unit dosage form.
  • said composition is provided in dry powder form.
  • said composition provides an aqueous solution comprising 0.1-0.5% w/w bicalutamide upon reconstitution in TDW.
  • said composition is formulated as a solid oral dosage form.
  • said dosage form is a tablet or a capsule.
  • the invention in another embodiment, relates to a process for preparing the pharmaceutical composition, comprising: a) dissolving the AR antagonist in a first water miscible solvent to form a first solution, b) dissolving the surfactant and the glycyrrhizic acid or salt thereof in a second water miscible solvent and water, to form a second solution, c) combining the first and second solutions resulting from steps a) and b), respectively, and d) rapidly evaporating the solvents by lyophilization or spray drying.
  • the AR antagonist is bicalutamide.
  • the first water miscible solvent is acetone.
  • step a) is performed by dissolving bicalutamide in acetone at a weight ratio of about 1:30.
  • the second water-miscible solvent is isopropanol.
  • step b) in the processes of the invention is performed by dissolving soybean lecithin and ammonium glycyrrhizinate in isopropanol and TDW at a weight ratio of about 1 : 1 : 25-60 : 10-30, typically about 1 : 1 : 35-50 : 20-30, including all iterations of ratios within the specified ranges.
  • step b) is performed by dissolving soybean lecithin and ammonium glycyrrhizinate in isopropanol and TDW at a weight ratio of about 1:1:42:24.
  • the process is performed so as to enhance the solubility of the AR antagonist by at least 100, at least 200, at least 500, or at least 1000- fold. Each possibility represents a separate embodiment of the invention.
  • a method of delivering an AR antagonist selected from the group consisting of bicalutamide, and isomers (including enantiomers) and mixtures thereof, to a brain tumor in a subject in need thereof comprising administering to the subject the pharmaceutical composition.
  • the method comprises delivering said AR antagonist preferentially to said brain tumor in said subject.
  • the method comprises delivering bicalutamide preferentially to the brain of said subject.
  • a method of treating an AR-expressing tumor in a subject in need thereof comprising administering to the subject the pharmaceutical composition.
  • the tumor is an AR-expressing brain tumor.
  • said tumor is a glial tumor.
  • said tumor is selected from the group consisting of glioblastoma, anaplastic astrocytoma, diffuse astrocytoma, oligodendroglioma, anaplastic oligodendroglioma, oligoastrocytoma, and anaplastic oligoastrocytoma.
  • glioblastoma anaplastic astrocytoma
  • diffuse astrocytoma oligodendroglioma
  • anaplastic oligodendroglioma oligoastrocytoma
  • anaplastic oligoastrocytoma anaplastic oligoastrocytoma.
  • said composition is administered in the form of an aqueous solution. In another embodiment, said composition is administered in the form of a solid oral dosage form. In another embodiment, said composition is administered to said subject by an administration route selected from the group consisting of intravenous, intraperitoneal, intrathecal, and oral administration. Each possibility represents a separate embodiment of the present invention.
  • said AR antagonist is bicalutamide. In a particular embodiment, said composition is administered to said subject so as to provide a daily dose of 50-500 pg/kg bicalutamide, including each value within the specified range. In another embodiment, said composition is administered to said subject to thereby provide brain bicalutamide levels as disclosed herein.
  • the administration is characterized by improved bioavailability, brain penetration and/or pharmacokinetic properties substantially as disclosed in Example 5 herein.
  • the AR antagonist is administered in concurrent or sequential combination with at least one anti- cancer agent.
  • the at least one anti-cancer agent is an alkylating agent (e.g. temozolomide), an EGFR antagonist, or a combination thereof.
  • an alkylating agent e.g. temozolomide
  • an EGFR antagonist e.g. a combination thereof.
  • a process for preparing a pharmaceutical composition for delivering an AR antagonist selected from the group consisting of bicalutamide, and isomers and derivatives thereof, to an AR-expressing tumor comprising: a) dissolving the AR antagonist in a first water miscible solvent to form a first solution, wherein said AR antagonist is selected from the group consisting of bicalutamide and isomers and derivatives thereof, b) dissolving glycyrrhizic acid or a salt thereof and a phospholipid surfactant in a second water miscible solvent and water, to form a second solution, c) combining the first and second solutions resulting from steps a) and b), respectively, and d) evaporating the solvents (including water) by lyophilization or spray drying, to form a solid composition.
  • said solid composition formed by the process is water-soluble.
  • the solid composition is characterized in that upon reconstitution at 1% w/w in TDW, said solid composition provides an aqueous solution retaining a clear liquid form for at least one day at 20°C.
  • the AR antagonist is bicalutamide.
  • the first water miscible solvent is acetone.
  • step a) is performed by dissolving bicalutamide in acetone at a weight ratio of about 1:30.
  • the second water- miscible solvent is isopropanol.
  • step b) is performed by dissolving soybean lecithin and ammonium glycyrrhizinate in isopropanol and TDW at a weight ratio of about 1:1:42:24. In another embodiment, step b) is performed at a weight ratio as disclosed herein.
  • the process is performed so as to enhance the solubility of the AR antagonist by at least 100, at least 200, at least 500, or at least 1000 -fold.
  • the resulting solid composition is a dry powder comprising 5-25% w/w of said AR antagonist, 35-50% w/w of said glycyrrhizic acid or salt thereof, and 35-50% w/w of said surfactant.
  • the process further comprises dissolving the pharmaceutical composition as disclosed herein (e.g. in water or another aqueous medium such as a physiological grade saline solution), to obtain a clear solution (also referred to herein as an aqueous pharmaceutical composition of the invention).
  • the solution comprises 0.1 -0.5% w/w bicalutamide, including each value within the specified range.
  • an aqueous pharmaceutical composition amenable for delivery of the AR antagonist to an AR-expressing tumor prepared by the process.
  • the pharmaceutical composition is amenable for intravenous, intraperitoneal, intrathecal, or oral administration. Each possibility represents a separate embodiment of the present invention.
  • said aqueous pharmaceutical composition is amenable for providing a daily dose of 50-500 pg/kg bicalutamide, including each value within the specified range.
  • the invention provides a pharmaceutical composition produced by a process as disclosed herein.
  • the composition is formulated as a solid oral dosage form.
  • said dosage form is a tablet or a capsule.
  • the composition is formulated as an aqueous solution.
  • the compositions of the invention are amenable for e.g. intravenous, intraperitoneal, intrathecal, or oral administration. Each possibility represents a separate embodiment of the present invention.
  • the compositions of the invention are amenable for e.g. providing a daily dose of 50-500 pg/kg bicalutamide, including each value within the specified range.
