WO2018005963A1 - Synthèse de nouveaux pro-médicaments de méthylumbelliférone et leur inclusion dans des formules d'administration de médicaments à base de lipides. - Google Patents

Synthèse de nouveaux pro-médicaments de méthylumbelliférone et leur inclusion dans des formules d'administration de médicaments à base de lipides. Download PDF

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Publication number
WO2018005963A1
WO2018005963A1 PCT/US2017/040282 US2017040282W WO2018005963A1 WO 2018005963 A1 WO2018005963 A1 WO 2018005963A1 US 2017040282 W US2017040282 W US 2017040282W WO 2018005963 A1 WO2018005963 A1 WO 2018005963A1
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substituted
unsubstituted
methylumbelliferone
prodrug
subject
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PCT/US2017/040282
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English (en)
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Francis C. Szoka, Jr.
Zhipeng Dai
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Zoneone Pharma, Inc.
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Publication of WO2018005963A1 publication Critical patent/WO2018005963A1/fr

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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7

Definitions

  • compositions include an active agent bound to a lipophilic moiety.
  • the lipophilic moiety is appropriate as a component of an emulsion, a liposome, a micelle or a lipid particle.
  • 4-methylumbelliferone (4MU) is a small molecule (M.W. 176) inhibitor of hyaluronic acid (HA) biosynthesis that has exhibited antitumor and tumor-preventive efficacies when it is administered PO or IP in various preclinical models (reviewed in Nagy et al, 2015;
  • 4-MU is extensively metabolized to a glucuronic acid (4MUG) and due to first pass metabolism in the liver has a 3% bioavailability in humans. This low bioavailability is a barrier to the use of 4MU as a cancer chemopreventive or therapeutic agent in humans.
  • 4-MU derivatives in which first pass metabolism was diminished or eliminated would provide therapeutic agents of value in treating cancer.
  • the present invention provides 4-MU prodrugs and formulations of these compounds for which first pass metabolism on administration to a subject is reduced or essentially eliminated.
  • the invention provides lipophilic 4-MU derivatives, which can be assembled into liposomes, micelles and lipid particles.
  • the 4- MU compounds of the invention are formulated into pharmaceutically acceptable oral lipid based drug delivery systems (LBDDS).
  • LBDDS oral lipid based drug delivery systems
  • Exemplary compounds and LBDDS formulations are characterized by improved bioavailability of 4MU in the circulation after oral administration of the compound and/or formulation.
  • the invention provides a method of treating cancer using a compound or formulation of the invention.
  • the invention includes administering to a subject in need thereof a therapeutically effective amount of a compound or formulation of the invention.
  • FIG. 1 Synthesis and characterization of the following three prodrugs of 4MU.
  • the fatty acid modification enables the facile incorporation of the prodrugs into lipid-based delivery systems and optionally enables the prodrug to bind to lipoproteins and albumin in circulation. They are also putative substrates for esterases or phosphatases (for prodrug review see Huttunen et al, 2011).
  • FIG. 2 Chemical structures of exemplary 4-MU prodrugs.
  • FIG. 3A - FIG. 3E show exemplary compounds of the invention.
  • the present invention addresses an unmet need for an orally administered 4-MU prodrug formulation that will increase the oral availability of 4-MU to the point that MU can be investigated as a cancer prevention oral compound in humans.
  • the invention provides lipophilic ester prodrugs of 4-MU.
  • the prodrugs are incorporated into lipid based oral formulations.
  • Exemplary oral lipid based drug formulations result in the prodrug being absorbed into the body via the intestinal lymphatic system. Absorption via the lymphatic system reduces or avoids the initial first pass hepatic metabolism of 4-MU into 4-MUG. Once in the systemic circulation, the prodrug are converted into 4-MU. In various embodiments, this tactic increases the oral bioavailability of 4-MU. In various embodiments, this tactic provides a sustained 4-MU plasma level due to the prodrug being associated with lipoproteins and/or albumin. In various embodiments the 4-MU prodrugs can be administered parenterally to enhance 4-MU concentration in tumors.
  • prodrug should be understood in the normal sense, namely as a drug which is masked or protected with the purpose of being converted (typically by cleavage, but also by in vivo chemical conversion) to the intended drug substance.
