WO2017006279A1 - Compositions et complexes de cyclodextrine-polymère et leurs procédés de préparation et d'utilisation - Google Patents

Compositions et complexes de cyclodextrine-polymère et leurs procédés de préparation et d'utilisation Download PDF

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Publication number
WO2017006279A1
WO2017006279A1 PCT/IB2016/054086 IB2016054086W WO2017006279A1 WO 2017006279 A1 WO2017006279 A1 WO 2017006279A1 IB 2016054086 W IB2016054086 W IB 2016054086W WO 2017006279 A1 WO2017006279 A1 WO 2017006279A1
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compound
cyclodextrin
alkyl
independently
hydroxyalkyl
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PCT/IB2016/054086
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English (en)
Inventor
Aditya Kulkarni
Niren Murthy
Santanu MAITY
Soniya JOHNY
Princy KHURANA
Manu MANJUNATH
Priya CHOUDHARY
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Aten Porus Lifesciences
The Regents Of The University Of California
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Publication of WO2017006279A1 publication Critical patent/WO2017006279A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/554—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A61K47/585—Ion exchange resins, e.g. polystyrene sulfonic acid resin
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/16—Cyclodextrin; Derivatives thereof

Definitions

  • the present disclosure is in the field of biomedical, pharmaceutical and polymeric sciences, including the synthesis of a macromolecular therapeutic agents and processes for preparing such agents.
  • the disclosure relates to conjugates of pendant polymers capable of forming guestrhost complexes with cyclodextrins or cyclodextrin derivatives, method of preparing such conjugates, and the use of such conjugates in the treatment of diseases including lipid storage disorders.
  • the present conjugates possess improved properties including but not limiting to prolonged duration of action in cells and increased efficacy in removal of lipids (e.g., cholesterol) from cel ls. BACKGROUND
  • Lipid storage diseases are a group of inherited metabolic disorders in which harmful amounts of lipids accumulate in various cells and tissues in the body. People with these disorders typically exhibit an elevated level of cholesterol in tissues of the body, since these people either do not produce adequate quantities of one or more enzymes needed to metabolize lipids, or they produce enzymes that do not function properly to remove lipids. In recent years, sedentary lifestyles and poor diet habits have also become factors leading to lipid storage disorders.
  • NPC Niemann-Pick type C disorder
  • Hydrophilic molecules such as cyclodextrin, which are generally employed to treat lipid storage disorders undergo rapid clearance from the bloodstream due to their high water solubility. Therefore, to maintain a minimum effective concentration of a therapeutic drug, usually high concentrations/doses or repeated administration of these hydrophilic drugs are required to be administered to the subject. Administration of higher concentrations/doses of any therapeutic agent/drug to the subject may lead to toxicity and adverse effects to various organs of the subject. Thus, hydrophilic therapeutic agents suffer drawbacks stemming from rapid clearance from the body.
  • R 1 is independently 2-hydroxy propyl, 1 -hydroxy methyl, OH, CO?H
  • P is a polymer
  • X 1 , X 2 and X J are each backbone moieties;
  • L 1 , L 2 , L 3 and K. are each linker moieties, wherein each of L f , L 2 and L 3 may he present or absent, provided at least one of L l , L 2 and L 3 is present;
  • H is host moiety attached directly to the backbone moiety or via the linker moiety
  • CD is a cyclodextrin, or a derivative thereof; wherein CD is non- covalently conjugated to H; m, n and o are each independently from 0 to 1000, wherein at least one of m, n and o is at least 4; and v, z and y are each independently 0 to 500,
  • the present disclosure provides a compound comprising the following structur
  • R 1 is independently 2 -hydroxy propyl, 1 -hydroxy methyl, OH, C0 2 H or H 2 ;
  • P is a polymer
  • X 1 , X 2 and X ' ' are each backbone moieties;
  • L 1 , L 2 , L J and K are each linker mo eties, wherein each of L 1 , L, 2 and V may be present or absent, provided at least one of L l , L 2 and L 3 is present;
  • CD is a cyclodextrin, or a derivative thereof wherein each CD is cova!ently attached to respective L 1 , L 2 , L 3 ; and m, n and o are each independently from 0 to 1000, wherein at least one HI, n and o is at least 4; and v, z and y are each independently 0 to 500,
  • the present disclosure provides a compound selected from:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutical excipient and a compound as described herein,
  • the pharmaceutical composition can further comprising a therapeutically active agent.
  • the present disclosure provides a method of treating a disease or a condition associated with abnormal NPCl and'Or NPC2 protein production, comprising administering to a subject in need thereof a compound or a composition as described herein, [0014] The present disclosure provides a method of treating lipid storage disorder comprising administering to a subject in need thereof a compound or a composition as described herein.
  • the present disclosure provides a method of treating Niemann-Pick disease, comprising administering to a subject in need thereof a compound or a composition as described herein,
  • the present disclosure provides a compound as described herein where the compound has an elimination half-life of from about 6 hours to about 24 hours.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described herein and a therapeutically active agent, wherein the bioavailability of the therapeutically active agent is impro ved.
  • Figure 1 represents ⁇ -cyclodextrin (CD), Hydroxy propyl-p-cyclodextrin ( ⁇ - ⁇ -CD) and Sulfobutyl ether beta-cyclodextrin (SBE- -CD).
  • Figure 2 represents different types of polymers, namely poly(vinyl alcohol) [left] and polyketal [center] and polyethylene glycol [right].
  • Figure 3 represents different types of endcapping group(s) hydrophobic moieties, namely adamantane carboxylate [left], nor-adamantane carboxylate
  • Figure 4 represents different types of linker group(s), namely ester, amide, carbonate carbamate and carbonyl.
  • Figure 5 represents the general structure of covalent conjugates of Cyclodextrin Pendant Polymers.
  • Figure 6 represents the general structure of non-covalent conjugates of Cyclodextrin Pendant Polymers.
  • Figure 7 represents different types of polymers covalently conjugated with cyclodextrin, namely (PEG-Glycine-(Lysine-p-CD) 9 ) [left] and Polyvinyl alcohol) ⁇ ([i-CD) 75 [right] .
