WO2014165676A1 - Dérivé d'amphotéricine b à toxicité réduite - Google Patents

Dérivé d'amphotéricine b à toxicité réduite Download PDF

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Publication number
WO2014165676A1
WO2014165676A1 PCT/US2014/032830 US2014032830W WO2014165676A1 WO 2014165676 A1 WO2014165676 A1 WO 2014165676A1 US 2014032830 W US2014032830 W US 2014032830W WO 2014165676 A1 WO2014165676 A1 WO 2014165676A1
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Prior art keywords
deoamb
amb
yeast
derivative
administration
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PCT/US2014/032830
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English (en)
Inventor
Martin D. Burke
Brandon C. WILCOCK
Matthew M. ENDO
Brice E. UNO
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The Board Of Trustees Of The University Of Illinois
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Publication of WO2014165676A1 publication Critical patent/WO2014165676A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • amphotericin B The polyene macrolide natural product, amphotericin B (AmB, 1), is the archetype for both small molecules that form ion channels in living cells 1 and antibiotics that are inherently refractory to microbial resistance. 2 AmB is also, unfortunately, highly toxic, 3 which often limits its effective utilization as the last line of defense against life-threatening systemic fungal infections. Because both the incidence of such fungal infections and resistance to all other classes of antifungals are on the rise, 2 finding a way to improve the therapeutic index of AmB has become an increasingly important problem. Some progress has been made with liposomal formulations, but they are often prohibitively expensive, 4 and substantial toxicity still remains. 5 Despite 50 years of extensive efforts worldwide, a clinically viable derivative of AmB with an improved therapeutic index has yet to emerge. 6
  • An aspect of the invention is a pharmaceutical composition, comprising C2'deOAmB, represented by
  • An aspect of the invention is a method of inhibiting growth of a yeast or fungus, comprising contacting the yeast or fungus with an effective amount of C2'deOAmB, represented by
  • An aspect of the invention is a method of treating a yeast or fungal infection, comprising administering to a subject in need thereof a therapeutically effective amount of C2'deOAmB, represented by
  • FIG. 1 depicts structures of amphotericin B (AmB) and synthetic derivatives (AmdeB and C2'deOAmB) thereof. Also depicted are structures of mycosamine, ergosterol, and cholesterol.
  • AmB amphotericin B
  • AmdeB and C2'deOAmB synthetic derivatives
  • FIG. 2 depicts a scheme (Scheme 1) for synthesis of C2'deOAmB.
  • FIG. 3 depicts a scheme (Scheme 2) for synthesis of C2'deOAmB.
  • FIG. 4A is a graph depicting binding of AmB, AmdeB, and C2'deOAmB to ergosterol.
  • FIG. 4B is a graph depicting binding of AmB, AmdeB, and C2'deOAmB to cholesterol.
  • NS not statistically significant.
  • FIG. 5 is a series of four photomicrographs depicting human renal epithelial cells treated with DMSO (negative control) or 2 ⁇ AmB, AmdeB, or C2'deOAmB. DETAILED DESCRIPTION OF THE INVENTION
  • Amphotericin B is a clinically vital antimycotic but its use is limited by its toxicity. Binding ergosterol, independent of channel formation, is the primary mechanism by which AmB kills yeast, and binding cholesterol may primarily account for toxicity to human cells.
  • a leading structural model predicts that the C2' hydroxyl group on the mycosamine appendage is critical for binding both sterols. To test this, this functional group was synthetically deleted and the sterol binding capacity of the resulting derivative, C2'deOAmB, was directly characterized via isothermal titration calorimetry. Surprisingly, C2'deOAmB retains the capacity to bind ergosterol but shows no evidence of binding cholesterol. Moreover, C2'deOAmB is nearly equipotent to AmB against yeast, but demonstrates essentially no toxicity to human cells. C2'deOAmB thus represents a powerful probe of AmB function and a promising new antifungal agent with an
  • AmB is generally obtained from a strain of Streptomyces nodosus. It is currently approved for clinical use in the United States for the treatment of progressive, potentially life -threatening fungal infections, including such infections as systemic candidiasis, aspergillosis, cryptococcosis, blastomycosis, coccidioidomycosis, histoplasmosis, and mucormycosis, among others. It is generally formulated for intravenous injection.
  • Amphotericin B is commercially available, for example, as Fungizone® (Squibb),
  • Amphocin® (Pfizer), Abelcet® (Enzon), and Ambisome® (Astellas). Due to its unwanted toxic side effects, dosing is generally limited to a maximum of about 1.0 mg/kg/day and total cumulative doses not to exceed about 3 g in humans.