  • the invention provides a pharmaceutical composition produced by a process as disclosed herein, for use in treating an AR-expressing tumor, or in delivering an AR antagonist to a brain tumor, in a subject in need thereof.
  • the tumor is as disclosed herein.
  • advantageous AR antagonists to be used in the context of the compositions, processes and methods of the invention include, in various embodiments bicalutamide or isomers and mixtures thereof.
  • the AR antagonist may be e.g. bicalutamide or flutamide.
  • the use of an AR antagonist in the form of an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt or solvate thereof, is contemplated.
  • the AR antagonist is bicalutamide.
  • the use of a bicalutamide enantiomer e.g. R-bicalutamide, is employed.
  • Figures 1A-1G Cryo-TEM micrographs of formulations obtained by the protocol of Example 1 (test formulations).
  • FIGS 2A-2L Cryo-TEM micrographs of test formulations obtained by the protocol of Example 1 (test formulations) for (2A-2B) powder without the active drug dispersed in water (1% w/w, negative control formulation), (2C-2F) powder comprising bicalutamide dispersed in water (1% w/w bicalutamide formulation), and (2G-2L) powder comprising bicalutamide dispersed in water (5% w/w bicalutamide formulation).
  • FIGS 3A-3B HPLC chromatograms of filtrates of test formulations dispersed in water (1% w/w).
  • FIGS 5A-5C Kaplan Meier survival curve of mice bearing intracranial xenograft of human GBM (U87MG).
  • Figures 8A-8B Kaplan Meier survival curve of mice bearing xenografts of GBM.
  • the invention relates to the field of cancer therapy, specifically to compositions and methods for the treatment of brain tumors and androgen receptor (AR) expressing tumors. More specifically, the invention provides novel formulations comprising AR antagonists, having improved therapeutic and pharmacokinetic properties. Embodiments of the invention provide pharmaceutical compositions characterized by enhanced water solubility of the active ingredient, in particular bicalutamide, and/or enhanced brain penetration upon oral administration.
  • compositions for delivering AR antagonists to AR-expressing tumors comprising an AR antagonist, and amphiphilic surface- active agents such as surfactants and emulsifiers.
  • AR antagonists as used herein includes agents, particularly small molecules that inhibit or reduce at least one activity of an AR polypeptide.
  • formulations according to embodiments of the invention are especially useful for delivering nonsteroidal anilide AR antagonists such as bicalutamide to brain tumors.
  • the AR antagonists can exist in enantiomeric or diastereomeric forms or in mixtures thereof.
  • the present invention contemplates the use of any racemates (i.e. mixtures containing equal amounts of each enantiomers), enantiomerically enriched mixtures (i.e., mixtures enriched for one enantiomer), pure enantiomers or diastereomers, or any mixtures thereof.
  • the AR antagonist is bicalutamide or an isomer (e.g. enantiomer) or a mixture thereof.
  • Bicalutamide is a non-steroidal AR inhibitor having the following chemical name propanamide, N [4 cyano-3- (trifluoromethyl)phenyl]-3-[(4- fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-,(+-). It is represented by the following chemical structure:
  • formulations according to embodiments of the invention typically include a racemic mixture of bicalutamide
  • a bicalutamide enantiomer e.g. the R-enantiomer of bicalutamide
  • the formulations of the invention include an AR antagonist (e.g. bicalutamide) salt.
  • AR antagonist e.g. bicalutamide
  • salt encompasses both base and acid addition salts formed by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids.
  • Such acids include hydrochloric, hydrofluoric, trifluoroacetic, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, D- camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicylic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and the like.
  • Each possibility represents a separate embodiment.
  • the formulations of the invention may be readily dispersed or advantageously dissolved in water, while providing an increased concentration of the active ingredient compared to the active ingredient alone.
  • formulations comprising a phospholipid surfactant, including various natural or synthetic lecithin surfactants, and in particular soybean lecithin.
  • the formulations of the invention comprise LIPOID ® S75 or an equivalent soybean lecithin containing fat-free soybean phospholipids with 70% phosphatidylcholine content (also referred to herein as lecithin S75).
  • LIPOID ® S75 comprises non phosphatidylcholine soybean phospholipids, characterized by weight ranges (%) as follows: up to 3% lysophosphatidylcholine, 7-10% phosphatidylethanolamine, up to 1.5% phosphatidylinositol, and up to 3% phosphatidic acid. LIPOID ® S75 is further characterized as comprising no more than 3% triglycerides, no more than 0.5% free fatty acids, and 0.1-0.2% D,L-a-Tocopherol.
  • a typical fatty acid composition in % of the total fatty acids in LIPOID ® S75 is as follows: 12-17% palmitic acid, 2- 5% stearic acid, 8-12% oleic acid, 58-65% linoleic acid, and 5-9% linolenic acid.
  • the composition of LIPOID ® S75 may further be characterized as comprising at least 80% acetone-insoluble matter and no more than 0.3% hexane-insoluble matter.
  • said surfactant comprises fat-free soybean phospholipids with a phosphatidylcholine content of at least 65%.
  • said surfactant comprises fat- free soybean phospholipids with a phosphatidylcholine content of no more than 90%.
  • said surfactant is a soybean lecithin comprising fat-free soybean phospholipids with a phosphatidylcholine content of at least 65%-90%.
  • said surfactant may be a soybean lecithin comprising a phosphatidylcholine content of 65-80%, 70%-85%, 65%-75%, 65-85%, 70-80% or 70%-75% (w/w), including each value within the specified range.
  • said surfactant may be a soybean lecithin comprising at least 7% and typically up to about 30 or 35% w/w non-phosphatidylcholine soybean phospholipids.
  • said surfactant may comprise 7-18.5, 10-18.5, 10-20%, 10-35%, 10-30%, 7-30% or 20-35% non phosphatidylcholine soybean phospholipids comprising lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidic acid (e.g. at the above-specified wight ratios), including each integer within the ranges, including each value within the specified range.
  • said surfactant is a soybean lecithin comprising fat-free soybean phospholipids with a phosphatidylcholine content of about 70% w/w. In another embodiment said surfactant is a soybean lecithin comprising fat-free soybean phospholipids with a phosphatidylcholine content of about 70% and about 30% non-phosphatidylcholine soybean phospholipids.
  • said surfactant is a soybean lecithin comprising fat-free soybean phospholipids with a phosphatidylcholine content of about 70% and about 10-30% non-phosphatidylcholine soybean phospholipids comprising lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidic acid.