  • Figure 8 represents pADK polymer and graphical image represents the microparticles of pADK polymer non-co valently conjugated with cyclodextrin.
  • Figure 9 represents schematic synthesis of pADK monomers and polymers.
  • Figure a represents schematic synthesis of 2,2-dipropergyloxy- propane
  • Figure 9b represents schematic synthesis of pADK polymers.
  • Figure 10 represents different types of pendent polymeric backbone (PPB) non-covalently conjugated with cyclodextrin: Polyvinyl alcohol)-(Adamantane) 65 [left], cyclodextrin: PE(j-Glycine-( Lysine- Adamantane) 9 [center] and cycl.odextrin:PEG-Glycine-(Lysine-Cholesterol)9 [right] cycl.odextrin:pADK polymer.
  • PPB pendent polymeric backbone
  • Figure 11 represents schematic mechanism of cholesterol mobilization from NPC cells by cyclodextrin pendant polymers.
  • Figure 12 represents pADK niicroparticle response to methyl-p-CD.
  • the terms “about” and/or “approximately” may be used in conjunction with numerical values and/or ranges.
  • the term “about” is understood to mean those values near to a recited value.
  • “about 40 [units]” may mean within ⁇ 25% of 40 (e.g., from 30 to 50), within ⁇ 20%, ⁇ 15%, ⁇ 10%, ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, ⁇ ! %, less than ⁇ 1%, or any other value or range of values therein or there below.
  • the phrases “less than about [a value]” or “greater than about [a value]” should be understood in view of the definition of the term “about” provided herein.
  • the terms “about” and “approximately” may be used interchangeably.
  • ranges are provided for certain quantities. It is to be understood that these ranges comprise all sub-ranges therein. Thus, for example the range “from 50 to 80" includes all possible ranges therein (e.g., 51 -79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).
  • a kinase inhibitor refers to one or more kinase inhibitors or at least one kinase inhibitor.
  • a kinase inhibitor refers to one or more kinase inhibitors or at least one kinase inhibitor.
  • the terms “a” (or “an”), “one or more” and “at least one” are used interchangeably herein.
  • treating means one or more of relieving, alleviating, delaying, reducing, reversing, improving, or managing at least one symptom of a condition in a subject.
  • the tenn “treating” may also mean one or more of arresting, delaying the onset (i.e., the period prior to clinical manifestation of the condition) or reducing the risk of developing or worsening a condition.
  • an “effective amount” means the amount of a formulation according to the invention that, when administered to a patient for treating a state, disorder or condition is sufficient to effect such treatment.
  • the “effective amount” will vary depending on the active ingredient, the state, disorder, or condition to be treated and its severity, and the age, weight, physical condition and responsiveness of the mammal to be treated.
  • terapéuticaally effective applied to dose or amount refers to that quantity of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof.
  • substantially refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result.
  • an object that is “substantially” enclosed would mean that the object is either completely enclosed or nearly completely enclosed.
  • the exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking, the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained.
  • the use of “substantially” is equally applicable when used in a negative connotation to refer to the complete or near complete lack of action, characteristic, property, state, structure, item, or result.
  • compositions that is "substantially free of other active agents would either completely lack other active agents, or so nearly completely lack other active agents that the effect would be the same as if it completely lacked other active agents.
  • a composition that is "substantially free of an ingredient or element or another active agent may still contain such an item as long as there is no measurable effect thereof
  • Amino refers to the -NH 2 radical.
  • Cyano refers to the CN radical.
  • Halo or halogen refers to bromo, chloro, fluoro or iodo radical.
  • Niro refers to the NO 2 radical.
  • Alkyl or "alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a CI -CI 2 alkyl, an alkyl comprising up to 10 carbon atoms is a CI -CIO alkyl, an alkyl comprising up to 6 carbon atoms is a C1-C6 alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl.
  • a C1-C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and CI alkyl (i.e., methyl).
  • a C1-C6 alkyl includes all moieties described above for C1 -C5 alkyls but also includes C6 alkyls.
  • a CI -CIO alkyl includes all moieties described above for C1-C5 alkyls and C1-C6 alkyls, but also includes C7, C8, C9 and C O alkyls.
  • a C1- C12 alkyl includes all the foregoing moieties, but also includes CI 1 and CI 2 alkyls.
  • Non-limiting examples of CI -CI 2 alkyl include methyl, ethyl, n-propyl, i- propyl, sec-propyl, n-butyl, i butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n- heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl.
  • an alkyl group can be optionally substituted
  • Alkylene or "alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms.
  • C1-C12 alkylene include methylene, ethylene, propylene, n butylene, ethenylene, propenylene, n butenylene, propynylene, n butynylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkvlene chain can be optionally substituted.
  • alkenyl or “alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included.
  • An alkenyl group comprising up to 12 carbon atoms is a C2-C12 alkenyl
  • an alkenyl comprising up to 10 carbon atoms is a C2- CIO alkenyl
  • an alkenyl group comprising up to 6 carbon atoms is a C2-C6 alkenyl
  • an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl.
  • a C2-C5 alkenyl includes C5 alkenyls, C4 alkenyl s, C3 alkenyls, and C2 alkenyls.
  • a C2-C6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes C6 alkenyls.
  • a C2-C10 alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C6 alkenyls, but also includes CI, C8, C9 and CIO alkenyls.
  • a C2-C12 alkenyl includes all the foregoing moieties, but also includes CI 1 and C12 alkenyls.
  • Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), 1 -propenyl, 2-propenyl (allyl), iso-propenyl, 2 -methyl- 1- propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4- pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1 -heptenyl, 2- heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3- octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3- nonenyl,
  • alkyl group can be optionally substituted.
  • alkenylene or "alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds.
  • C2 ⁇ C12 alkenylene include ethene, propene, butene, and the like.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
  • alkenylene chain can be optionally substituted.
  • "Aikynyi” or “alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included.