  • amphoteronolide B (AmdeB, 4), was also found to be non-toxic to yeast. 8 ' 9 The roles played by each heteroatom contained in the mycosamine appendage, however, have remained unclear.
  • the C2' hydroxyl group was deleted from AmB and the impact of this deletion on binding ergosterol and cholesterol was determined.
  • An aspect of the invention is C2'deOAmB, represented by
  • the invention specifically embraces stereoisomers of the compound C2'deOAmB.
  • the invention specifically embraces mixtures of individual stereoisomers of the compound C2'deOAmB, as well as isolated individual stereoisomers of the compound C2'deOAmB.
  • a “compound of the invention” as used herein refers to C2'deOAmB and any of the foregoing pharmaceutically acceptable salts and stereoisomers thereof.
  • An aspect of the invention is a pharmaceutical composition, comprising
  • pharmaceutically acceptable carrier means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other subject.
  • An aspect of the invention is a method of inhibiting growth of a yeast or fungus, comprising contacting the yeast or fungus with an effective amount of C2'deOAmB, represented by
  • Yeasts are eukaryotic organisms classified in the kingdom Fungi. Yeasts are typically described as budding forms of fungi. Of particular importance in connection with the invention are species of yeast that can cause infections in mammalian hosts. Such infections most commonly occur in immunocompromised hosts, including hosts with compromised barriers to infection (e.g., burn victims) and hosts with compromised immune systems (e.g., hosts receiving chemotherapy or immune suppressive therapy, and hosts infected with HIV).
  • Pathogenic yeast include, without limitation, various species of the genus Candida, as well as of Cryptococcus . Of particular note among pathogenic yeasts of the genus Candida are C albicans, C tropicalis, C stellatoidea, C. glabrata, C. krusei, C. parapsilosis, C. guilliermondii, C. viswanathii, and C. lusitaniae.
  • Cryptococcus specifically includes Cryptococcus neoformans.
  • Yeast can cause infections of mucosal membranes, for example oral, esophageal, and vaginal infections in humans, as well as infections of bone, blood, urogenital tract, and central nervous system. This list is exemplary and is not limiting in any way.
  • Fungi include, in addition to yeasts, other eukaryotic organisms including molds and mushrooms.
  • a number of fungi can cause infections in mammalian hosts. Such infections most commonly occur in immunocompromised hosts, including hosts with compromised barriers to infection (e.g., burn victims) and hosts with
  • Pathogenic fungi include, without limitation, species of Aspergillus, Rhizopus, Mucor, Histoplasma, Coccidioides,
  • Blastomyces, Trichophyton, Microsporum, and Epidermophyton are A. fumigatus, A.flavus, A. niger, H. capsulatum, C. immitis, and B.
  • Fungi can cause deep tissue infections in lung, bone, blood, urogenital tract, central nervous system, to name a few. Some fungi are responsible for infections of the skin and nails.
  • inhibit or inhibiting means reduce by at least a statistically significant amount compared to control. In one embodiment, inhibit or inhibiting means reduce by at least 5 percent compared to control. In various individual embodiments, inhibit or inhibiting means reduce by at least 10, 15, 20, 25, 30, 33, 40, 50, 60, 67, 70, 75, 80, 90, or 95 percent compared to control.
  • An aspect of the invention is a method of treating a yeast or fungal infection, comprising administering to a subject in need thereof a therapeutically effective amount of C2'deOAmB, represented by
  • treating and “treat” refer to performing an intervention that results in (a) preventing a condition or disease from occurring in a subject that may be at risk of developing or predisposed to having the condition or disease but has not yet been diagnosed as having it; (b) inhibiting a condition or disease, e.g., slowing or arresting its development; or (c) relieving or ameliorating a condition or disease, e.g., causing regression of the condition or disease.
  • treating and “treat” refer to performing an intervention that results in (a) inhibiting a condition or disease, e.g., slowing or arresting its development; or (b) relieving or ameliorating a condition or disease, e.g., causing regression of the condition or disease.
  • yeast or fungal infection refers to an infection with a yeast or fungus as defined herein.
  • a subject refers to a living mammal.
  • a subject is a non-human mammal, including, without limitation, a mouse, rat, hamster, guinea pig, rabbit, sheep, goat, cat, dog, pig, horse, cow, or non-human primate.
  • a subject is a human.
  • a "subject having a yeast or fungal infection” refers to a subject that exhibits at least one objective manifestation of a yeast or fungal infection.