  • said surfactant is a soybean lecithin comprising fat- free soybean phospholipids with a phosphatidylcholine content of about 70% and non phosphatidylcholine soybean phospholipids comprising up to 3% lysophosphatidylcholine, 7-10% phosphatidylethanolamine, up to 1.5% phosphatidylinositol, and up to 3% phosphatidic acid, wherein the total content of non-phosphatidylcholine soybean phospholipids is 7-30%.
  • phosphatidylcholine soybean phospholipids comprising up to 3% lysophosphatidylcholine, 7-10% phosphatidylethanolamine, up to 1.5% phosphatidylinositol, and up to 3% phosphatidic acid, wherein the total content of non-phosphatidylcholine soybean phospholipids is 7-30%.
  • the composition comprises 35-50% w/w of a soybean lecithin, the soybean lecithin characterized by a phosphatidylcholine content of 65-80% w/w and/or a non phosphatidylcholine soybean phospholipids content of 7-30%, wherein each possibility represents a separate embodiment of the invention.
  • the non-phosphatidylcholine soybean phospholipids comprise lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidic acid.
  • the composition comprises 35-50% w/w of a soybean lecithin as disclosed herein.
  • additional surfactants including, but not limited to a natural lecithin such as egg lecithin and soybean lecithin, a synthetic saturated lecithin such as dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine and distearoyl phosphatidylcholine, a synthetic unsaturated lecithin such as dioleyl phosphatidylcholine and dilinoleyl phosphatidylcholine, a pegylated phospholipid, or a mixture thereof is contemplated within the scope of the present invention.
  • a natural lecithin such as egg lecithin and soybean lecithin
  • a synthetic saturated lecithin such as dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine and distearoyl phosphatidylcholine
  • a synthetic unsaturated lecithin such as dioleyl phosphatidylcho
  • nonionic surfactants including, but not limited to, block copolymer surfactants such as Pluronic ® F127 or Pluronic ® F68, and solid sorbitan fatty acid polyoxyethylene esters such as TWEEN ® 65, and combinations thereof, is contemplated within the scope of the present invention.
  • additional surfactants may be used in combination with soybean lecithin.
  • said composition comprises soybean lecithin (e.g. lecithin S75 or a soybean lecithin comprising a phosphatidylcholine content as disclosed herein) as the sole phospholipid surfactant.
  • said composition comprises soybean lecithin and glycyrrhizic acid or salt thereof as the sole surface-acting agents.
  • formulations comprising glycyrrhizic acid or a salt thereof.
  • the formulations of the invention comprise ammonium glycyrrhizinate (AG).
  • AG ammonium glycyrrhizinate
  • MAG monoammonium glycyrrhizinate
  • triammonium glycyrrhizinate is available e.g. from Sigma.
  • additional salts of glycyrrhizic acid including, but not limited to monopotassium glycyrrhizinate, dipotassium glycyrrhizinate (DPG), tripotassium glycyrrhizinate, monosodium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, or mixtures thereof, is contemplated within the scope of the present invention. Each possibility represents a separate embodiment.
  • the compositions of the invention are prepared using water-miscible organic solvents.
  • advantageous preparation processes in accordance with the principles of the invention include the step of rapid evaporation to remove the solvents used to dissolve the solid ingredients (such as the active ingredients and surfactants). Accordingly, all liquid constituents, including the water-miscible organic solvents and water, are removed rapidly and simultaneously, to form a substantially dry solid composition that may be reconstituted in water prior to administration.
  • the rapid evaporation may be performed by suitable processes such as lyophilization or spray-drying.
  • compositions of the invention does not typically employ the use of water-immiscible organic solvents (such as butyl acetate), and does not include the formation of an oil-in-water microemulsion prior to solvent evaporation.
  • water-immiscible organic solvents such as butyl acetate
  • a typical preparation process for the formulations of the invention includes dissolving the active ingredients in a first water-miscible organic solvent to form a first solution, dissolving the excipients in a second water-miscible organic solvent and water to form a second solution, combining the first and second solutions to obtain a clear liquid, and rapid evaporation of solutes of the combined solutions, to form a water-dispersible (and advantageously water-soluble) solid composition.
  • the first and the second water-miscible organic solvents may be the same or different with each possibility representing a separate embodiment.
  • particularly advantageous water-miscible organic solvents for dissolving an acylanilide active ingredient such as bicalutamide include aprotic organic solvents such as acetone.
  • particularly advantageous water-miscible organic solvents for dissolving solid excipients such as surfactants include organic solvents such as isopropanol.
  • the formulations of the invention comprise 1-30%, typically 5-25% w/w of the active ingredient prior to reconstitution in water, including each value within the specified range.
  • the active ingredient is an AR antagonist, typically an acylanilide, e.g. bicalutamide and isomers thereof.
  • the formulation comprises 1-30%, 5- 25%, 10-20%, 1-15%, or 5-15% bicalutamide when provided in dry form, including each value within the specified ranges. In a particular embodiment, said formulation comprises about 10% bicalutamide.
  • the formulations of the invention comprise 70-99%, typically 75- 95% w/w in total of surfactants prior to reconstitution in water, including each value within the specified ranges.
  • the formulations contain 25-60%, typically 35-50% w/w of a first surfactant e.g. soybean lecithin, including each value within the specified ranges.
  • the formulation may contain 25-60%, 35-50%, or 40-45% lecithin S75, including each value within the specified ranges.
  • the formulations of the invention comprise 25-60%, typically 35-50% w/w of a second, distinct surfactant, e.g. glycyrrhizic acid or salt thereof, including each value within the specified range.
  • the formulation may contain 25-60%, 35-50%, or 40-45% AG, including each value within the specified ranges.
  • the first surfactant which is other than glycyrrhizic acid or salt thereof and is typically an advantageous phospholipid surfactant as disclosed herein such as soybean lecithin
  • the second surfactant e.g. glycyrrhizic acid or salt thereof
  • the formulation comprises lecithin S75 and AG at a weight ratio of 1 : 1 and at a total amount of 80-90% by weight.
  • the formulations of the invention do not necessitate the use of polymers, and do not substantially contain polymers such as hypromellose or other polysaccharides.
  • the formulations of the invention are essentially polymer-free.
  • the formulation when provided in solid form, consists essentially of the active ingredient (AR antagonist, e.g. bicalutamide), the phospholipid surfactant (e.g. lecithin S75) and the glycyrrhizic acid or a salt thereof (e.g. AG).
  • solid formulations of the invention are characterized in that, upon reconstitution at 1% w/w of said solid formulation in distilled water, the resulting composition retains a clear liquid form at 20°C.
  • the term “clear liquid form” relates to a liquid that is transparent and has no visible particles or precipitates, when inspected visually.