  • An alkynyl group comprising up to 12 carbon atoms is a C2-C12 alkynyl
  • an alkynyl comprising up to 10 carbon atoms is a C2- C10 alkynyl
  • an alkynyl group comprising up to 6 carbon atoms is a C2-C6 alkynyl
  • an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl.
  • a C2-C5 alkynyl includes C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls.
  • a C2-C6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes C6 alkynyls.
  • a C2-C10 alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes C7, C8, C9 and CIO alkynyls.
  • a C2-C 12 alkynyl includes all the foregoing moieties, but also includes Cl l and C12 alkynyls.
  • Non-limiting examples of C2-C12 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.
  • Alkynylene or "alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds.
  • C2- C12 alkynylene include ethynyl ene, propargylene and the like.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted.
  • Alkoxy refers to a radical of the formula ORa where Ra is an alkyl, alkenyl or alknyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.
  • Alkylamino refers to a radical of the formula - i [Ra or -NRaRa where each Ra is, independently, an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted.
  • a non-limiting example of an alkyl carbonyl is the methyl carbonyl ("acetal") moiety.
  • Aikyicarbonyl groups can also be referred to as "Cw-Cz acyl” where w and z depicts the range of the number of carbon in Ra, as defined above.
  • CI -CIO acyl refers to aikyicarbonyl group as defined above, where R a is C I -CI O alkyl, CI -CIO alkenyl, or CI -CIO alkynyl radical as defined above. Unless stated otherwise specifically in the specification, an alkyl carbonyl group can be optionally substituted.
  • Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring.
  • the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems.
  • Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fiuorene, as-indacene, s indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • aryl is meant to include aryl radicals that are optionally substituted.
  • Aralkyl or "arylalkyl” refers to a radical of the formula -R b ⁇ R c where 3 ⁇ 4 is an al.kyl.ene group as defined above and Rc is one or more aryl radicals as defined above, for example, benzyl, diphenylmeihyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.
  • alkenyl or "arylalkenyl” refers to a radical of the formula -Rb-R c where R b is an alkenylene o group as defined above and Rc is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkenyl group can be optionally substituted.
  • alkynyi or "arylalkynyl” refers to a radical of the formula -R -R c where Rb is an alkynyiene group as defined above and Rc is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkynyi group can be optionally substituted.
  • Carbocyclyl refers to a rings structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkvl. cvcloalkenyl and cycloalkynvl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.
  • Cycioalkyl refers to a stable non aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Monocyclic cycioalkyl radicals include, for example, cyclopropyl, cyclobutyL cyclopentyl, cyclohexyi, cycloheptyl, and cyclooctyl.
  • Polycyclic cycioalkyl radicals include, for example, adamantyl, norbornyl, deealinyl, 7,7 dimethyl bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted,
  • Heterocyclyl refers to a stable 3 to 20 membered non aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclycl or heterocyclic rings include heteroaryls as defined below.
  • the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated.
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, mienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2 oxopiperazinyl, 2 oxopiperidinyl, 2 oxopyrrolidmyl, oxazolidinyl, piperidinyl, piperazinyl, 4 piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 oxox
  • N-heterocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a N- heterocyclyl. group can be optionally substituted.
  • Heteroaryl refers to a 5 to 20 membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
  • the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazoiyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l ,4]dioxepinyl, 1,4 benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2 ajpyridinyi, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiopheny
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group can be optionally substituted.
  • Heteroarylalkyl refers to a radical of the formula Rb-Rf where Rb is an alkylene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group can he optionally substituted,
  • Thioalkyl refers to a radical of the formula -SRa where Ra is an alkyl, alkenyl, or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group can be optionally substituted.
  • substituted means any of the above groups (i. e., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyi, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycioalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, V-heteroaryl and'Or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, CI, Br, and I; an oxygen atom in groups such as hydroxy!
  • a non-hydrogen atoms such as, but not limited to:
  • a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups
  • a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines
  • a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups,
  • Substituted also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple- bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyL and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitril.es.
  • a higher-order bond e.g., a double- or triple- bond
  • nitrogen in groups such as imines, oximes, hydrazones, and nitril.es.
  • R g and R h are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyialkyl, haloalkyl, haloalkenyi, haloalkynyl, heterocyclyl, iV-heierocyclyL helerocyclylalkyl, heteroaryl, jV-heteroaryl and/or heteroaryialkyl , "Substituted" further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxy!, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino,
  • a point of attachment bond denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond.
  • “ " indicates that the chemical entity "XY” is bonded to another chemical entity via the point of attachment bond.
  • the specific point of attachment to the non depicted chemical entity can be specified by inference. For example, the compound C3 ⁇ 4R J , wherein
  • R J is H or " I " infers that when R is "XY", the point of attachment bond is the same bond as the bond by which R 3 is depicted as being bonded to CHU.
  • the present disclosure is addressed to the aforementioned needs of the art and provides gues host complexes and their application as a therapeutic agent containing drug delivery system useful for removing cholesterol from the cells,
  • the guest includes but is not limited to a polymer.
  • the host includes but is not limited to niacrocyclic compounds, wherein said macrocyclic compound is cyclodextrin or its derivatives.
  • the present disclosure relates to pendant polymer: cyclodextrin conjugates.
  • the polymer of the aforesaid pendant polymerxyclodextrin conjugate comprises a polymer backbone that is modified with ⁇ -cyclodextrin or its derivative.
  • the polymerxyclodextrin conjugate is a covalent conjugate or a non-covalent conjugate.
  • the polymerxyclodextrin conjugate includes but is not limited to "covalent conj ugates of polymers with cyclodextrin" and "non-co valent conjugates of polymers with cyclodextrin” and their combination.
  • the polymer is attached to the cyclodextrin through a linker.
  • the covalent polymerxyclodextrin conjugate is represented as polymer-linker-cyclodextrin.
  • hydrophobic moiety of a Pendant Polymeric Backbone is complexed with cyclodextrin, wherein the PPB is composed of polymer attached with hydrophobic moiety through linker i.e. polymer-linker-hydrophobic moiety.
