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WO2018026794A1 - Méthodes de préparation de liposomes - Google Patents

Méthodes de préparation de liposomes Download PDF

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Publication number
WO2018026794A1
WO2018026794A1 PCT/US2017/044865 US2017044865W WO2018026794A1 WO 2018026794 A1 WO2018026794 A1 WO 2018026794A1 US 2017044865 W US2017044865 W US 2017044865W WO 2018026794 A1 WO2018026794 A1 WO 2018026794A1
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WIPO (PCT)
Prior art keywords
antibody
liposomes
liposome
encapsulated
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2017/044865
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English (en)
Inventor
Indu Javeri
Kaliappanadar Nellaiappan
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Curirx Inc
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Curirx Inc
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Filing date
Publication date
Priority claimed from US15/226,364 external-priority patent/US10143652B2/en
Application filed by Curirx Inc filed Critical Curirx Inc
Priority to CA3032810A priority Critical patent/CA3032810A1/fr
Priority to EP17837525.9A priority patent/EP3493790A4/fr
Priority to CN201780047019.3A priority patent/CN109562067A/zh
Priority to JP2019527768A priority patent/JP7019201B2/ja
Publication of WO2018026794A1 publication Critical patent/WO2018026794A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes

Definitions

  • bioavailability of a pharmaceutical drug depends largely in part on the solubility and stability of the drug. Many methods have been employed to improve bioavailability of a drug, including, but not limited to, pH adjustment, associating the drug in micelles of detergents, solubilization in an organic solvent, complexation with cyclodextrin or other polymers, and encapsulating the drug in a liposome bilayer (Strickley, R.G., Pharmaceutical Research, No. 21, 2004: 201-230). Either the drug itself or the excipients used to solubilize the drug may have side effects such as allergic reaction or hemolysis.
  • solvents e.g., ethanol, propylene glycol, polyethylene glycol, dimethylacetamide, dimethylsulfoxide (“DMSO”)
  • complexing agents for example, nicotinamide
  • surfactants for example, sodium oleate
  • organic solvents in injectable products include precipitation, pain, and inflammation upon injection.
  • Liposomes are microscopic lipid vesicles that are composed of a central aqueous cavity surrounded by a lipid membrane formed by concentric bilayer(s) (lamellas). Liposomes are able to incorporate hydrophilic substances (in the aqueous interior) or hydrophobic substances (in the lipid membrane). Liposomes can be unilamellar vesicles ("UMV”), having a single lipid bilayer, or multilamellar vesicles (“MLV”), having a series of lipid bilayers (also referred to as "oligolamellar vesicles”). The multilamellar vesicles typically range in size from 0.2 ⁇ to 10 ⁇ in diameter.
  • Unilamellar vesicles with a diameter of less than 0.2 ⁇ e.g. between 0.02 and 0.2 ⁇
  • the bilayer(s) of liposomes most often comprise phospholipids, but may also comprise lipids including but not limited to fatty acids, fatty acid salts and/or fatty alcohols.
  • lipids including but not limited to fatty acids, fatty acid salts and/or fatty alcohols.
  • the properties of the liposomes depend, among other factors, on the nature of the constituents. Consequently, if liposomes with certain characteristics are to be obtained, the charge of its polar group and/or the length and the degree of saturation of its fatty acid chains must be taken into account.
  • liposomes may be modified, e.g., to incorporatecholesterol and other lipids into the membrane, change the number of lipidic bilayers, or covalently join natural molecules (e.g., proteins, polysaccharides, glycolipids, antibodies, enzymes) or synthetic molecules (e.g., polyethyl glycol) to the surface.
  • natural molecules e.g., proteins, polysaccharides, glycolipids, antibodies, enzymes
  • synthetic molecules e.g., polyethyl glycol
  • the rigidity of the lipidic bilayer is the rigidity of the lipidic bilayer.
  • the hydrated lipid that foams part of the bilayer may be in either a liquid-crystalline (fluid) or gel state. As the temperature increases, the gel state is converted into the liquid-crystalline state. This occurs at a temperature known as the transition temperature (Tc), which is specific to each lipid.
  • Tc transition temperature
  • the Tc is directly proportional to chain length and inversely proportional to the degree of unsaturation of the fatty acids and depends on the nature of the polar group.