  • a subject having a yeast or fungal infection is a subject that has been diagnosed as having a yeast or fungal infection and is in need of treatment thereof.
  • administering has its usual meaning and encompasses
  • administering by any suitable route of administration, including, without limitation, intravenous, intramuscular, intraperitoneal, subcutaneous, direct injection (for example, into a tumor), mucosal, inhalation, oral, and topical.
  • routes of administration including, without limitation, intravenous, intramuscular, intraperitoneal, subcutaneous, direct injection (for example, into a tumor), mucosal, inhalation, oral, and topical.
  • the administration is systemically administering.
  • the administration is topically administering.
  • effective amount refers to any amount that is sufficient to achieve a desired biological effect.
  • a therapeutically effective amount is an amount that is sufficient to achieve a desired therapeutic effect, e.g., to treat a yeast or fungal infection.
  • Compounds of the invention can be combined with other therapeutic agents.
  • the compound of the invention and other therapeutic agent may be administered simultaneously or sequentially.
  • the other therapeutic agents When the other therapeutic agents are administered simultaneously, they can be administered in the same or separate formulations, but they are administered substantially at the same time.
  • the other therapeutic agents are administered sequentially with one another and with compound of the invention, when the administration of the other therapeutic agents and the compound of the invention is temporally separated. The separation in time between the administration of these compounds may be a matter of minutes or it may be longer.
  • therapeutic agents include other antifungal agents, including AmB, as well as other antibiotics, anti-viral agents, anti-inflammatory agents, and others.
  • an "effective amount” refers to any amount that is sufficient to achieve a desired biological effect.
  • an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject.
  • the effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition.
  • a maximum dose that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds.
  • Appropriate systemic levels can be determined by, for example, measurement of the patient's peak or sustained plasma level of the drug. "Dose” and “dosage” are used interchangeably herein.
  • daily intravenous doses of active compounds of the invention e.g., C2'deOAmB
  • daily other parenteral doses of active compounds of the invention e.g., C2'deOAmB
  • intravenous administration of a compound of the invention may typically be from 0.1 mg/kg/day to 20 mg/kg/day. In one embodiment, intravenous administration of a compound of the invention may typically be from 0.1 mg/kg/day to 2 mg/kg/day. In one embodiment, intravenous administration of a compound of the invention may typically be from 0.5 mg/kg/day to 5 mg/kg/day. In one embodiment, intravenous administration of a compound of the invention may typically be from 1 mg/kg/day to 20 mg/kg/day. In one embodiment, intravenous administration of a compound of the invention may typically be from 1 mg/kg/day to 10 mg/kg/day.
  • Intravenous dosing thus may be similar to, or advantageously, may exceed maximal tolerated doses of AmB.
  • daily oral doses of active compounds will be, for human subjects, from about 0.01 milligrams/kg per day to 1000 milligrams/kg per day. It is expected that oral doses in the range of 0.5 to 50 milligrams/kg, in one or more administrations per day, will yield therapeutic results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day.
  • the therapeutically effective amount can be initially determined from animal models.
  • a therapeutically effective dose can also be determined from human data for compounds of the invention which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents (e.g., AmB). Higher doses may be required for parenteral administration.
  • the applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well- known in the art is well within the capabilities of the ordinarily skilled artisan.
  • compositions of the invention are administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.
  • an effective amount of the compound of the invention can be administered to a subject by any mode that delivers the compound of the invention to the desired surface.
  • Administering the pharmaceutical composition of the present invention may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical.
  • the compounds of the invention e.g., C2'deOAmB
  • C2'deOAmB can be formulated similarly to AmB.
  • C2'deOAmB can be formulated as a lyophilized preparation with desoxycholic acid, as a lyophilized preparation of liposome-intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a cholesteryl sulfate complex.
  • Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration.
  • the compounds i.e., compounds of the invention, and other therapeutic agents
  • the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the oral formulations may also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions or may be administered without any carriers.
  • oral dosage forms of the above component or components may be chemically modified so that oral delivery of the derivative is efficacious.
  • contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine.
  • moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski and Davis, "Soluble Polymer-Enzyme Adducts", In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp.
  • the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine.
  • the release will avoid the deleterious effects of the stomach environment, either by protection of the compound of the invention (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine.
  • a coating impermeable to at least pH 5.0 is essential.
  • examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings may be used as mixed films.
  • a coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow.
  • Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell may be used.
  • the shell material of cachets could be thick starch or other edible paper.