  • linker i.e. polymer-linker-hydrophobic moiety.
  • polymencyclodextrin conjugate As used herein, the expressions "polymencyclodextrin conjugate”, “polymencyclodextrin complex”, “polymencyclodextrin molecule”, “conjugate of polymer with cyclodextrin”, “conjugate” and “polymencyclodextrin nanoparticle” are employed interchangeably within the instant disclosure and refer to the polymencyclodextrin compound/therapeutic molecule/product of the instant disclosure.
  • covalent polymer As used herein, the expressions "covalent polymer”, “covalent conjugate”, “covalent complex”, “covalent conjugate of polymer with cyclodextrin” and “Covalent Cyclodextrin Polymer” are employed interchangeably within the instant disclosure and refer to complex containing polymer covalently linked with cyclodextrin.
  • non-covalent polymer As used herein, the expressions "non-covalent polymer”, “non-covalent conjugate”, “non-covalent complex”, “non-covalent conjugate of polymer with cyclodextrin” and “non-covalent Cyclodextrin Polymer” are employed interchangeably within the instant disclosure and refer to complex containing polymer non-covalently linked with cyclodextrin.
  • R 1 is independently 2 -hydroxy propyl, 1 -hydroxy methyl, OH, C0 2 H or
  • P is a polymer
  • X ! , X' and X 3 are each backbone moieties
  • L 1 , L 2 , L 3 and K. are each linker moieties, wherein each of L f , L 2 and L 3 may be present or absent, provided at least one of L l , L 2 and L 3 is present;
  • H is host moiety attached directly to the backbone moiety or via the linker moiety
  • CD is a cyciodexirin, or a derivative thereof wherein CD is non- covalently conjugated to H; m, n and o are each independently from 0 to 1000, wherein at least one of m, n and o is at least 4; and v, z and y are each independently 0 to 500, [0079]
  • each instance of X 1 , X 2 and X 3 is independently selected from (Cj-C 4 alkyl)-0- (C. -C4 aikyl)-()-(CrC 4 alkyl), (C C 4 alkyl)-0-(C C alkyl), peptide, Gly-Lys,
  • linker moiety or hydrophobic moiety is directly attached to CI carbon of cyclic ketal moiety; and wherein when X ! or X 2 or X 3 is independently
  • linker moiety or hydrophobic moiety is directly attached to C3 carbon of pentane chain.
  • L l , L 2 , L J and K independently is selected from an alkyl ester, an alkyl amide, an alkyl carbonate, an alkyl carbamate,
  • Ar 1 is an optionally substituted 5- or 6- membered aryl, heteroaryl comprising 1, 2, 3 or 4 heteroatoms individually selected from N, O, and S,
  • Ar 1 is triazole
  • the polymer is selected from poly vinyl alcohol, polyketal or polyethylene glycol.
  • the cyclodextrin or its derivative employed in the conjugate includes but is not limited to ⁇ - cyclodextrin ( Figure 1), a-cyclodextrin, ⁇ -cyclodextrin, derivatives thereof, or combinations thereof.
  • the cyclodextrin derivative is selected from a group comprising Hydroxy propyl ⁇ -cyclodextrin ( ⁇ - ⁇ -CD), Sulfobutyl ether-P-cyclodextrin (SBE-P-CD), Methyl ⁇ -eydodextrin (Me ⁇ P ⁇ CD, and other charged or uncharged derivatives of ⁇ -CD derivatives thereof, or combinations thereof.
  • the alky] group in hydroxyalkyl-a-cyclodextrin, hydroxyalkyl- -cyclodextrin, hydroxyalkyl- ⁇ - cyclodextrin or their derivatives is selected from Ci ⁇ Cio l nea alkyl, Ci-C 10 branched alkyl or Cj -Cio cycloalkyl, each having one or more optional substituents.
  • the H is selected from cycloalkyl, heterocycloalkyl, aryl or heterocyloaryl.
  • the H is adamantine, noradamantane or cholesterol .
  • m, n and o are each independently from 0 to 1000.
  • m, n and o are each independently from 0 to 100.
  • n, n and o are each independently from 3 to 30.
  • m, n and o are each independently from 10 to 100.
  • m, n and o are each independently from 15 to 65. [0093] In still another preferred embodiment, m, n and o are each independently from 20 to 30,
  • n, n and o are each independently from 50 to 65, [0095]
  • the present disclosure provides a compound comprising the following structure:
  • R 1 is independently 2-hydroxy propyl, 1 -hydroxy methyl, OH, CO?H or
  • P is a polymer
  • X 1 , X 2 and X J are each backbone moieties
  • L 1 , If, If and K are each linker moieties, wherein each of L 1 , L 2 and L 3 may be present or absent, provided at least one of L f , L 2 and L 3 is present;
  • CD is a cyclodextrin, or a derivative thereof, wherein each CD is covalently attached to respective L 1 , If, If: and m, n and o are each independently from 0 to 1000, wherein at least one of m, n and o is at least 4; and V, z and y are each independently 0 to 500,
  • each instance of X 1 , X 2 and X 3 is independently selected from C 1 -C4 alkyl, Ci-C 4 alkoxy, Ci-C 4 hydroxyaikyi, (Ci-C 4 alkyl)-0-(Ci-C 4 alkyl)-0-(Ci-C 4 alkyl), (CVC 4 alkyl)-0-(Ci- C 4 alkyl), alkyl ester, peptide, Gly-Lys, or an amino acid; wherein when X ! or or X J is independently Gly-Lys, the linker moiety is attached to omega amino group of Lysine.
  • the polymer includes but is not limited to polyketal, poly(vinyl alcohol), polyethylene glycol, polysaccharide, polyester, polycarbonate, or polyamide, and combinations thereof,
  • the polymer is selected from a group comprising polvketal, polyvinyl alcohol) and polyethylene glycol (Figure 2),
  • the cyclodextrin or a derivative thereof is selected from a-cyclodextrin, ⁇ -cyclodextrin, ⁇ - cyclodextrin, hydroxyalkyl-a-cyclodextrin, hydroxyalkyl-p-cyclodextrin, hydroxyalkyl-y-cyclodextrm, derivatives thereof, or combinations thereof.