  • prodrug typically by cleavage, but also by in vivo chemical conversion
  • Exemplary prodrugs of the invention are structures according to Formula I:
  • R 1 and R 2 are members independently selected from H, halo, OH, NH 2 , SH, substituted or unsubsituted alkyl, substituted or unsubstituted aryl, substituted or
  • the index n is an integer from 2 to 24, e.g., 6-20, e.g., 8-16, e.g., 6-9, e.g., 5, 6, 7, 8, 9 or 10, inclusive of any ranges contained within these ranges.
  • the R 1 and R 2 moieties for each (CR X CR 2 ) subunit are selected independently from those for other such subunits.
  • Adjacent (CR X CR 2 ) are optionally interrupted by one or more heteroatom (e.g., O, S, B, N) to which are attached one or more moiety necessary to satisfy the valence of the heteroatom, e.g, H, substituted or unsubstituted alkyl, substituted or unsubstituted
  • R 3 is selected from H, CH 3 , OR 4 , COOR 4 , and CON(R 4 ) 2 .
  • Each R 4 is independently selected from H, a negative charge and a counterion, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl.
  • X is O, OC(O), OC(0)0, -OP(0)(OR 5 ) 2 0- or OP(0)(OR 5 )NH-.
  • R 5 is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl.
  • Exemplary prodrugs of the invention include, without limitation:
  • R 1 , R 2 , R 3 and R 5 and n are as discussed for Formula I.
  • the index m is an integer from 1 to 23. Incorporating the C(O) moiety, this gives the same alkyl chain value as the methylene chains with "n".
  • the prodrug is selected from:
  • alkyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon, which may be fully saturated, mono- or polyunsaturated and includes mono-, di- and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t- butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds (i.e., alkenyl and alkynyl moieties).
  • unsaturated alkyl groups include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • alkyl can refer to "alkylene", which by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified, but not limited, by -CH2CH2CH2CH2-.
  • an alkyl (or alkylene) group will have from 1 to 30 carbon atoms.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • alkyl refers to an alkyl or combination of alkyls selected from Ci, C 2 , C 3 , C 4 , C5, C 6 , C 7 , C 8 , C9, Cio, C11, C12, Ci3, C 14 , C15, C 16 , C 17 , C 18 , C19, C20, C 21 , C22, C23, C24, C25, C26, C27, C28, C29 and C3o alkyl.
  • alkyl refers to C1-C25 alkyl.
  • alkyl refers to C1-C2 0 alkyl.
  • alkyl refers to C1-C15 alkyl.
  • alkyl refers to C1-C1 0 alkyl.
  • alkyl refers to C1-C6 alkyl.
  • heteroalkyl by itself or in combination with another term, means an alkyl of at least two carbons in which one or more but not all carbons are replaced with one or more heteroatoms selected from the group consisting of O, N, Si and S, (preferably O, N and S), wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized.
  • the heteroatoms O, N, Si and S may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • the heteroatom may be bonded to one or more H or substituents such as (C 1; C 2 , C3, C 4 , C5 or C 6 ) alkyl according to the valence of the heteroatom.
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-.
  • the designated number of carbons in heteroforms of alkyl, alkenyl and alkynyl includes the heteroatom count.
  • a (Ci, C 2 , C3, C 4 , C5 or C 6 ) heteroalkyl will contain, respectively, 1, 2, 3, 4, 5 or 6 atoms selected from C, N, O, Si and S such that the heteroalkyl contains at least one C atom and at least one heteroatom, for example 1-5 C and 1 N or 1-4 C and 2 N.
  • a heteroalkyl may also contain one or more carbonyl groups.
  • a heteroalkyl is any C2-C 30 alkyl, C2-C25 alkyl, C2-C20 alkyl, C2-C15 alkyl, C2-C1 0 alkyl or C2-C6 alkyl in any of which one or more carbons are replaced by one or more heteroatoms selected from O, N, Si and S (or from O, N and S). In some embodiments, each of 1, 2, 3, 4 or 5 carbons is replaced with a heteroatom.
  • alkoxy alkylamino and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl and heteroalkyl groups attached to the remainder of the molecule via an oxygen atom, a nitrogen atom (e.g., an amine group), or a sulfur atom, respectively.
  • heterocycloalkyl a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1 - cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, 1 -(1 ,2,5,6-tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3- piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
  • aryl means a polyunsaturated, aromatic substituent that can be a single ring or optionally multiple rings (preferably 1 , 2 or 3 rings) that are fused together or linked covalently. In some embodiments, aryl is a 3, 4, 5, 6, 7 or 8 membered ring, which is optionally fused to one or two other 3, 4, 5, 6, 7 or 8 membered rings.