  • a composition characterized by a clear liquid form may be readily differentiated from particle-containing dispersions that are characterized by an opaque or turbid appearance.
  • such compositions are typically substantially devoid of particles as described in further detail below.
  • visual inspection may be assisted by the use of directed light beams, to detect light scattering by fine particles (Tyndall effect), as will be discussed in greater detail below.
  • liquid compositions of the invention (generated by reconstitution of solid formulations in water as disclosed herein) are characterized as being colorless, transparent and not causing a Tyndall effect.
  • the resulting composition is in solution form.
  • the resulting composition is stable in said form at 20°C for at least several hours, days or weeks.
  • the resulting aqueous composition is substantially devoid of particles larger than 200 nm, 150 nm, 100 nm, 75 nm, 50 nm, 10 nm or 1 nm.
  • the term particle refers to a structured entity of the above-mentioned diameter size distribution, which may be e.g. a solid particle or a substantially uniform (e.g. single-phase) particle.
  • formulations in the form of particle-containing dispersions typically contain the active ingredient enclosed within and/or adherent to the surface of the particles.
  • compositions of the invention were determined to contain the active ingredient in the aqueous phase (including organic solvents but filtered to remove any putative particles or liposomes), and did not substantially contain non-aqueous phases (e.g. consistent with the presence of particles or liposomes).
  • the form of the resulting composition e.g. identification as a solution and lack of particles
  • said composition is devoid of said particles as evaluated by DLS.
  • said aqueous composition substantially devoid of particles comprises less than 2%, 1%, 0.5%, 0.1% or 0.01% (w/w) of any precipitates or residual elements that may be visualized by TEM.
  • the formation of the nanoparticles can also be detected by the human eye by the so-called "Tyndall effect".
  • the Tyndall effect is a well-known phenomenon in which light is scattered by particles in a colloid or particles in a fine suspension. The Tyndall effect occurs when one shines a light through a dispersion. The dispersion looks transparent but when viewed from the side, i.e. 90° to the light source, the dispersion appears turbid. In laboratory environments, a hand-held laser pointer can be used as the source of the light beam to identify particles in (an apparent) solution. As used herein, lack of a Tyndall effect meant is that the phenomenon is visible to the human eye without any instrumental aid (such as microscopy), i.e.
  • solid formulations in accordance with the invention are substantially completely dissolved when dispersed in water as indicated by the transparency of the thus formed solution and the absence of visible particles in filtration and dynamic light scattering (DLS) measurements. Without limitation, it is believed that these characteristics stem from the unique combination of ingredients providing a synergetic effect not afforded by other surfactants and combinations thereof, resulting in turbidity and nanoparticle-containing formulations as previously described.
  • the formulations of the invention are characterized by favorable dissolution properties.
  • the formulations provide for enhanced water solubility of the active ingredient, e.g. bicalutamide.
  • the solubility is enhanced by at least 100, at least 200, at least 500, or at least 1000-fold.
  • the solubility of the bicalutamide active ingredient when provided in formulations prepared according to the principles of the invention is at least 1000- fold greater than the solubility of the bicalutamide in unprocessed form.
  • the water solubility of said bicalutamide is about 1 mg/mL.
  • the formulations of the invention are characterized by favorable pharmacokinetic properties. As disclosed herein in embodiments of the invention, the formulations provide for enhanced oral bioavailability of bicalutamide. As further disclosed herein in embodiments of the invention, the formulations provide for enhanced brain penetration of bicalutamide following oral administration. As exemplified herein, the C m ax of the bicalutamide active ingredient in brain and plasma when provided in formulations prepared according to the principles of the invention, is at least 1.5-fold greater than that obtained using a conventional, immediate-release bicalutamide formulation.
  • the C m ax of bicalutamide obtained following oral administration of the formulation may be 1.5, 1.6, 1.7, 1.8, 1.9 or 2-fold greater than that obtained by administration of an equivalent dosage of a conventional, immediate-release bicalutamide formulation (for example a bicaluamide solution prepared as recommended by the manufacturer of the bicalutamide active ingredient, e.g. as described in Example 5 herein).
  • a conventional, immediate-release bicalutamide formulation for example a bicaluamide solution prepared as recommended by the manufacturer of the bicalutamide active ingredient, e.g. as described in Example 5 herein.
  • the AUCINF of said formulation is at least 1.5-fold greater than that obtained using an equivalent dosage of a conventional, immediate-release bicalutamide formulation, e.g. 1.5, 1.6, 1.7, 1.8, 1.9 or 2-fold greater.
  • Each possibility represents a separate embodiment.
  • the formulations of the invention are characterized by oral bioavailability substantially equivalent to the bioavailability obtained by intravenous (IV) administration.
  • the brain (or in other embodiments, plasma) Cmax for bicalutamide upon oral administration of the formulation is less than 25%, 20%, 15% or 10% lower than its level upon IV administration of said formulation.
  • the brain (or in other embodiments, plasma) AUCINF for bicalutamide upon oral administration of the formulation is less than 25%, 20%, 15% or 10% lower than its level upon IV administration of said formulation.
  • the brain or plasma Cmax and/or AUCINF values upon oral administration of the bicalutamide formulation of the present invention are substantially similar to the Cmax and/or AUCINF values upon IV administration of the formulation.
  • the brain levels of bicalutamide obtained upon oral administration of the formulation are at least 25% and typically at least 30% higher than the plasma bicalutamide levels obtained upon oral administration of said formulation.
  • said formulation is characterized by pharmacokinetic properties substantially as described in Example 5 below. Each possibility represents a separate embodiment of the invention.
  • a pharmaceutical composition comprising by dry weight 5-25% w/w bicalutamide, 35-50% w/w ammonium glycyrrhizinate and 35-50% w/w lecithin S75, characterized in that, upon reconstitution at 1% w/w in triple distilled water (TDW), an aqueous solution retaining a clear liquid form for at least 4 hours and typically at least 1-4 days is obtained.
  • Certain exemplary bicalutamide compositions in solid form are presented in Table 1 below: Table 1 - Exemplary bicalutamide formulations
  • invention provides a process for preparing a pharmaceutical composition for delivering an androgen receptor (AR) antagonist to an AR-expressing tumor, comprising: a) dissolving the AR antagonist in a first water miscible solvent to form a first solution, wherein said AR antagonist is selected from the group consisting of bicalutamide and isomers, and derivatives thereof, b) dissolving glycyrrhizic acid or a salt thereof and a phospholipid surfactant in a second water miscible solvent and water, to form a second solution, c) combining the solutions resulting from steps a) and b), and d) evaporating the solvents by lyophilization or spray drying, to form a solid composition.