  • moist massing techniques can be used.
  • the therapeutic can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm.
  • the formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets.
  • the therapeutic could be prepared by compression.
  • Colorants and flavoring agents may all be included.
  • the compound of the invention (or derivative) may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.
  • diluents could include carbohydrates, especially mannitol, a-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch.
  • Certain inorganic salts may be also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride.
  • Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.
  • Disintegrants may be included in the formulation of the therapeutic into a solid dosage form.
  • Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate,
  • Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used.
  • Another form of the disintegrants are the insoluble cationic exchange resins.
  • Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.
  • Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin.
  • MC methyl cellulose
  • EC ethyl cellulose
  • CMC carboxymethyl cellulose
  • PVP polyvinyl pyrrolidone
  • HPMC hydroxypropylmethyl cellulose
  • Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.
  • the glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate.
  • Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate.
  • anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate.
  • Cationic detergents which can be used and can include benzalkonium chloride and benzethonium chloride.
  • Non-ionic detergents that could be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound of the invention or derivative either alone or as a mixture in different ratios.
  • Pharmaceutical preparations which can be used orally include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g.,
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. Also contemplated herein is pulmonary delivery of the compounds of the invention
  • the compound of the invention (or derivatives thereof).
  • the compound of the invention (or derivative) is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream.
  • Other reports of inhaled molecules include Adjei et al, Pharm Res 7:565- 569 (1990); Adjei et al, Int J Pharmaceutics 63: 135-144 (1990) (leuprolide acetate);
  • Contemplated for use in the practice of this invention are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.
  • Ultravent nebulizer manufactured by Mallinckrodt, Inc., St. Louis, Mo.
  • Acorn II nebulizer manufactured by Marquest Medical Products, Englewood, Colo.
  • the Ventolin metered dose inhaler manufactured by Glaxo Inc., Research Triangle Park, North Carolina
  • the Spinhaler powder inhaler manufactured by Fisons Corp., Bedford, Mass.
  • each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and/or carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated.
  • Chemically modified compound of the invention may also be prepared in different formulations depending on the type of chemical modification or the type of device employed.
  • Formulations suitable for use with a nebulizer will typically comprise compound of the invention (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of biologically active compound of the invention per mL of solution.
  • the formulation may also include a buffer and a simple sugar (e.g., for compound of the invention stabilization and regulation of osmotic pressure).
  • the nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compound of the invention caused by atomization of the solution in forming the aerosol.
  • Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the compound of the invention (or derivative) suspended in a propellant with the aid of a surfactant.
  • the propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a
  • hydrochlorofluorocarbon a hydrofluorocarbon, or a hydrocarbon, including
  • Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.
  • Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing compound of the invention (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation.
  • the compound of the invention (or derivative) should advantageously be prepared in particulate form with an average particle size of less than 10 micrometers ( ⁇ ), most preferably 0.5 to 5 ⁇ , for most effective delivery to the deep lung.
  • Nasal delivery of a pharmaceutical composition of the present invention is also contemplated.
  • Nasal delivery allows the passage of a pharmaceutical composition of the present invention to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung.
  • Formulations for nasal delivery include those with dextran or cyclodextran.
  • a useful device is a small, hard bottle to which a metered dose sprayer is attached.
  • the metered dose is delivered by drawing the pharmaceutical composition of the present invention solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed.
  • the chamber is compressed to administer the pharmaceutical composition of the present invention.
  • the chamber is a piston arrangement.
  • Such devices are commercially available.
  • a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used.
  • the opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation.
  • the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug.
  • the compounds when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.
  • a suitable vehicle e.g., sterile pyrogen- free water
  • the compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation.
  • Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto
  • the pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above.
  • the pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249: 1527- 33 (1990).
  • the compounds of the invention and optionally other therapeutics may be administered per se (neat) or in the form of a pharmaceutically acceptable salt.
  • the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof.
  • Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2- sulphonic, and benzene sulphonic.
  • such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.
  • Suitable buffering agents include: acetic acid and a salt (1-2% w/v); citric acid and a salt (1-3% w/v); boric acid and a salt (0.5-2.5%) w/v); and phosphoric acid and a salt (0.8- 2%> w/v).
  • Suitable preservatives include benzalkonium chloride (0.003-0.03%) w/v);
  • chlorobutanol (0.3-0.9% w/v); parabens (0.01-0.25% w/v) and thimerosal (0.004-0.02% w/v).