  • heteroaryl refers to aryl groups (or rings) that contain 1, 2, 3 or 4 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl and heteroaryl groups include phenyl,
  • any of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted. That is, in some embodiments, any of these groups is substituted or unsubstituted.
  • substituents for each type of radical are selected from those provided below.
  • alkyl, heteroalkyl, cycloalkyl and heterocycloalkyl radicals are generically referred to as "alkyl group substituents".
  • R', R", R'" and R" are each independently selected from hydrogen, alkyl (e.g., Ci, C 2 , C 3 , C 4 , C 5 and C 6 alkyl).
  • R', R", R'" and R" each independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g. , aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
  • R', R", R'" and R" are each independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, thioalkoxy groups, and arylalkyl.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7- membered ring.
  • -NR'R" can include 1-pyrrolidinyl and 4-morpholinyl.
  • an alkyl group substituent is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
  • R', R", R'" and R" are independently selected from hydrogen and alkyl (e.g., C 1; C 2 , C 3 , C 4 , C5 and Ce alkyl). In some embodiments,
  • R', R", R'" and R" are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. In some embodiments, R', R", R'" and R"" are independently selected from hydrogen, alkyl, heteroalkyl, aryl and heteroaryl.
  • an aryl group substituent is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(0)-(CRR') q -U-, wherein T and U are independently -NR-, -0-, -CRR'- or a single bond, and q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR'-, -0-, -NR-, -S-, -S(O)-, -S(0) 2 -, -S(0) 2 NR'- or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the
  • acyl refers to a species that includes the moiety -C(0)R, where R has the meaning defined herein.
  • exemplary species for R include H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl.
  • R is selected from H and (Ci-C 6 )alkyl.
  • halo or halogen
  • haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(Ci-C4)alkyl is mean to include, but not be limited to, trifiuoromethyl, 2,2,2- trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • halogen refers to an atom selected from F, CI and Br.
  • heteroatom includes oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
  • a heteroatom is selected from N and S.
  • the heteroatom is O.
  • R is a general abbreviation that represents a substituent group that is selected from acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
  • R is a general abbreviation that represents a substituent group that is selected from acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
  • R is a general abbreviation that represents a substituent group that is selected from acyl, substituted or unsubstitute
  • -COOH also refers to -COO " and -OH also refers to -O " .
  • lipid-based drug delivery system should encompass macromolecular structures which as the main constituent include lipid or lipid derivatives. Suitable examples hereof are liposomes and micelles. It is presently believed that liposomes offer the broadest scope of applications and those have been described most detailed in the following. Although liposomes currently are believed to be the preferred lipid-based system, micellular systems and lipid particles also provide useful embodiments within the present invention.
  • An exemplary formulation of the invention exhibits one or more of the following properties: it solubilizes a therapeutic amount of MU prodrug, provides a reasonable shelf- life, contains approved excipients, and facilitates dispersion of the dose in the intestine to present the prodrug in such a way that the prodrug is taken up by the intestinal lymphatic system where the prodrug is optionally incorporated into lipoproteins.
  • Exemplary lipid based drug delivery systems of the invention include: detergent micelles/lipid emulsion, liposomes prepared from palmitoyloleoylphosphatidylcholine, hydrogenated soy phosphatdylcholine, and solid lipid nanoparticles prepared from steric acid or tripalmitin
  • Lipids of use in the various formulations of the invention are exemplified by their description in conjunction with the formation of liposomes as set forth hereinbelow.
  • liposome is used herein in accordance with its usual meaning, referring to microscopic lipid vesicles composed of a bilayer of phospholipids or any similar amphipathic lipids encapsulating an internal aqueous medium.
  • the liposomes of the present invention can be unilamellar vesicles such as small unilamellar vesicles (SUVs) and large unilamellar vesicles (LUVs), and multilamellar vesicles (MLV), typically varying in size from 30 nm to 200 nm.
  • SUVs small unilamellar vesicles
  • LUVs large unilamellar vesicles
  • MLV multilamellar vesicles
  • liposomal membrane refers to the bilayer of phospholipids separating the internal aqueous medium from the external aqueous medium.
  • Exemplary liposomal membranes useful in the current invention may be formed from a variety of vesicle-forming lipids, typically including dialiphatic chain lipids, such as phospholipids, diglycerides, dialiphatic glycolipids, single lipids such as sphingomyelin and glycosphingolipid, cholesterol and derivates thereof, and combinations thereof.