  • L 2 and L 3 independently is selected from an alkyl, an alkyl ester, an alkyl amide, an alkyl carbonate, an alkyl carbamate, or Ar 1 , wherein Ar 5 is an optionally substituted 5- or 6- membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms individual ly selected from N, (), and S.
  • Ar 1 is an optionally substituted triazole or
  • m, n and o are each independently from 0 to 1000.
  • m, n and o are each independently from 0 to 100.
  • n, n and o are each independently from 3 to 30.
  • m, n and o are each independently from 10 to 100.
  • m, n and o are each independently from 15 to 65.
  • m, n and o are each independently from 20 to 30.
  • m, n and o are each independently from 50 to 65.
  • the polymers of the present invention can be long circulating, biocompatible, and can substantially increase cholesterol clearance from cells, specifically NPC deficient cells. Further, the said polymers can deliver multiple "copies/units" of cyclodextrin or its derivatives e.g., ⁇ - € ⁇ / ⁇ - ⁇ - € ⁇ /8 ⁇ - ⁇ -CD to the lysosomes of cells.
  • the linker employed in the conjugate includes but is not limited to bio-degradable linker.
  • the linker is selected from a group comprising acetal, amide, ketal, orthoester, ester, vinyl ether, carbamate, carbonyl, hydrazine, triazole, phenoxy, and combinations thereof,
  • the hydrophobic moiety employed in the conjugate includes but is not limited to cholesterol, adamantane, noradamantane, cyciohexane, dodecane, its derivatives and combinations thereof.
  • the covalent polymerxyclodextrin conjugate of the present disclosure is provided in Figure 7, PEG-[Glycine- (Lysine- -CD)]9 and Polyvinyl alcohoi)-trz-(P-CD) 7 5 and the non-covalent polymer: cyclodextrin conjugate of the present disclosure is provided in Figures 8, (conjugate of Polyadamantane-trz-ketal and ⁇ -cyclodextrin). Pendent polymeric backbone (PPB) viz.
  • polymer-linker-hydrophobic moiety of non-covalent polymerxyclodextrin conjugates of the present disclosure is provided in Figures 8 and 10, Polyadamantane-trz-ketal, Polyfvinyl alcohol)-(Adamantane) 6 5, PEG- [Glycine-(Lysine-Adamantane)]9 and PEG-[Glyci.ne-(Lysine-Cholesterol.)]9. )1 J 5]
  • the present disclosure provides a compound selected from:
  • non-covaleni polymencyclodextrin conjugates comprising polymer, linker, hydrophobic moiety and cyclodextrin.
  • the non-covalent conjugate is represented as polymer-linker-hydrophobic moiety-cyclodextrin ( Figure 6).
  • the polymer, linker, hydrophobic moiety and cyclodextrin groups of the non-covalent polymerxyclodextrin conjugates are selected from the groups/alternatives provided in the above embodiments.
  • the non-covalent polymerxyclodextrin conjugate of the present disclosure comprises polyketal as the polymer along with linker, adamantane as the hydrophobic moiety and cyclodextrin.
  • the present disclosure provides polyketal polymer based non-covalent conjugates of polymerxyclodextrin.
  • the polyketal polymer based non-covalent conjugate comprises polyketal, triazole based linker, adamantane and cyclodextrin.
  • a polyketal polymer based non- covalent conjugate is provided in Figure 8.
  • the non- covalent conjugate comprises 'ketal or polyketal' in combination with any linker, hydrophobic moiety and cyclodextrin/cyclodextrin derivative.
  • the present disclosure further provide covalent polymerxyclodextrin conjugates.
  • said covalent conjugate comprises polymer, linker and cyclodextrin.
  • the covalent conjugate is represented as polymer-linker-cyclodextrin Figure 5.
  • the polymer, linker and cyclodextrin groups of the covalent polymerxyclodextrin conjugates are selected from the groups/alternatives provided in the previous embodiments.
  • the covalent polymerxyclodextrin conjugate of the present disclosure comprises polyketal as the polymer along with linker and cyclodextrin attached to the backbone.
  • the present disclosure provides polyketal polymer based covalent conjugates of polymerxyclodextrin.
  • the polyketal polymer based covalent conjugate comprises polyketal, triazole based linker and cyclodextrin.
  • covalent conjugate comprise 'polyketal' in combination with any linker and cyclodextrin/cyclodextrin derivative.
  • the polymencyclodextrin conjugate including covalent conjugate and non-covalent conjugate is a nanoparticle or nanocarrier system.
  • the present disclosure also relates to a process for preparing gues host complex
  • the guest includes but is not limited to polymer.
  • the host includes but is not limited to macrocyclic compounds, wherein said macrocyclic compound is cyclodextrin or its derivatives.
  • a non-limiting embodiment of the present disclosure relates to the synthesis of pendant polymer: cyclodextrin complexes.
  • the aforementioned process includes but is not limited to the process for preparing "covalent conjugates of polymers with cyclodextrin" and "non-covalent conjugates of polymers with cyclodextrin” and their combination.
  • the cyclodextrin is attached directly to polymeric backbone via a linker to afford the final complex.
  • the process of preparing covalent conjugate comprises steps of:
  • Synthesis of a polymeric backbone such as polypeptide, polydisulfide, polyketal, or poly(vinyl) through synthetic techniques selected from solid phase peptide synthesis or polymerization techniques, or a combination thereof, wherein the synthesized polymer is usually designed to have a reactive modifiable linker side-chain such as an amine, hydroxy, alkyne, or azide; and
  • mono-tosylated ⁇ -CD can be used as a reactive intermediate for the displacement of the tosyl group by the reactive amine or hydroxy group.
  • linker sidechains such as alkyne or azide
  • the inverse reactive group that is, mono-azido ⁇ -CD or mono-alkynyl ⁇ -CD can be used to attach to the polymer via a 1 ,3-dipolar cycloaddition reaction.