  • AR androgen receptor
  • the processes for preparing the pharmaceutical compositions disclosed herein may further utilize a bicalutamide derivative.
  • Bicalutamide derivatives as used herein are structurally and functionally related small molecules, whose chemical structure is based on bicalutamide with certain substitutions or modifications, that retain the biological functions associated with the activity of bicalutamide as described herein.
  • the use of bicalutamide esters e.g. phosphoric acid esters
  • substitutions in the phenyl rings may be employed, as long as the functional properties with respect to AR inhibition are retained.
  • bicalutamide acts as a selective competitive silent antagonist of the AR.
  • Bicalutamide derivatives used in embodiments (e.g. processes) of the invention are pharmacologically equivalent to bicalutamide.
  • bicalutamide derivatives retain a similar or substantially comparable affinity to the AR, e.g. ⁇ 5%, 10%, 20%, 30%, 40% or 50% with respect to the IC50 (which is 159-243 nM for bicalutamide).
  • a pharmaceutical composition prepared by a process of the invention comprising: a) dissolving bicalutamide in acetone; b) dissolving lecithin S75 and ammonium glycyrrhizinate in isopropanol and water (e.g. TDW); c) combining the solutions of steps a) and b), and d) rapidly evaporating the solvents by lyophilization or spray drying.
  • step a) is performed by dissolving bicalutamide in acetone at a 1:30 weight ratio.
  • step b) is performed by dissolving lecithin S75 and ammonium glycyrrhizinate in isopropanol and TDW at a 1:1:42:24 weight ratio.
  • the combined solution of step c) does not form an emulsion (such as an oil-in water microemulsion).
  • the lyophilization may include or be preceded by rapid freezing e.g. using liquid nitrogen. Each possibility represents a separate embodiment of the invention.
  • the compositions of the invention are particularly advantageous for delivering an active ingredient into the brain, for example in the treatment of brain tumors.
  • the compositions of the invention provide enhanced therapeutic efficacy of bicalutamide in the treatment of glial tumors.
  • the enhancement may be based in part on increased water solubility of the active ingredient, enhanced penetration of the blood-brain-barrier (BBB), favorable pharmacokinetics and/or synergistic action of the formulation ingredients.
  • the formulations of the invention may demonstrate further beneficial biological effects, for example on steroid metabolism.
  • a method of delivering an AR antagonist to a brain tumor in a subject in need thereof comprising administering to the subject a pharmaceutical composition of the invention.
  • the method comprises administering to said subject a pharmaceutical composition comprising by dry weight (i) 5-25% w/w of an AR antagonist selected from the group consisting of bicalutamide, and isomers and mixtures thereof, (ii) 35-50% w/w glycyrrhizic acid or a salt thereof, and (iii) 35-50% w/w of a phospholipid surfactant.
  • a method of treating an AR-expressing brain tumor in a subject in need thereof comprising administering to the subject a pharmaceutical composition of the invention.
  • the method comprises administering to said subject a pharmaceutical composition comprising by dry weight (i) 5-25% w/w of an AR antagonist selected from the group consisting of bicalutamide, and isomers and mixtures thereof, (ii) 35-50% w/w glycyrrhizic acid or a salt thereof, and (iii) 35-50% w/w of a phospholipid surfactant.
  • compositions of the invention are administered to the subject in liquid form, e.g. in the form of an aqueous solution as described herein.
  • said composition is administered by an administration route selected from the group consisting of intravenous, intraperitoneal, intrathecal, and oral administration.
  • the AR antagonist may be administered at a dose of 50-2000 pg/kg, typically 700-2000 pg/kg, including each value within the specified range.
  • the formulations of the invention provide for enhanced efficacy, they enable the reduction of the active ingredient dose to be administered to the subject, without compromising the therapeutic efficacy.
  • the methods of the invention may include administration of bicalutamide at a dose of 50-500, typically 100-400 pg/kg/day, including each value within the specified ranges which are administered e.g. orally.
  • the formulations of the invention provide for reduction of adverse effects associated with administration of AR antagonists, e.g. bicalutamide.
  • the tumor is selected from the group consisting of glioblastoma, anaplastic astrocytoma, diffuse astrocytoma, oligodendroglioma, anaplastic oligodendroglioma and mixed tumors (e.g. oligoastrocytoma or anaplastic oligoastrocytoma).
  • the tumor is selected from the group consisting of glioblastoma, anaplastic astrocytoma, diffuse astrocytoma, and oligodendroglioma.
  • said tumor is glioblastoma.
  • said tumor is meningioma.
  • treating includes, but is not limited to, preventing the disorder or disease from occurring in a subject or arresting the development or progression of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or ameliorating the symptoms of the disease or disorder.
  • the term “treating” includes, but is not limited to, at least one of the following: a decrease in the rate of growth of the tumor, cessation of tumor growth, and, in preferred cases, the tumor diminishes or is reduced in size. Additionally included within this term is lengthening of the survival period of the subject undergoing treatment, lengthening the time of diseases progression, tumor regression, and the like. The term further includes a decrease in at least one of the following: number of cancer cells (due to cell death which may be necrotic, apoptotic or any other type of cell death or combinations thereof) as compared to control; decrease in growth rates of cancer cells, i.e.
  • the total number of cancer cells may increase but at a lower level or at a lower rate than the increase in control; decrease in the invasiveness of cancer cells (as determined for example by soft agar assay) as compared to control even if their total number has not changed; progression from a less differentiated cell type to a more differentiated cell type; a deceleration in the neoplastic transformation; or alternatively the slowing of the progression of the cancer cells from one stage to the next.
  • the subject is a human. In another embodiment, the subject is a female. In another embodiment, the subject is a male. In another embodiment, said subject is not afflicted with prostate cancer or breast cancer.
  • the AR antagonist or inhibitor is administered in combination (concurrent or sequential) with at least one anti-cancer agent.
  • the at least one anti-cancer agent is selected from the group consisting of a chemotherapeutic drug, a RTK inhibitor, an immunotherapy (e.g. anti-PDl antibodies) and an anti-angiogenic therapy (e.g. bevacizumab).
  • chemotherapeutic drug refers to a cytotoxic or cytostatic chemical or biological substance that can cause death of cancer cells, or specifically interfere with growth, division, repair, and/or function of cancer cells.
  • the chemotherapeutic drug is an alkylating agent.
  • alkylating agent refers to a chemotherapeutic drug giving an alkyl group in the alkylation reaction in which a hydrogen atom of an organic compound is substituted with an alkyl group, having antitumor activity.