  • dialiphatic chain lipids such as phospholipids, diglycerides, dialiphatic glycolipids, single lipids such as sphingomyelin and glycosphingolipid, cholesterol and derivates thereof, and combinations thereof.
  • phospholipids are amphiphilic agents having hydrophobic groups formed of long- chain alkyl chains, and a hydrophilic group containing a phosphate moiety.
  • the group of phospholipids includes phosphatidic acid, phosphatidyl glycerols, phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, phosphatidylserines, and mixtures thereof.
  • the phospholipids are chosen from l,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), dimyristoyl-phosphatidylcholine (DMPC), distearoylphosphatidylcholie (DSPC), hydrogenated soy phosphatidylcholine (HSPC), soy phosphatidylcholine (SPC),
  • DMPG dimyristoylphosphatidylglycerol
  • DSPG distearoylphosphatidylglycerol
  • POPC palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
  • DOPC l,2-dioleoyl-sn-glycero-3- phosphocholine
  • DSPC egg yolk
  • EYPC phosphatidylcholine
  • HEPC hydrogenated egg yolk phosphatidylcholine
  • SML sterol modified lipids
  • cationic lipids cationic lipids and inverse-zwitterlipids.
  • Liposomal membranes according to the present invention may further comprise ionophores like nigericin and A23187.
  • an exemplary liposomal phase transition temperature is between -25°C and 100°C, e.g., between 4°C and 65°C.
  • phase transition temperatures of liposomes can, among other parameters, be influenced by the choice of phospholipids and by the addition of steroids like cholesterol, lanosterol, cholestanol, stigmasterol, ergosterol, and the like.
  • a method according to any of the foregoing is provided in which the liposomes comprise one or more components selected from different phospholipids and cholesterol in several molar ratios in order to modify the transition, the required process temperature and the liposome stability in plasma.
  • An exemplary phospholipid composition of use in the invention comprises between about 10 and about 50 mol% of steroids, preferably cholesterol.
  • liposomes can be prepared by any of the techniques now known or subsequently developed for preparing liposomes.
  • the liposomes can be formed by the conventional technique for preparing multilamellar lipid vesicles (MLVs), that is, by depositing one or more selected lipids on the inside walls of a suitable vessel by dissolving the lipids in chloroform and then evaporating the chloroform, and by then adding the aqueous solution which is to be encapsulated to the vessel, allowing the aqueous solution to hydrate the lipid, and swirling or vortexing the resulting lipid suspension. This process engenders a mixture including the desired liposomes.
  • MLVs multilamellar lipid vesicles
  • the liposomes can be in the form of steroidal lipid vesicles, stable plurilamellar lipid vesicles (SPLVs), monophasic vesicles (MPVs), or lipid matrix carriers (LMCs).
  • SPLVs stable plurilamellar lipid vesicles
  • MPVs monophasic vesicles
  • LMCs lipid matrix carriers
  • the liposomes can be subjected to multiple (five or more) freeze-thaw cycles to enhance their trapped volumes to provide a more uniform interlamellar distribution of a solute.
  • the liposomes are optionally sized to achieve a desired size range and relatively narrow distribution of liposome sizes.
  • a size range of about 20-200 nanometers allows the liposome suspension to be sterilized by filtration through a conventional filter, typically a 0.22 or 0.4 micron filter.
  • the filter sterilization method can be carried out on a high through-put basis if the liposomes have been sized down to about 20- 200 nanometers.
  • Several techniques are available for sizing liposomes to a desired size. Sonicating a liposome suspension either by bath or probe sonication produces a progressive size reduction down to small unilamellar vesicles less than about 50 nanometer in size.
  • Homogenization is another method which relies on shearing energy to fragment large liposomes into smaller ones.
  • multilamellar vesicles are recirculated through a standard emulsion homogenizer until selected liposome sizes, typically between about 50 and 500 nanometers, are observed.
  • the particle size distribution can be monitored by conventional laser-beam particle size determination.
  • Extrusion of liposome through a small-pore polycarbonate membrane or an asymmetric ceramic membrane is also an effective method for reducing liposome sizes to a relatively well-defined size distribution.
  • the suspension is cycled through the membrane one or more times until the desired liposome size distribution is achieved.
  • the liposomes may be extruded through successively smaller-pore membranes, to achieve a gradual reduction in liposome size.
  • controlled size liposomes can be prepared using microfluidic techniques werein the lipid in an organic solvent such as ethanol or ethanol-aprotic solvent mixtures is rapidly mixed with the aqueous medium, so that the organic solvent/ water ratio is less than 30%, in a microchannel with dimensions less than 300 microns and preferable less than 150 microns in wide and 50 microns in height.