  • compositions of the invention contain an effective amount of a compound of the invention and optionally therapeutic agents included in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal.
  • carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
  • the components of the pharmaceutical compositions also are capable of being commingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.
  • the therapeutic agent(s) including specifically but not limited to the compound of the invention, may be provided in particles.
  • Particles as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the compound of the invention or the other therapeutic agent(s) as described herein.
  • the particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating.
  • the therapeutic agent(s) also may be dispersed throughout the particles.
  • the therapeutic agent(s) also may be adsorbed into the particles.
  • the particles may be of any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc.
  • the particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof.
  • the particles may be microcapsules which contain the compound of the invention in a solution or in a semi-solid state.
  • the particles may be of virtually any shape.
  • Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s).
  • Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired.
  • Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney H S et al.
  • Macromolecules 26:581-7 the teachings of which are incorporated herein.
  • These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).
  • the therapeutic agent(s) may be contained in controlled release systems.
  • controlled release is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release
  • sustained release also referred to as “extended release”
  • extended release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period.
  • delayed release is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug there from. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.”
  • Long-term sustained release implant may be particularly suitable for treatment of chronic conditions.
  • Long-term release as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days.
  • Long-term sustained release implants are well- known to those of ordinary skill in the art and include some of the release systems described above.
  • reactions were monitored by RP-HPLC using an Agilent 1100 series HPLC system equipped with a SYMMETRY® C 18 5 micron 4.6 x 150 mm column (Waters Corp. Milford, MA) with UV detection at 383 nm and the indicated eluent and flow rate of 1 mL/min.
  • intermediate 13 having suitably stable yet readily cleavable silyl ethers protecting all of the hydroxyl groups and the carboxylic acid at C41.
  • the mycosamine appendage was then oxidatively cleaved, and subsequent diastereoselective reduction at ci9 8b ' 9 ' 16 resulted in protected AmdeB derivative 14.
  • Glycosidation 14 with 11 proceeded smoothly to yield the alternatively protected C2'deOAmB derivative 15 as a 1 : 1 mixture of a and ⁇ anomers.
  • Derivative 15 proved to be much more amenable to deprotection than 7.
  • TIPS ester 13 Intermediate 12 (15.8 g, 7.20 mmol, 1 eq) was azeotropically dried with toluene and placed under vacuum overnight. Hexane (240 mL) and 2,6-lutidine (2.9 mL, 25.2 mmol, 3.5 eq) were added. The resulting solution was cooled to 0 °C and triisopropylsilyl triflate (2.9 mL, 10.8 mmol, 1.5 eq) was added slowly over 15 min. The reaction was quenched after 1 hr with saturated aqueous sodium bicarbonate and extracted with ether. The organic layer was washed with copper sulfate, water, and finally saturated sodium chloride.
  • the enone intermediate was azeotropically dried with toluene.
  • THF (10 mL) and MeOH (20 mL) was added.
  • the resulting solution was cooled to 0 °C, and NaBH 4 (1.08 g, 28.6 mmol, 5.3 eq) was added.
  • the reaction was quenched after 30 min with 1 M aqueous ammonium chloride and extracted with ether.
  • the organic layer was washed with water and then saturated sodium chloride.
  • the organic layer was dried with sodium sulfate and filtered.
  • the solvent was removed under reduced pressure, and flash column
  • 2,6-lutidine (675 ⁇ ,, 5.79 mmol, 4.5 eq) was added, and the reaction was cooled to -60 °C.
  • Triflic anhydride (1 M in DCM) (2.57 mL, 2.57 mmol, 2 eq) was added slowly. The reaction was warmed to -20 °C and stirred for 1.5 hrs.
  • 2,6-lutidine (600 ⁇ , 5.15 mmol, 4.0 eq) was added to the solution of 14, and it was cooled to -30 °C.
  • the sugar donor reaction was cannulated over to the solution of 14.
  • the reaction was warmed to 0 °C for lhr.
  • the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ether.
  • the glycosidated intermediate 15 (710 mg, 352 ⁇ , 1 eq) was azeotropically dried with toluene in a teflon vial.
  • THF (3 mL) was added, and the solution was cooled to 0 °C.
  • Pyridine (3 mL) in a teflon vial was cooled to 0 °C, and MeOH (0.5 mL) was added.
  • 70% HF-pyridine was added slowly to the pyridine-MeOH solution at 0 °C. This solution was transferred slowly to the THF solution of glycosylated intermediate. The reaction was allowed to stir for 12 hours at room temperature.