  • exemplary alkylating agents include, but are not limited to carmustine or temozolomide. Each possibility represents a separate embodiment.
  • the at least one anti-cancer agent comprises a RTK inhibitor.
  • RTK inhibitor refers to a compound capable of specifically inhibiting the activity of a member of the RTK family of proteins.
  • the RTK inhibitor is an EGFR inhibitor or antagonist.
  • EGFR inhibitor or “EGFR antagonist” as used herein refers to a molecule having the ability to specifically inhibit a biological function of a native epidermal growth factor receptor (EGFR).
  • EGFR antagonists include, but are not limited to, erlotinib or afatinib. Each possibility represents a separate embodiment.
  • said at least one anti-cancer agent comprises at least one chemotherapeutic drug and at least one RTK inhibitor.
  • said at least one anti-cancer agent comprises at least one alkylating agent and at least one EGFR antagonist.
  • the methods of the invention comprise administering to the subject a composition of the invention in combination with afatinib, temozolomide, afatinib and temozolomide, carmustine and erlotinib, or carmustine and afatinib.
  • afatinib temozolomide
  • afatinib and temozolomide carmustine and erlotinib
  • carmustine and afatinib comprises radiotherapy.
  • a pharmaceutical composition referred to according to embodiments of the invention comprises by dry weight (i) 5-25% w/w of an AR antagonist selected from the group consisting of bicalutamide, and isomers and mixtures thereof, (ii) 35-60% w/w glycyrrhizic acid or a salt thereof (e.g. AG), and (iii) 35-60% w/w of a phospholipid surfactant (e.g. a lecithin surfactant as disclosed herein).
  • an AR antagonist selected from the group consisting of bicalutamide, and isomers and mixtures thereof
  • 35-60% w/w glycyrrhizic acid or a salt thereof e.g. AG
  • a phospholipid surfactant e.g. a lecithin surfactant as disclosed herein.
  • the pharmaceutical compositions prepared in accordance with the formulations and processes of the invention may conveniently be further processed to form various pharmaceutical compositions, comprising one or more pharmaceutically acceptable carriers or excipients.
  • the compositions as disclosed herein may be formulated in the form of an aqueous solution, e.g. by dissolving a composition of the invention provided in the form of dry powder in water or another aqueous medium such as phosphate buffer saline (PBS).
  • PBS phosphate buffer saline
  • the compositions may be formulated in the form of solid oral dosage forms, including, but not limited to tablets and capsules, as disclosed herein.
  • Pharmaceutically acceptable carriers or excipients may include, but are not limited to, a binder, a filler, a diluent, a surfactant or emulsifier, a glidant or lubricant, buffering or pH adjusting agent, a tonicity enhancing agent, a wetting agent, a preservative, an antioxidant, a flavoring agent, a colorant, and a mixture or combination thereof.
  • Suitable binders include, but are not limited to, polyvinylpyrrolidone, copovidone, hydroxypropyl methylcellulose, starch, and gelatin. Each possibility represents a separate embodiment.
  • Suitable fillers include, but are not limited to, sugars such as lactose, sucrose, mannitol or sorbitol and derivatives therefore (e.g. amino sugars), ethylcellulose, microcrystalline cellulose, and silicified microcrystalline cellulose. Each possibility represents a separate embodiment.
  • Suitable lubricants include, but are not limited to, sodium stearyl fumarate, stearic acid, polyethylene glycol or stearates, such as magnesium stearate. Each possibility represents a separate embodiment.
  • Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, sugars, lactose, calcium phosphate, cellulose, kaolin, mannitol, sodium chloride, and dry starch. Each possibility represents a separate embodiment.
  • Surfactants, emulsifiers and polymers may include, but are not limited to, polyvinyl alcohol (PVA), polysorbate, polyethylene glycols, polyoxyethylene-polyoxypropylene block copolymers known as “poloxamer”, polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate, sorbitan fatty acid ester such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monooleate (Tween ® ), polyethylene glycol fatty acid ester such as polyoxyethylene monostearate, polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether, polyoxyethylene castor oil and hardened castor oil such as polyoxyethylene hardened castor oil.
  • PVA polyvinyl alcohol
  • polysorbate polyethylene glycols
  • Surfactants may be generally classified as cationic surfactants, anionic surfactants, amphoteric surfactants (e.g. phosphatidylcholine surfactants), nonionic surfactants, or polymeric surfactants.
  • compositions of the invention need not contain any additional surfactants or emulsifiers other than glycyrrhizic acid or a salt thereof and the advantageous surfactants (e.g. phosphatidylcholine-containing surfactants) as disclosed herein, and need not contain any polymers.
  • the compositions do not substantially contain polymers such as hydroxypropyl methylcellulose (hypromellose) or other polysaccharides.
  • the compositions of the invention are essentially polymer-free.
  • the compositions are substantially devoid of polysaccharides.
  • the compositions of the invention consist (or consist essentially) of, the AR antagonist (e.g. bicalutamide), the glycyrrhizic acid or a salt thereof (e.g. AG) and the phospholipid surfactant (e.g. soybean lecithin).
  • compositions containing AG and lecithin S75 as the inactive ingredients were effective in administering bicalutamide to brain tumors with desirable efficacy and safety profiles.
  • Suitable glidants or lubricants may include, but are not limited to, colloidal silicon dioxide, magnesium stearate, talc, and mineral oil. Each possibility represents a separate embodiment.
  • Suitable buffering or pH adjusting agents include, but are not limited to, acidic buffering agents such as short chain fatty acids, citric acid, acetic acid, hydrochloric acid, sulfuric acid and fumaric acid; and basic buffering agents such as tris, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, and magnesium hydroxide. Each possibility represents a separate embodiment.
  • Suitable tonicity enhancing agents include, but are not limited to, ionic and non-ionic agents such as, alkali metal or alkaline earth metal halides, urea, glycerol, sorbitol, mannitol, propylene glycol, and dextrose. Each possibility represents a separate embodiment.
  • Suitable wetting agents include, but are not limited to, glycerin, cetyl alcohol, and glycerol monostearate. Each possibility represents a separate embodiment.
  • Suitable preservatives include, but are not limited to, benzalkonium chloride, benzoxonium chloride, thiomersal, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate, methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenyl alcohol, chlorohexidine, and polyhexamethylene biguanide. Each possibility represents a separate embodiment.
  • Suitable antioxidants may include, but are not limited to, sorbic acid, ascorbic acid, ascorbate, glycine, a-tocopherol, butylated hydroxy anisole (BHA), and butylated hydroxy toluene (BHT). Each possibility represents a separate embodiment.