  • representative molecules of covalent conjugates of polymers with cyclodextrin are PEG-[Glycine-(Lysine-P-CD)] 9 and Polyvinyl alcohol)-trz-(P-CD) 7 5 as shown in Figure 7.
  • cyclodextrin is complexed with hydrophobic moiety of the Pendant Polymeric Backbone (PPB) to obtain non-covalent conjugates of polymers with cyclodextrin.
  • PPB Pendant Polymeric Backbone
  • the process of preparing non-covalent conjugate comprises steps of:
  • representatives of Pendant Polymeric Backbone are polyketal-trz-adamantane (pADK) as shown in Figure 8, Polyvinyl alcohol)-(Adamantane) 6 s, PEG-[Glycine-(Lysine- Adamantanejjg and PEG-[Glycine-(Lysine-Cholesterol)]9 as shown in Figure 10.
  • pADK polyketal-trz-adamantane
  • hydrophobic groups selected from a group comprising Adamantane, Cholesterol and any other group known to form gues host complexes with cyclodextrin is attached to the polymeric backbone (guest).
  • the guest pendant polymer is then complexed with cyclodextrin or its derivative in a ratio of one pendant group to one cyclodextrin or its derivative to afford the non- covalent conjugates.
  • a non-covalent conjugate of polymer with cyclodextrin is pADK.:fi-CD is shown in Figure 8, pAD polymer repeating unit 't' value [number of repeating units] ranges from 5 to 500 and molecular weight ranges from 3000 to 300000.
  • a process for preparing pendant polymers is also provided.
  • the pendant polymers can be synthesized by first producing the polymeric backbone either by solid phase peptide synthesis, bacterial cell culture, or synthetic polymerization techniques with -OH, -SH, - N3 ⁇ 4, -N 3 , alkyne or any other functional group side chains tha can allow for easy conjugation of the guest molecule or cyclodextrin directly.
  • the present disclosure also relates to a method for managing or treating lipid storage disorders/lipidoses comprising administering a therapeutically effective amount of the host:guest conjugates such as, polymer: cyclodextrin conjugate.
  • said polymer: cyclodextrin conjugate is selected from a group comprising non-covalent conjugate, covalent conjugate, or a combination thereo Said non-covalent and covalent conjugates are described in above paragraphs of the present specification.
  • the lipid storage disorder is lysosomal lipid storage disorder.
  • the lysosomal lipid storage disorder is selected from a group comprising sphingolipidoses, and wolman disease, or any combination thereof.
  • the sphingolipidoses are selected from a group comprising Niemann-Pick type C (NPC), Fabry disease, Krabbe disease, Gaucher disease, Tay-Sachs disease, Metachromatic leukodystrophy, multiple sulfatase deficiency and Farber disease, or any combination thereof.
  • the present method is for managing or treating Niemann-Pick type C (NPC).
  • the present disclosure provides a method for managing or treating lipid storage disorder/lipidose comprising administering a therapeutically effective amount of the host: guest conjugates such as, polymerxyclodextrin conjugate, wherein said conjugate is a non-covalent conjugate or a covalent conjugate disclosure comprising polyketal as the polymer.
  • said polyketal containing non-covalent conjugate comprises polyketal polymer, linker, hydrophobic moiety and cyclodextrin or its derivative.
  • non-covalent conjugate comprises polyketal, triazole based linker, adamantane and cyclodextrin.
  • the non-covalent conjugate comprises 'polyketal' in combination with any linker, hydrophobic moiety and cyclodextrin/cyclodextrin derivative.
  • the lipid storage disorder is Niemann- Pick type C (NPC).
  • management refers to preventing a disease or disorder or condition from occurring in a subject, decreasing the risk of death due to a disease or disorder or condition, delaying the onset of a disease or disorder or condition, inhibiting the progression of a disease or disorder or condition, partial or complete cure of a disease or disorder or condition and/or adverse effect attributable to the said disease or disorder or condition, obtaining a desired pharmacologic and/or physiologic effect (the effect may be prophylactic in terms of completely or partially preventing a disorder or disease or condition, or a symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease or disorder or condition and/or adverse effect attributable to the disease or disorder), relieving a disease or disorder or condition (i.e. causing regression of the disease or disorder or condition).
  • the present disclosure also provides a pharmaceutical composition or formulation comprising a therapeutically effective amount of polymerxyclodextrin conjugate, optionally along with excipient(s).
  • the excipient is selected from a group comprising, but not limited to, granulating agent, binding agent, lubricating agent, disintegrating agent, sweetening agent, glidant, anti- adherent, anti-static agent, surfactant, anii-oxidant, gum, coating agent, coloring agent, flavouring agent, coating agent, plasticizer, preservative, suspending agent, emulsifying agent, plant cellulosic material, spheronization agents and combinations thereof.
  • the pharmaceutical composition further comprises a therapeutically active agent.
  • the pendent polymer:cyclodextrin conjugates are administered by mode selected from group comprising intravenous, subcutaneous, transdermal, intrathecal, oral and any other compatible mode, or any combination thereof.
  • the pharmaceutical composition/formulation is formulated into forms selected from a group comprising, but not limited to, solution, aqueous suspension, capsule, tablet, injection, cream, gel, ointment, lotion, emulsion, foam, troche, lozenge, oily suspension, patch, dentifrice, spray, drops, dispersible powder or granule, syrup, elixir, food stuff, and any combination of forms thereof.
  • the present disclosure provides a method of treating a disease or a condition associated with abnormal NPC l and/or NPC2 protein production, comprising administering to a subject in need thereof a compound or a composition as described herein.
  • the present disclosure provides a method of treating lipid storage disorder comprising administering to a subject in need thereof a compound or a composition as described herein.
  • the present disclosure provides a method of treating Niemann-Pick disease, comprising administering to a subject in need thereof a compound or a composition as described herein.