  • Epoxide intermediate SI3 (8 g, 21 mmol, 1 eq) was dissolved in THF (263 mL). The resulting solution was cooled to 0 °C, and LiHBEt 3 (1 M in THF) (105 mL, 105 mmol, 5eq) was added slowly. The reaction heated to 60 °C for 2.5 hrs. The reaction was cooled to 0 °C and quenched with 1 M ammonium chloride. The mixture was extracted with ether. The organic layer was washed with water and saturated sodium chloride. The organic layer was dried with sodium sulfate and filtered. The solvent was removed under reduced pressure, and column chromatography (Si0 2 ; Ether:Hexane 1 :4 ⁇ 1 :3) purification yielded 9 as an oil (5.47 g, 14.3 mmol, 68 %).
  • Palmitoyl oleoyl phosphatidylcholine (POPC) was obtained as a 20 mg/mL solution in CHCI 3 from Avanti Polar Lipids (Alabaster, AL) and was stored at -20 °C under an atmosphere of dry argon and used within 1 month.
  • a 4 mg/mL solution of ergosterol in CHCI 3 was prepared monthly and stored at 4 °C under an atmosphere of dry argon. Prior to preparing a lipid film, the solutions were warmed to ambient temperature to prevent condensation from contaminating the solutions.
  • a 13 x 100 mm test tube was charged with 800 POPC and 230 of the ergosterol solution.
  • a 13 x 100 mm test tube was charged with 800 ⁇ , POPC and 224 ⁇ of the ergosterol solution.
  • a 13 x 100 mm test tube was charged with 800 ⁇ , POPC.
  • the solvent was removed with a gentle stream of nitrogen and the resulting lipid film was stored under high vacuum for a minimum of eight hours prior to use.
  • the film was then hydrated with 1 mL of K buffer and vortexed vigorously for approximately 3 minutes to form a suspension of multilamellar vesicles (MLVs).
  • MLVs multilamellar vesicles
  • the resulting lipid suspension was pulled into a Hamilton (Reno, NV) 1 mL gastight syringe and the syringe was placed in an Avanti Polar Lipids Mini-Extruder.
  • the lipid solution was then passed through a 0.20 ⁇ Millipore (Billerica, MA) polycarbonate filter 21 times, the newly formed large unilamellar vesicle (LUV) suspension being collected in the syringe that did not contain the original suspension of MLVs to prevent the carryover of MLVs into the LUV solution.
  • LUV large unilamellar vesicle
  • Ergosterol content was determined spectrophotometrically.
  • a 50 portion of the LUV suspension was added to 450 ⁇ , 2: 18:9 hexane:isopropanol:water (v/v/v).
  • Three independent samples were prepared and then vortexed vigorously for approximately one minute.
  • the solutions were then analyzed by UV/Vis spectroscopy and the concentration of ergosterol in solution was determined by the extinction coefficient of 10400 L mol "1 cm "1 at the UV max of 282 nm and was compared to the concentration of phosphorus to determine the percent sterol content.
  • the extinction coefficient was determined independently in the above ternary solvent system. LUVs prepared by this method contained between 7 and 14%) ergosterol.
  • NanoAnalyze software (TA Instruments) was used for baseline determination and integration of the injection heats, and Microsoft Excel was used for subtraction of dilution heats and the calculation of overall heat evolved. To correct for dilution and mixing heats, the heat of the final injection from each run was subtracted from all the injection heats for that particular experiment. See, for example, te Welscher, YM et al. (2008) J. Biol. Chem. 283:6393. By this method, the overall heat evolved during the experiment was calculated using the following formula:
  • yeast peptone dextrose (YPD) growth media consisting of 10 g/L yeast extract, 20 g/L peptone, 20 g/L dextrose, and 20 g/L agar for solid media.
  • the media was sterilized by autoclaving at 250 °F for 30 min.
  • Dextrose was subsequently added as a sterile 40% w/v solution in water (dextrose solutions were filter sterilized).
  • Solid media was prepared by pouring sterile media containing agar (20 g/L) onto Corning (Corning, NY) 100 x 20 mm polystyrene plates. Liquid cultures were incubated at 30 °C on a rotary shaker and solid cultures were maintained at 30 °C in an incubator.
  • C albicans was cultured in a similar manner to S. cerevisiae except both liquid and solid cultures were incubated at 37 °C.
  • the solution was diluted 10-fold with YPD, and 195 ⁇ _, aliquots of the dilute cell suspension were added to sterile Falcon (Franklin Lakes, NJ) Microtest 96-well plates in triplicate.