  • the organic solvent is then removed from the liposomes by dialysis.
  • Other useful sizing methods such as sonication, solvent vaporization or reverse phase evaporation are known to those of skill in the art.
  • Exemplary liposomes for use in various embodiments of the invention have a size of from about 30 nanometers to about 40 microns.
  • the internal aqueous medium typically is the original medium in which the liposomes were prepared and which initially becomes encapsulated upon formation of the liposome.
  • freshly prepared liposomes encapsulating the original aqueous medium can be used directly.
  • the liposomes, after preparation are dehydrated, e.g. for storage.
  • the present process may involve addition of the dehydrated liposomes directly to an external pharmaceutically acceptable, e.g., aqueous, medium.
  • liposomes are optionally dehydrated under reduced pressure using standard freeze-drying equipment or equivalent apparatus.
  • the liposomes and their surrounding medium are frozen in liquid nitrogen before being dehydrated and placed under reduced pressure.
  • one or more protective sugars are typically employed to interact with the lipid vesicle membranes and keep them intact as the water in the system is removed.
  • sugars can be used, including such sugars as trehalose, maltose, sucrose, glucose, lactose, and dextran.
  • disaccharide sugars have been found to work better than monosaccharide sugars, with the disaccharide sugars trehalose and sucrose being most effective.
  • Other more complicated sugars can also be used.
  • aminoglycosides including streptomycin and dihydrostreptomycin, have been found to protect liposomes during dehydration.
  • one or more sugars are included as part of either the internal or external media of the lipid vesicles. Most preferably, the sugars are included in both the internal and external media so that they can interact with both the inside and outside surfaces of the liposomes' membranes.
  • Inclusion in the internal medium is accomplished by adding the sugar or sugars to the buffer which becomes encapsulated in the lipid vesicles during the liposome formation process.
  • the external medium used during the active loading process should also preferably include one or more of the protective sugars
  • polyethylene glycol (PEG)-lipid conjugates have been used extensively to improve circulation times for liposome- encapsulated functional compounds, to avoid or reduce premature leakage of the functional compound from the liposomal composition and to avoid detection of liposomes by the body's immune system.
  • Attachment of PEG-derived lipids onto liposomes is called PEGylation.
  • the liposomes are PEGylated liposomes. PEGylation can be accomplished by incubating a reactive derivative of PEG with the target liposomes.
  • Suitable PEG-derived lipids include conjugates of DSPE-PEG, functionalized with one of carboxylic acids, glutathione (GSH), maleimides (MAL), 3-(2-pyridyldithio) propionic acid (PDP), cyanur, azides, amines, biotin or folate, in which the molecular weight of PEG is between 2000 and 5000 g/mol.
  • Other suitable PEG-derived lipids are mPEGs conjugated with ceramide, having either C 8 - or details, in which the molecular weight of mPEG is between 750 and 5000 daltons.
  • Still other appropriate ligands are mPEGs or functionalized PEGs conjugated with glycerophospholipds like l,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1,2-dipalmitoyl-sn-glycero- 3-phosphoethanolamine (DPPE), l,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and l,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), l,2-distearoyl-s??-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000], and the like.
  • PEGylation of liposomes is a technique generally known by those skilled in the art.
  • the liposomes are PEGylated with DSPE-PEG-GSH conjugates (up to 5 mol %) and/or DSPE-mPEG conjugates (wherein the molecular weight of PEG is typically within the range of 750-5000 daltons, e.g. 2000 daltons).
  • the phospholipid composition of an exemplary PEGylated lipsome of the invention may comprise up to 5-20 mol % of PEG-lipid conjugates.
  • one or more moieties specifically targeting the liposome to a particular cell type, tissue or the like are incorporated into the membrane.
  • targeting moieties e.g., ligands, receptors and monoclonal antibodies
  • targeting moieties include hyaluronic acid, anti-ErbB family antibodies and antibody fragments, lipoprotein lipase (LPL), [a]2-macroglobulin ([a]2M), receptor associated protein (RAP), lactoferrin, desmoteplase, tissue- and urokinase-type plasminogen activator (tPA/uPA), plasminogen activator inhibitor (PAI-I), tPA/uPA:PAI-l complexes, melanotransferrin (or P97), thrombospondin 1 and 2, hepatic lipase, factor Vila/tissue-factor pathway inhibitor (TFPI), factor Villa, factor IXa, ⁇ [ ⁇ ]1-40, amyloid-[ ] precursor protein (APP), CI inhibitor, complement C3, apolipoproteinE (apoE), pseudomonas exotoxin A, CRM66, HIV -I Tat protein, rhinovirus, matrix metalloproteinase 9 (LPL), [
  • Targeting mechanisms generally require that the targeting agents be positioned on the surface of the liposome in such a manner that the target moieties are available for interaction with the target, for example, a cell surface receptor.