  • the present disclosure provides a compoimd as described herein where the compound has an elimination half-life of from about 6 hours to about 24 hours.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described herein and a therapeutically active agent, wherein the bioavailability of the therapeutically active agent is improved
  • the present pendent polymerxyclodextrin conjugates Upon administration of the present pendent polymerxyclodextrin conjugates, said conjugates accumulates in different organs in the body such as liver, kidney, lungs, spleen and brain. Once in the organs and upon cellular internalization, the polymers enter the cells and disassemble to afford free cyclodextrins, allowing the cyclodextrins to complex with the excess cholesterol in the lysosomes and removing them from there. This removal of cholesterol then reduces the diseased state of the cells/organs hence affording the therapeutic effect.
  • the Schematic mechanism of cholesterol mobilization from PC cells by cyclodextrin pendant polymers of the present disclosure is shown in Figure 11.
  • the pendant polymer technology approach adopted in the present invention helps to increase the retention time of the drag in the body and hence shows prolonged therapeutic action because of the reduced rate of renal clearance due to its large size (>10 tira) and presence of polymeric moiety. Due to this, the dose required to maintain therapeutic concentrations are significantly reduced due to the prolonged circulation time in the body. This in turn potentially results in less frequent administrations and intravenous administration which increases patient compliance drastically.
  • the present invention further discloses the use of polymencyclodextrin conjugate including cova ent/'non-cova ent conjugate, or compositions/formulations comprising the same for management of lipid storage disorders, preferably lysosomal lipid storage disorders, and more preferably, Niemann-pick disease type C.
  • Step 1 Synthesis of CBz-G-(K) 9 :
  • the polypeptide of sequence Glycine-(Lysine)9 is synthesized using an Fmoc-based, solid-phase strategy on the Wang resin.
  • the peptide is purified to homogeneity by reverse-phase HPLC and characterized by 1H NMR, MS, and HPLC.
  • the synthesized peptide is produced with a CBz-protected N- terminus glycine.
  • Step 2 Synthesis of CBz ⁇ G-(K-p-CD) 9 :
  • lOOmg (0.055mmol) of the polypeptide from the previous step is dissolved in 5ml dry DM SO under N 2 .
  • 0.15mL (0.825 mmol, 1.6eq) of diisopropylethylamine is added and stirred, followed by addition of 2.8g (2.2mmol, 40eq) of ⁇ -CD-monotosylate.
  • the reaction mixture is stirred overnight under N 2 atmosphere after which it is dialyzed exhaustively against DMSO (thrice), followed by deionized water (thrice) using a 2000 MWCO dialysis membrane to remove any unreacted ⁇ -CD and base.
  • the dialyzed sample is then lyophilized to afford a dry powder.
  • the product is then analyzed by 1H NMR, HPLC, and GPC.
  • Step 3 Synthesis of PEG-G-(K-p-CD) 9 :
  • the number of CDs are variable based on the lysines in the polypeptide and can be varied from 6 to 15.
  • the MW of the Polyi ethylene glycol) used here is 3400 (i.e. 77 EO units); however larger or smaller MW PEG can also be used.
  • Glutathione or other targeting ligands could be attached to the other end of PEG to increase uptake of polymers in the brain.
  • Step 2 Synthesis of Polyi vinyl alcohol)-trz-( -CD) 75 :
  • the alkyne-PVA was reacted with monoazido- -CD (150 eq) in the presence of Sodium Ascorbate, Copper Sulfate, Diisopropylamine, in a mixture of 20 mL DMSO:Water (1 : 1).
  • the reaction mixture is allowed to stir for 24 hours followed by purification by dialysis to remove any small molecule impurities.
  • the dialyses is carried out against DMSO (thrice), dilute EDTA solution (ihrice), deionized water (thrice), followed by lyophilization to afford the product as a white powder.
  • the product is analysed by 1H NMR, GPC to determine the number of CDs attached and the avg. MW.
  • the number of CDs in the PEG-G-(K-fi-CD) 9 can be as high as 200 - 300.
  • PEG can also be grafted on the PVA backbone to increase blood circulation time.
  • a flame dried two-neck round bottom flask is equipped with stirred bar and cooled down under an argon stream.
  • Dry DCM (3 mL), 9 (4.4 g, 0.034 mol) and 8 (1.2 mL, 0.017 mol) are added under inert atmosphere at rt.
  • the reaction mixture is cooled down to -78°C and trimethylsilyl trifluoromethanesulphonate (50 ,uL, 20 mol%) is added to the reaction mixture.
  • the solution is stirred at -78 °C for 2,5 h. After completion of the reaction pyridine (0.6 mL) is added.
  • the pADK polymer self-assembles with ⁇ -CD and its derivatives to form nanoparticles to improve the biodistribution and pharmacokinetic profile of the monomeric ⁇ -CD ( Figure 12).
  • the chemical structure of pADK is shown in Figure 9b, it is composed of a polyketal that has adamantane groups embedded in its backbone, flanked by triazole groups, and in the presence of acid degrades into low molecular weight diols and acetone, both of which are membrane permeable and rapidly excretable.
  • pADK is designed to complex CD, generating a nanoparticle carrier with multiple copies of CD.
  • pADK hydrolyzes into small molecules, due to hydrolysis of the ketal linkage, and causes endosomal disruption via. the colloid osmotic mechanism.
  • the cellular degradation products of pADK are an adamantane diol and acetone, both of which cause minimal toxicity due to their rapid excretion.
  • pADK:CD nanoparticles are assembled at room temperature by mixing them in a 1 : 1 molar ratio of the pendant adamantane group to CD.
  • pADK microparticles are formulated and is encapsulated with rhodhamine B ( Figure 12), and investigated if ⁇ -CD could stimulate release from these microparticles.
  • pADK microparticles are suspended into solutions that contained 5 mM methyl- -CD or PBS, and the release of rhodamine-B is measured.
  • the number of adamantane groups are variable and can be as high as 200 - 300.
  • PEG can also be grafted on the backbone to increase blood circulation time.