  • Suitable flavoring agents include, but are not limited to, sweeteners such as sucralose and synthetic flavor oils and flavoring aromatics, natural oils, extracts from plants, leaves, flowers, and fruits, and combinations thereof.
  • Exemplary flavoring agents include cinnamon oils, oil of wintergreen, peppermint oils, clover oil, hay oil, anise oil, eucalyptus, vanilla, citrus oil such as lemon oil, orange oil, grape and grapefruit oil, and fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot. Each possibility represents a separate embodiment.
  • Suitable colorants include, but are not limited to, alumina (dried aluminum hydroxide), annatto extract, calcium carbonate, canthaxanthin, caramel, b-carotene, cochineal extract, carmine, potassium sodium copper chlorophyllin (chlorophyllin-copper complex), dihydroxyacetone, bismuth oxychloride, synthetic iron oxide, ferric ammonium ferrocyanide, ferric ferrocyanide, chromium hydroxide green, chromium oxide greens, guanine, mica-based pearlescent pigments, pyrophyllite, mica, dentifrices, talc, titanium dioxide, aluminum powder, bronze powder, copper powder, and zinc oxide.
  • alumina dried aluminum hydroxide
  • annatto extract calcium carbonate
  • canthaxanthin caramel
  • b-carotene cochineal extract
  • carmine potassium sodium copper chlorophyllin (chlorophyllin-copper complex)
  • dihydroxyacetone bismut
  • the pharmaceutical composition of the present invention is formulated as tablet, pill, capsule (e.g. soft or hard gelatin capsule), pellets, granules, powder, a wafer, coated or uncoated beads, lozenge, sachet, cachet, elixir, an osmotic pump, a depot system, an iontophoretic system and the like.
  • capsule e.g. soft or hard gelatin capsule
  • pellets granules, powder, a wafer, coated or uncoated beads, lozenge, sachet, cachet, elixir, an osmotic pump, a depot system, an iontophoretic system and the like.
  • the active pharmaceutical ingredient is mixed with a pharmaceutical carrier or excipient to form a solid pre-formulation composition containing a substantially homogeneous distribution of the compound of the present invention in the pharmaceutical carrier or excipient.
  • Step 1 0.225 gr of lecithin S75 (LIPOID ® S75, Lipoid), 0.225 gr of ammonium glycyrrhizinate (Sigma), 9.5 gr of isopropanol (Alfaaesar), and 5.5 gr of TDW (Triple Distilled Water) were combined in a glass vial and mixed by magnetic stirrer until a clear solution was obtained.
  • Step 2 0.05 gr of the active drug (Bicalutamide, apex biotech LLC, or enzalutamide) was dissolved in 1.5 gr acetone.
  • Step 3 The solutions of Step 1 and Step 2 were combined, and mixed by magnetic stirrer until a clear solution was obtained.
  • Step 4 The solution of Step 3 was poured into a round bottom flask and frozen in a bath of liquid nitrogen for 5 minutes.
  • Step 5 The round bottom flask was lyophilized at an absolute pressure of less than 1 mbar for 48 hours (Labconcofreezone 2.5).
  • Step 6 The powder obtained at the end of the lyophilization process was dispersed, 1% w/w, in distilled water by vortex for 5 min.
  • Step 3 the solution of Step 3 was spray dried (Mini Spray Dryer B-290) at an air inlet temperature of 120 °C and a liquid feed rate of 10 mL.min 1 .
  • the formulation was prepared with either bicalutamide or enzalutamide as the active ingredient.
  • a control formulation without an active ingredient was further prepared.
  • the bicalutamide dispersion retained a clear liquid form, consistent with substantial dissolution of its ingredients.
  • the bicalutamide-containing liquid maintained the appearance of a clear solution for several days.
  • the solubility of the bicalutamide was found to have increased from 0.005 mg/mL (20 °C) to at least 1 mg/ml.
  • no Tyndall effect was observed upon visual inspection of the bicalutamide dispersion using a laser pointer.
  • Example 1 In order to characterize the bicalutamide formulation produced in Example 1, samples comprising bicalutamide were analyzed using transmission electron cryomicroscopy (Cryo-TEM). The formulations obtained using the protocol of Example 1 comprising enzalutamide or lacking any active ingredient were also examined and served as controls.
  • the amount of the active ingredient (bicalutamide or enzalutamide) in the powder prior to dispersion was 10% w/w.
  • 1% or 5% (as indicated) of the total weight of the powder was added to a vial with water (TDW) and vortexed for 5 minutes in Step 6 of the process.
  • test sample A 2-4 pL drop of the test sample was applied to a TEM grid (300 mesh Cu Lacey substrate, Ted Pella, Ltd.) following a short pre-treatment of the grid by glow discharge. The excess liquid was blotted off and the specimen was vitrified by rapid plunging into liquid ethane pre-cooled by liquid nitrogen using a vitrification robot system (Vitrobot mark IV, FEI). Images of the samples are presented in Figs. 1A-1G and 2A-2L.
  • the formulation comprising enzalutamide was characterized by the presence of spherical particles of about 70 nm in diameter, whereas the formulation lacking the active ingredient (Figs. 1A-1C) was substantially devoid of such particles, with only a few liposome-like shapes apparent.
  • the bicalutamide formulation was substantially devoid of particles (Figs. ID- IF), with a few liposome-like shapes apparent at the largest magnification (Fig. IE), as was the negative control formulation.
  • Figs. 2A-2L the results were also maintained when the bicalutamide formulation was reconstituted at 5% w/w of the total powder in water.
  • the potential of the new bicalutamide formulation to inhibit human glioblastoma growth was studied in an intracranial in vivo model and compared to control formulations comprising bicalutamide or enzalutamide. 6- to 8-week-old athymic nude (nu/nu) mice were injected with 2xl0 5 of U87MG glioma cells into their right cerebral hemisphere (1 mm posterior and 2.3 mm lateral to the bregma, to a depth of 3 mm).
  • enzalutamide either prepared as described in Example 1 or a commercially available formulation (Xtandi)
  • bicalutamide either prepared as described in Example 1 or dissolved in DMSO
  • the endpoint of the experiment was defined as the number of days that elapsed from tumor implantation to the day of overt symptoms (significant weight loss, lethargy, hunched posture or other neurological signs). The results are presented in Figs. 5A-5B.
  • the commercially available formulation comprising 20 mg/kg enzalutamide (“20 mg/kg Xtandi”) was less effective than the new bicalutamide formulation in enhancing survival of GBM-bearing mice.
  • Attempts to enhance the dose of enzalutamide administered to the test animals (50 or 100 mg of the Xtandi formulation), failed to improve their survival.