  • the targeting agents be positioned on the surface of the liposome in such a manner that the target moieties are available for interaction with the target, for example, a cell surface receptor.
  • the liposome is manufactured to include a connector portion incorporated into the membrane at the time of forming the membrane.
  • An exemplary connector portion has a lipophilic portion which is firmly embedded and anchored in the membrane.
  • An exemplary connector portion also includes a hydrophilic portion which is chemically available on the aqueous surface of the liposome. The hydrophilic portion is selected so that it will be chemically suitable to form a stable chemical bond with the targeting agent, which is added later. Techniques for incorporating a targeting moiety in the liposomal membrane are generally known in the art.
  • the liposome includes HSPC, cholesterol, PEG-DSPE and a combination thereof.
  • the liposome includes from about 50 mol to about 70 mol HSPC, from about 30 mol to about 50 mol cholesterol and from about 1 mol to about 10 mol PEG-DSPE. In one embodiment, the liposome includes about 60 mol HSPC, about 40 mol cholesterol and about 5 mol PEG DSPE.
  • Exemplary prodrugs of the invention provide for enhanced in vivo stability of 4- methylumbelliferone.
  • the amount of the dose of 4-MU administered to a patient via the prodrug, which is metabolized during the first passage of the prodrug through the liver is significantly reduced.
  • the amount of 4-MU undergoing first pass hepatic metabolism is less than about 75%, less than about 65%, less than about 55%, less than about 45%, less than about 35%, less than about 25% or less than about 15% of the total administered dose of 4-MU.
  • the 4-methylumbelliferone prodrug upon oral administration to a subject in need thereof, is taken up by the subject's intestinal lymphatic system and passed thence into the plasma.
  • at least about 15%, at least about 25%, at least about 35%, at least about 45%, at least about 55%, at least about 65%, at least about 75% of the administered dose of 4-methylumbelliferone is taken up by the subject's intestinal lymph system and passed thence into the subject's plasma.
  • an exemplary formulation is an oral or parenteral formulation.
  • the invention provides a pharmaceutical formulation of the lipid based drug delivery system incorporating the 4-MU prodrug.
  • the formulation includes the lipid based drug delivery system combined with a pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carriers” as used herein are those media generally acceptable for use in connection with the administration of lipids and liposomes, including liposomal drug formulations, to mammals, including humans.
  • Pharmaceutically acceptable carriers are generally formulated according to a number of factors well within the purview of the ordinarily skilled artisan to determine and account for, including without limitation: the particular active drug substance and/or second drug or label substance used, the liposome preparation, its concentration, stability and intended bioavailability; the disease, disorder or condition being treated with the liposomal composition; the subject, its age, size and general condition; and the composition's intended route of administration, e.g., nasal, oral, ophthalmic, subcutaneous, intramammary, intraperitoneal, intravenous, or intramuscular.
  • Exemplary pharmaceutically acceptable carriers used in parenteral drug administration include, for example, D5W, an aqueous solution containing 5% weight by volume of dextrose, and physiological saline.
  • Pharmaceutically acceptable carriers can contain additional ingredients, for example those which enhance the stability of the active ingredients included, such as preservatives and anti-oxidants.
  • the pharmaceutical formulation of the invention is an oral dosage formulation providing bioavailable 4-MU to a subject to whom it is administered via an oral route.
  • the pharmaceutical formulation of the invention is a parenteral dosage formulation providing bioavailable 4-MU to a subject to whom it is administered via a parenteral route.
  • Exemplary formulations of the invention provide for enhanced in vivo stability of 4- methylumbelliferone.
  • the amount of the dose of 4-MU administered to a patient via the formulation, which is metabolized during the first passage of the prodrug through the liver is significantly reduced.
  • the amount of 4-MU undergoing first pass hepatic metabolism is less than about 75%, less than about 65%, less than about 55%, less than about 45%, less than about 35%, less than about 25% or less than about 15% of the total administered dose of 4-MU.
  • the 4-methylumbelliferone prodrug formulation upon oral administration to a subject in need thereof, provides 4-MU, which is taken up by the subject's intestinal lymphatic system as the prodrug and passed thence into the plasma.