  • Compounds were prepared either as 400 ⁇ (AmB, C2'deOAmB) or 2 mM (AmdeB) stock solutions in DMSO and serially diluted to the following concentrations with DMSO: 1600, 1200, 800, 400, 320, 240, 200, 160, 120, 80, 40, 20, 10 and 5 ⁇ . 5 ⁇ aliquots of each solution were added to the 96-well plate in triplicate, with each column representing a different concentration of the test compound.
  • the concentration of DMSO in each well was 2.5% and a control well to confirm viability using only 2.5% DMSO was also performed in triplicate. This 40-fold dilution gave the following final concentrations: 50, 40, 30, 20, 10, 8, 6, 4, 1, 0.5, 0.25 and 0.125 ⁇ .
  • the plates were covered and incubated at 30 °C (S. cerevisiae) or 37 °C (C. albicans) for 24 hours prior to analysis.
  • the MIC was determined to be the concentration of compound that resulted in no visible growth of the yeast.
  • the experiments were performed in duplicate and the reported MIC represents an average of two experiments.
  • AmB causes 90% loss of cell viability of primary human renal proximal tubule epithelial cells at a concentration of 2.4 ⁇ [the minimum toxic concentration (MTC)].
  • MTC minimum toxic concentration
  • C2'deOAmB showed no evidence of toxicity up to their limits of solubility. 16 As shown in FIG. 5, microscopy further revealed that human primary renal cells treated with AmB showed severe abnormalities compared to DMSO treated controls. In contrast, cells treated AmdeB and C2'deOAmB showed no visual evidence of toxicity. Details of this experiment are as follows:
  • erythrocyte pellet was suspended in 1 mL of RBC buffer (10 mM NaH 2 P0 4 , 150 mM NaCl, 1 mM MgCl 2 , pH 7.4) to form the erythrocyte stock suspension.
  • MHC Minimum Hemolysis Concentration
  • Positive and negative controls were prepared by adding 1 ⁇ ⁇ of DMSO to MilliQ water or RBC buffer, respectively to 0.2 mL PCR tube. To each PCR tube, 0.63 ⁇ , of the erythrocyte stock suspension was added and mixed by inversion. The samples were incubated at 37 °C for 2 hours. The samples were mixed by inversion and centrifuged at 10,000 g for 2 minutes. 15 ⁇ ⁇ of the supernatant from each sample was added to a 384-well place. Absorbances were read at 540 nm using a Biotek HI Synergy Hybrid Reader (Wanooski, VT). Experiments were performed in triplicate and the reported MHC represents an average of three experiments.
  • Percent hemolysis was determined according to the following equation:
  • RPTECs Primary human renal proximal tubule epithelial cells
  • ATCC Manassas, VA
  • Complete growth media was prepared using renal epithelial cell basal medium (ATCC, PCS-400-030), renal epithelial cell growth kit (ATCC, PCS-400-040), and penicillin-streptomycin (10 units/mL and 10 ⁇ g/mL).
  • Complete media was stored at 4 °C in the dark and used within 28 days.
  • Primary RPTECs were grown in C0 2 incubator at 37 °C with an atmosphere of 95% air/5% C0 2 .
  • WST-8 Reagent Preparation WST-8 cell proliferation assay kit (10010199) was purchased from Cayman
  • WST-8 reagent and electron mediator solution were thawed and mixed to prepare the WST-8 reagent solution.
  • the solution was stored at -20 °C and used within one week.
  • WST-8 Assay A suspension of primary RPTECs in complete growth media was brought to a concentration of 1 x 10 5 cells/mL. A 96-well plate was seeded with 99 xL of the cell suspension and incubated at 37 °C with an atmosphere of 95% air/5% C0 2 for 3 hours. Positive and negative controls were prepared by seeding with 100 of the cell suspension or 100 of the complete media.
  • the media was aspirated and 100 ⁇ , of serum- free media was added and 10 ⁇ , of the WST-8 reagent solution was added to each well.
  • the 96-well plate was mixed in a shaking incubator at 200 rpm for 1 minute and incubated at 37 °C with an atmosphere of 95% air/5% C0 2 for 2 hours. Following incubation, the 96-well plate was mixed in a shaking incubator at 200 rpm for 1 minute and absorbances were read at 450 nm using a Biotek Hl Synergy Hybrid Reader (Wanooski, VT). Experiments were performed in triplicate and the reported cytotoxicity represents an average of three experiments.