  • the results demonstrate that the bicalutamide formulation prepared as described in Example 1 is more effective than a commercially available formulation comprising enzalutamide, despite the fact that the dose used in the enzalutamide formulation was five times higher than that used in the bicalutamide formulation.
  • PK pharmacokinetics
  • a bicalutamide formulation was prepared as described in Example 1, combined with water to obtain a concentration of 20 mg/mL of the bicalutamide formulation in DDW, and vortexed for two minutes.
  • the appearance of the resulting test formulation (herein designated “new bicalutamide formulation” or “bicalutamide test formulation”) was of a colorless clear solution.
  • control bicalutamide formulation for PO dosing to mice, bicalutamide was dissolved to obtain a concentration of 2 mg/mL bicalutamide in 5% DMSO and 95% of corn oil as follows. Bicalutamide was first dissolved in DMSO, and then combined with corn oil and vortexed for two minutes. The appearance of the resulting control formulation (herein designated “control bicalutamide formulation” or “bicalutamide control”) was of a yellow clear solution.
  • the concentration of the bicalutamide active ingredient in both the resulting test formulation and control formulation was 2 mg/mL.
  • Plasma samples were processed to plasma and analyzed for bicalutamide using a qualified liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.
  • Brain samples were analyzed for bicalutamide using a qualified liquid chromatography-tandem mass spectrometry (LC- MS/MS) method.
  • the mixture was vortexed for 1 min, and centrifuged at 5800 rpm for 10 min.
  • the sample was homogenized with 3 volumes (v/w) of PBS.
  • the diluted factor was 4. The following operation was the same as undiluted ones.
  • PK parameters are presented in Table 3 below.
  • the concentration ratio of brain to plasma at 2, 4, 8, 12 and 96 hrs post dose flowing IV administration of the test formulation were 0.351, 0.380, 0.307, 0.306 and 0.206 folds, respectively.
  • the concentration ratio of brain to plasma at 2, 4, 8, 12 and 96 hrs post dose following oral administration of the bicalutamide test formulation were 0.252, 0.297, 0.305, 0.252 and 0.156 folds, respectively.
  • the concentration ratio of brain to plasma at 2, 4, 8, 12 and 96 hrs post dose for the control bicalutamide formulation were 0.240, 0.308, 0.230, 0.202 and 0.138 folds, respectively.
  • the results demonstrate that the new bicalutamide formulation is characterized by improved PK properties compared to the control bicalutamide formulation.
  • the mean AUCiast of the test formulation following PO administration was 132% of that obtained by the control formulation.
  • the enhancement was even higher than that measured following IV administration, in which the AUCiast of the test formulation was 116% of that of the control formulation.
  • the enhancement in bicalutamide levels obtained by the new formulation was even greater in brain tissue than in plasma.
  • bicalutamide levels in brain tissue (AUC ) were 176% of that of the control formulation. This was also evident when comparing the relative C max values obtained by the test formulation as compared to the control (189% in brain tissue and 142% in plasma).
  • the new formulation is unexpectedly more effective in delivering bicalutamide to the brain than the control formulation.
  • the new bicalutamide formulation produced as described in Example 1 herein, exhibited remarkable enhancement in oral bioavailability and particularly in brain penetration compared to the control, hitherto known formulation.
  • Toxicity testing of the new bicalutamide formulation as monotherapy and in combination with temozolomide was performed.
  • TMZ 0.75 mg/KG 0.75 mg/Kg/day of temozolomide formulation
  • a combination therapy of 0.75mg/kg/day of TMZ and 8mg/kg/day of the new bicalutamide formulation (“8 mg/kg bic sol + 0.75 mg/
  • mice The weights of the mice were evaluated, and blood samples from the heart of the mice were collected and analyzed for liver function (alanine aminotransferase (ALT) and aspartate aminotransferase (AST) testing), white blood cells (WBC) count and platelet (PLT) count.
  • liver function alanine aminotransferase (ALT) and aspartate aminotransferase (AST) testing
  • WBC white blood cells
  • PTT platelet
  • the efficacy of the new bicalutamide formulation in the treatment of glioblastoma as compared to the current standard of care temozolamide was tested.
  • two additional mouse models for GBM were used.
  • the first model utilized mice bearing intracranial xenograft of the very aggressive human U87 cells in which mice show loss of weight already 4-5 days upon tumor inoculation and the median survival rate of the mice is only 26 days. In this model, a very narrow therapeutic window is available.
  • the second model utilized an in-vivo mice model inoculated with GIC (GBM initiated Cells).
  • mice were inoculated intacranially with 4xl0 5 U87MG cells. After one week when the tumor was established, the mice were randomized for the different study groups and were treated by PO administration for 5 days per week with either vehicle, 0.75mg/Kg/day TMZ, or a combination therapy of 0.75mg/Kg/day TMZ and 2, 4 or 8mg/Kg/day of the new bicalutamide formulation (“Bic Sol”).
  • lxlO 5 cells of the GIC glioma initiating cells
  • ZH-161 glioma initiating cells
  • the mice were randomized to four study groups and were treated by PO administration for 5 days per week with either vehicle, 0.75mg/kg/day of temozolomide formulation (TMZ) or 4 or 8mg/kg/day of the new bicalutamide formulation as monotherapy.
  • TMZ temozolomide formulation
  • Kaplan Meier curve Fig.
  • the new bicalutamide formulation produced as described in Example 1 herein, significantly prolonged the lifespan of mice as compared to untreated mice as well as mice treated with the current standard of care temozolamide as monotherapy.
  • the results demonstrate that formulations in accordance with the invention exhibited enhanced efficacy as compared to other available treatments, and adequate safety as monotherapy or in combination. Further, the results show that the formulations are amenable with combination therapy providing enhanced anti-tumor activity, as demonstrated for combination therapy with temozolomide, a common first-line chemotherapy used in the treatment of brain tumors.

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Abstract

L'invention concerne le domaine de la thérapie du cancer, spécifiquement des compositions et des méthodes pour le traitement de tumeurs cérébrales et de tumeurs exprimant le récepteur des androgènes (RA). Plus spécifiquement, l'invention concerne de nouvelles formulations comprenant des antagonistes du RA, ayant des propriétés thérapeutiques améliorées. Des modes de réalisation de l'invention concernent des compositions pharmaceutiques caractérisées par une meilleure solubilité dans l'eau du principe actif, en particulier du bicalutamide.
PCT/IL2022/050570 2021-05-30 2022-05-29 Compositions pour le traitement de tumeurs cérébrales Ceased WO2022254426A1 (fr)

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Citations (2)

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