  • 4-MU which is taken up by the subject's intestinal lymphatic system as the prodrug and passed thence into the plasma.
  • at least about 15%, at least about 25%, at least about 35%, at least about 45%, at least about 55%, at least about 65%, at least about 75% of the administered dose of 4-methylumbelliferone is taken up by the subject's intestinal lymph system and passed thence into the subject's plasma.
  • an exemplary formulation is an oral or parenteral formulation.
  • the formulation is a unit dosage formulation, which is formulated to provide a therapeutically effective amount of 4-MU following a single administration of the unit dosage formulation.
  • the formulation is formulated as an infusion formulation. This formulation provides a therapeutically effective amount of 4-MU to a subject to whom it is administered over a protracted period, e.g., at least about lh, at least about 3h, at least about 5h, at least about 7h, or at least about 24 hours
  • the invention provides a method of treating a proliferative disorder, e.g., a cancer, in a subject, e.g., a human, the method comprising administering a composition that comprises a pharmaceutical formulation of the invention to a subject in an amount effective to treat the disorder, thereby treating the proliferative disorder.
  • a proliferative disorder e.g., a cancer
  • a subject e.g., a human
  • the method comprising administering a composition that comprises a pharmaceutical formulation of the invention to a subject in an amount effective to treat the disorder, thereby treating the proliferative disorder.
  • the pharmaceutical formulation is administered in combination with one or more additional anticancer agent, e.g., chemotherapeutic agent, e.g., a chemotherapeutic agent or combination of chemotherapeutic agents described herein, and radiation.
  • additional anticancer agent can be external to the lipid formulation or it can be a component of a single formulation, e.g., encapsulated within a liposome.
  • the cancer is a cancer described herein.
  • the cancer can be a cancer of the bladder (including accelerated and metastatic bladder cancer), breast (e.g., estrogen receptor positive breast cancer; estrogen receptor negative breast cancer; HER- 2 positive breast cancer; HER-2 negative breast cancer; progesterone receptor positive breast cancer; progesterone receptor negative breast cancer; estrogen receptor negative, HER-2 negative and progesterone receptor negative breast cancer (i.e., triple negative breast cancer); inflammatory breast cancer), colon (including colorectal cancer), kidney (e.g., transitional cell carcinoma), liver, lung (including small and non-small cell lung cancer, lung
  • adenocarcinoma and squamous cell cancer genitourinary tract
  • ovary including fallopian tube and peritoneal cancers
  • cervix e.g., prostate, testes, kidney, and ureter
  • lymphatic system e.g., rectum, larynx
  • pancreas including exocrine pancreatic carcinoma
  • esophagus stomach, gall bladder, thyroid
  • skin including squamous cell carcinoma
  • brain including glioblastoma multiforme
  • head and neck e.g., occult primary
  • soft tissue e.g., Kaposi's sarcoma (e.g., AIDS related Kaposi's sarcoma), leiomyosarcoma, angiosarcoma, and histiocytoma).
  • Kaposi's sarcoma e.g., AIDS related Kaposi's sarcoma
  • the cancer is multiple myeloma or a solid tumor.
  • the pharmaceutical formulation of the invention includes carfilzomib as the sparingly water-soluble therapeutic agent.
  • an "effective amount” or “an amount effective” refers to an amount of the pharmaceutical formulation of the invention which is effective, upon single or multiple dose administrations to a subject, in treating a cell, or curing, alleviating, relieving or improving a symptom of a disorder.
  • An effective amount of the composition may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual.
  • An effective amount is also one in which any toxic or detrimental effects of the composition are outweighed by the
  • the term "prevent” or "preventing” as used in the context of the administration of an agent to a subject refers to subjecting the subject to a regimen, e.g., the administration of a pharmaceutical formulation of the invention such that the onset of at least one symptom of the disorder is delayed as compared to what would be seen in the absence of the regimen.
  • the term "subject” is intended to include human and non-human animals.
  • exemplary human subjects include a human patient having a disorder, e.g., a disorder described herein, or a normal subject.
  • non-human animals includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc.
  • the term "treat" or "treating" a subject having a disorder refers to subjecting the subject to a regimen, e.g., the administration of a pharmaceutical formulation of the invention such that at least one symptom of the disorder is cured, healed, alleviated, relieved, altered, remedied, ameliorated, or improved. Treating includes administering an amount effective to alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder or the symptoms of the disorder. The treatment may inhibit deterioration or worsening of a symptom of a disorder.