  • ⁇ -CD, SBE-p-CD, and ⁇ - ⁇ -CD, are used in 1 CD: 1 Adamantane molar ratio to formulate the final complex
  • Step 3 Process for preparing complexes of Ad-PVA and cyclodextrin:
  • Ad-PVA pendant polymer is dissolved in a DMSO:Water mixture (1 : 1) at a concentration of ImM [Ad], that is, ImM concentration of the monomeric unit.
  • Step 1 Synthesis of CBz-(GK) 9 :
  • the polypeptide of sequence Glycine-(L,ysme)9 peptides are synthesized using an Fmoc-based, solid-phase strategy on the Wang resin.
  • the peptide is purified to homogeneity by reverse-phase HPLC and characterized by 1H NMR, MS, and HPLC.
  • the synthesized peptide is produced with a CBz- protected N-terminus glycine, Step 2: Synthesis of CBz-[G(K-Adamantane)]9:
  • lOOmg (0.055mmoi) of the polypeptide from the previous step is dissolved in 5ml dry DMSO under N 2 .
  • 0.15mL (0.825 mmol, 1.6eq) of diisopropvlethylamine is added and stirred, followed by addition of 22 mg (O.l lmmol, 2eq) of adamantane carbonyl chloride.
  • the reaction mixture is stirred overnight under N 2 atmosphere after which it is dialyzed exhaustively against DMSO (thrice), followed by deionized water (thrice) using a 2000 MWCO dialysis membrane to remove any unreacted adamantane carbonyl chloride and base.
  • the dialyzed sample is then lyophilized to afford a dry powder,
  • the product is then analyzed by 1HNMR, HPLC, and GPC.
  • Step 3 Synthesis of PEG-[G( -Adamantane)9] :
  • PEG-[G(K-Adamantane)9] pendant polypeptide is dissolved in water mixture at a concentration of I mM [Ad], that is, ImM concentration of the monomeric unit.
  • Example 6 Procedure for synthesis of PEG-Glycine-(Lysine-Cholesterol)9 and cyclodextrin conjugates:
  • Step I Synthesis of CBz-(GK) 9 :
  • polypeptide of sequence Glycine-(Lysine)9 is synthesized as mentioned in the previous Example.
  • Step 2 Synthesis of CBz-[G(K-Cholesterol)] 9 :
  • lOOmg (0.055mmol) of the polypeptide from the previous step is dissolved in 5ml dry DMSO under N 2 .
  • 0.15mL (0.825 rnmol, 1.6eq) of diisopropylethylamine is added and stirred, followed by addition of 50 mg (O.l lmmol, 2eq) of cholesteryl chloro formate.
  • the reaction mixture is stirred overnight under N2 atmosphere after which it is diaiyzed exhaustively against DMSO (thrice), followed by deionized water (thrice) using a 2000 MWCO dialysis membrane to remove any unreacted cholesteryl chloroformate and base.
  • the diaiyzed sample is then lyophilized to afford a dry powder.
  • the product is then analyzed by 1 H NMR, HPLC, and GPC.
  • Step 3 Synthesis of PEG-[G(K ⁇ Cholesteroi) 9 ] :
  • the PEGylated peptide is synthesized in a similar manner to the PEG-G ⁇ (K-Adamantane)o as described in the previous Example, and analyzed accordingly.
  • Step 4 Process for preparing complexes of PEG-G-(K- Cholesterol)9 and cyclodextrin:
  • the present disclosure introduces pendant guest-host complexes, corresponding methods and applications wherein said complexes possess improved properties such as, prolonged duration of action along with efficacy for removing cholesterol from the c ell s/tr eating lipid storage disorders.

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Abstract

La présente invention concerne le domaine des sciences biomédicales, pharmaceutiques et des polymères. La présente invention concerne des conjugués de polymères pendants susceptibles de former des complexes invité-hôte ou des conjugués covalents/non covalents avec des cyclodextrines (ou leurs dérivés), un procédé de préparation correspondant et leur application dans le traitement de troubles de stockage lipidique. Ces conjugués possèdent des propriétés améliorées, incluant mais sans s'y limiter, une durée d'action prolongée dans les cellules et une efficacité d'élimination accrue du cholestérol dans les cellules.
PCT/IB2016/054086 2015-07-08 2016-07-07 Compositions et complexes de cyclodextrine-polymère et leurs procédés de préparation et d'utilisation WO2017006279A1 (fr)

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CN110944718A (zh) * 2017-05-18 2020-03-31 里珍纳龙药品有限公司 环糊精蛋白质药物偶联物
US11279774B2 (en) 2019-01-03 2022-03-22 Underdog Pharmaceuticals, Inc. Cyclodextrin dimers, compositions thereof, and uses thereof
CN115160454A (zh) * 2021-04-01 2022-10-11 四川大学 一种基于聚-β-环糊精与金刚烷主客体作用的超分子多醛化合物及其制备方法
US11760775B2 (en) 2016-11-08 2023-09-19 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017125889A1 (fr) * 2016-01-21 2017-07-27 Aten Porus Lifesciences Polymères à base de cyclodextrine, et leurs procédés, compositions et applications
US11447577B2 (en) 2016-01-21 2022-09-20 Aten Porus Lifesciences Cyclodextrin based polymers, methods, compositions and applications thereof
US11760775B2 (en) 2016-11-08 2023-09-19 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
CN110944718A (zh) * 2017-05-18 2020-03-31 里珍纳龙药品有限公司 环糊精蛋白质药物偶联物
US12070506B2 (en) 2018-01-08 2024-08-27 Regeneron Pharmaceuticals, Inc. Steroids and antibody-conjugates thereof
US12134631B2 (en) 2018-11-06 2024-11-05 Regeneron Pharmaceuticals, Inc. Hydrophilic linkers for antibody drug conjugates
US11279774B2 (en) 2019-01-03 2022-03-22 Underdog Pharmaceuticals, Inc. Cyclodextrin dimers, compositions thereof, and uses thereof
CN115160454A (zh) * 2021-04-01 2022-10-11 四川大学 一种基于聚-β-环糊精与金刚烷主客体作用的超分子多醛化合物及其制备方法

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