  • % hemolysis Abs'samPle ⁇ M s. neg . ⁇
  • Concentration vs. percent hemolysis was plotted and fitted to 4-parameter logistic (4PL) 8 dose response fit using OriginPro 8.6.
  • the MTC was defined as the concentration to cause 90%) loss of cell viability.
  • Cells were imaged using an AMG (Bothell, WA) EVOS fl Microscope. Images were taken using transmitted light at lOx objective.

Abstract

Cette invention concerne un dérivé d'amphotéricine B (AmB) ayant un indice thérapeutique amélioré par rapport à l'amphotéricine B, des compositions pharmaceutiques contenant ledit dérivé d'AmB, des procédés de production du dérivé d'AmB et de la composition pharmaceutique, et leur utilisation dans des méthodes destinées à inhiber la croissance d'une levure ou d'un champignon et à traiter une infection provoquée par ladite levure ou ledit champignon. Le dérivé d'amphotéricine B, dénoté C2'deOAmB, diffère du composé parent en ce qu'il est dépourvu de groupe hydroxyle à la position 2' sur la mycosamine. Cette différence structurale résulte en (i) une capacité conservée de liaison à l'ergostérol et d'inhibition de la croissance de la levure, (ii) une capacité considérablement réduite de liaison au cholestérol, et (iii) essentiellement aucune toxicité vis-à-vis des cellules humaines.
PCT/US2014/032830 2013-04-03 2014-04-03 Dérivé d'amphotéricine b à toxicité réduite WO2014165676A1 (fr)

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WO2016040779A1 (fr) * 2014-09-12 2016-03-17 The Board Of Trustees Of The University Of Illinois Dérivés d'urée d'antibiotiques macrolides polyéniques
WO2016112260A1 (fr) 2015-01-08 2016-07-14 The Board Of Trustees Of The University Of Illinois Synthèse concise de dérivés d'urée d'amphotéricine b
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US11028114B2 (en) 2013-10-07 2021-06-08 The Board Of Trustees Of The University Of Illinois Amphotericin B derivatives with improved therapeutic index
US11117920B2 (en) 2013-10-07 2021-09-14 The Board Of Trustees Of The University Of Illinois Amphotericin B derivatives with improved therapeutic index
US10323057B2 (en) 2013-10-07 2019-06-18 The Board Of Trustees Of The University Of Illinois Amphotericin B derivatives with improved therapeutic index
WO2016014779A1 (fr) * 2014-07-23 2016-01-28 The Board Of Trustees Of The University Of Illinois Dérivés macrolides de polyènes antifongiques à toxicité réduite pour les mammifères
WO2016040779A1 (fr) * 2014-09-12 2016-03-17 The Board Of Trustees Of The University Of Illinois Dérivés d'urée d'antibiotiques macrolides polyéniques
US10683318B2 (en) 2014-10-17 2020-06-16 The Board Of Trustees Of The University Of Illinois Scalable synthesis of reduced toxicity derivative of amphotericin B
EP3242554A4 (fr) * 2015-01-08 2018-06-06 The Board of Trustees of the University of Illionis Synthèse concise de dérivés d'urée d'amphotéricine b
JP2018502851A (ja) * 2015-01-08 2018-02-01 ザ ボード オブ トラスティーズ オブ ザ ユニヴァーシティ オブ イリノイＴｈｅ Ｂｏａｒｄ Ｏｆ Ｔｒｕｓｔｅｅｓ Ｏｆ Ｔｈｅ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｉｌｌｉｎｏｉｓ アムホテリシンｂの尿素誘導体の簡便な合成法
WO2016112260A1 (fr) 2015-01-08 2016-07-14 The Board Of Trustees Of The University Of Illinois Synthèse concise de dérivés d'urée d'amphotéricine b
AU2016205187B2 (en) * 2015-01-08 2020-02-27 The Board Of Trustees Of The University Of Illinois Concise synthesis of urea derivatives of amphotericin B
WO2016168568A1 (fr) 2015-04-15 2016-10-20 Revolution Medicines, Inc. Dérivés d'amphotéricine b
EP3929203A1 (fr) 2015-04-15 2021-12-29 Sfunga Therapeutics, Inc. Dérivés d'amphotéricine b
US11970512B2 (en) 2021-09-02 2024-04-30 The Board Of Trustees Of The University Of Illinois Amphotericin B derivatives with improved therapeutic index
WO2024010968A3 (fr) * 2022-07-08 2024-03-07 The Board Of Trustees Of The University Of Illinois Transfert de sucres épimérisés en c2 à l'amphotéricine b aglyconique

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