  • the lipophilic 4-MU ester derivatives are synthesized, purified, and the structures of prodrugs are confirmed.
  • the conversion of the prodrugs into the parent 4MU is measured in vitro in serum from three different species: human, rat and mouse.
  • Each of the prodrug compounds is formulated in a lipid-based system to enable their administration via the oral route directed towards the intestinal lymphatic system.
  • Four different lipid based drug delivery systems are used: an emulsion system, a micelle system, a solid lipid nanoparticle and a liposome.
  • the components of these systems can be selected from glycerylmonosterate, glycercyl tricapsylate, tripalmitin, soy lecithin, hydrogenated soy phosphatidylcholine, cholesterol, Compritol® 888 ATO, PEG400, poloxamer 188®, polyvinyl alcohol, PEG- stearate, Soluplus, Tween 20, Tween 40, Tween 60, Tween 80, l,2-distearoyl-OT-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000], and others known to those skilled in the art (Kalepu et al, 2013).
  • the compounds are synthesized by standard chemical routes (Jacks et al., Trevaskis 1967), starting from MU or MU phosphate (Heiati et al, 1997).
  • the saturated acyl chains enable the target prodrugs to be crystallized.
  • the synthesized MU prodrugs are characterized by: melting point, elemental analysis, proton and carbon NMR, MALDI TOF, TLC and HPLC analysis (Perttu et al., 2012; Kohli et al, 2014).
  • the hydrophobic portion of the MU prodrugs enables their insertion into a lipid phase.
  • the enzymatic hydrolysis studies solubilize the prodrugs in a detergent micelle, and incubation in animal (mouse, rat and human) serum for various times at 37 °C.
  • the products of the reactions are assayed by the HPLC assay (Kohli et al, 2014).
  • the simple esters are only slowly hydrolyzed in serum.
  • the phosphodiester derivative is a good substrate of serum phosphatases so will be more rapidly hydrolyzed by serum esterases/phosphatases (Kohli et al, 2014).
  • the phosphodiester prodrug MUPT might also be a substrate of prostate specific acid phosphatases secreted by prostate tumors, which might enhance their delivery into prostate tumors.
  • the prodrugs that are substrates for serum esterases or phosphatases are formulated in three of the four LBDDS.
  • the LBDDS formulation area has been extensively reviewed (Porter et al, 2008; Trevaskis, 2008; Kalepu et al, 2013) over the past decade.
  • the simple formulation of the invention solubilizes a therapeutic amount of MU prodrug, provides a reasonable shelf-life, contains approved excipients, and facilitates dispersion of the dose in the intestine to present the prodrug in such a way that the prodrug is taken up by the intestinal lymphatic system where the prodrug might be incorporated into lipoproteins.
  • Exemplary systems of the invention include: detergent micelles/lipid emulsion, liposomes prepared from palmitoyloleoylphosphatidyl choline, and solid lipid nanoparticles prepared from steric acid.
  • Serum level of MU, MU prodrug and MU metabolites in mouse serum at 4 hours post- dosing Serum level of MU, MU prodrug and MU metabolites in mouse serum at 4 hours post- dosing.
  • each formulation of each prodrug (3 X 3) plus one MU control group is gavaged into the stomach of C57BL6 female mice at a dose level of 200 mg/kg MU equivalents. There are four mice in each group. Animals are sacrificed at 4 hours post dosing and serum levels of the prodrug, MU and MUG are determined by the HPLC assay. The four-hour sampling time point is selected based upon absorption of a fluorescent lipid from a LBDDS (Yuan et al., 2007). The total number of animals in this study is 40. 10 additional animals are included in the protocol in the event animals are removed from the study due to unexpected events.

Abstract

Les pro-médicaments lipophiles de 4-méthylumbelliférone sont incorporés dans des systèmes d'administration de médicament à base de lipides (par exemple, des émulsions, des micelles, des liposomes et des particules lipidiques). La formule protège le 4-méthylumbelliférone du métabolisme hépatique de premier passage à 4-MUG. Les formules sont, à titre d'exemple, des formules orales et parentérales. L'invention porte sur des méthodes de traitement de maladies prolifératives, tels que le cancer, par l'administration de la formule à un sujet en ayant besoin.
PCT/US2017/040282 2016-07-01 2017-06-30 Synthèse de nouveaux pro-médicaments de méthylumbelliférone et leur inclusion dans des formules d'administration de médicaments à base de lipides. WO2018005963A1 (fr)

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