  • lipid vesicles such as liposomes
  • common methods in the preparation of lipid vesicles comprise evaporating an organic solvent in which the lipids are dissolved and then dispersed in an optionally buffered aqueous solution.
  • One exemplary method known as the Bangham method, was originally described in Bangham et al., J. Hot. Biol, 11 :238-252 (1965). Variations of the Bangham method are known by those skilled in the art, some of which are described below.
  • lipidic film is prepared through removal of organic solvent, which can be achieved by means of evaporation (e.g., at reduced pressure in a rotary evaporator) or by lyophilization.
  • the dry lipidic film obtained is hydrated by adding an aqueous solution and agitating the mixture at temperatures above the Tc.
  • lipidic film is prepared through removal of the organic solvent.
  • the system is purged with nitrogen and the lipids are re-dissolved in a second organic solution, usually constituted by diethyl ether and/or isopropyl ether.
  • the aqueous phase is added to the redissolved lipids.
  • the system is maintained under continuous nitrogen.
  • a gel is formed by removing the second organic solvent.
  • Solvent injection The lipids, dissolved in an organic solvent, are injected slowly intoan aqueous solution.
  • the organic solvent used is often a water-miscible solvent, and the aqueous solution may be warmed.
  • the lipids shouldremain homogeneously distributed in the liposomal vesicles. Traditionally, this is achieved by previously dissolving the lipids in an organic solvent and using the resulting organic solvent for preparing the liposomes.
  • U.S. Pat. No. 4,508,703 describes a method for obtaining powdery mixtures of atleast one amphyphilic lipid and, optionally, at least one component of a hydrophobic or partially hydrophobic nature, a method which includes dissolving the components of the mixture in at least one organic solvent and atomizing the obtained solution into an inert gas.
  • the method permits the preparation of lipidic mixtures which can be easily dispersed in an aqueous medium but does not avoid the use of organic solvents.
  • WO 92/10166 describes a method for preparing liposomes with an elevated encapsulation capacity.
  • the method permits the use of mixtures of lipids; however, the mixture is obtained by means of previous dissolution of the lipids in an organic solvent and subsequent evaporation.
  • the contact between the lipids and the aqueous solution of active agent is carried out at a temperature above the Tc.
  • liposomes are prepared without using heat, organic solvents, proteins, and/or inorganic salts in the process.
  • a method for the preparation of liposomes comprising:
  • the liposomal preparation contains one or more activeagents.
  • the active agent is a pharmaceutical agent.
  • active agents include, but are not limited to lapachone; transferrin; cyclosporine; colchicine; and combinations of lapachone and transferrin in a single liposome formulation.
  • the one or more active agents are added after the liposome orsolution of liposomes has been prepared. In other embodiments, the one or more active agents are added during formation of the liposome.
  • liposomal preparations in the treatment of diseases or disorders.
  • the liposomal preparation is suitable for parenteral administration to a patient suffering from said disease or disorder.
  • the patient is a human.
  • lipid is understood to be a fatty acid, fatty acid salt, fatty alcohol, or phospholipid. Lipids may also be read to include sterols, including, but not limited to, cholesterol; sphingolipids, including, but not limited to, sphingomyelin; glycosphingolipids including, but not limited to, gangliosides, globocides and cerebrosides; and surfactant amines including, but not limited to, stearyl, oleyl and linoleyl amines.
  • phospholipid is understood to be anamphyphilic derivative of glycerol, in which one of its hydroxyl groups is esterified with phosphoric acid and the other two hydroxyl groups are esterified with long-chain fatty acids that can be equal to or different from each other and can be saturated or unsaturated.
  • a neutral phospholipid is generally one in which the other phosphoric acid hydroxyl is esterified by an alcohol substituted by a polar group (usually hydroxyl or amino) and whose net charge is zero.
  • a phospholipid with a charge is generally one in which the other phosphoric acid hydroxyl is esterified by an alcohol substituted by a polar group and whose net charge is positive or negative.
  • phospholipids include, but are not limited to phosphatidic acid (“PA”),phosphatidylcholine (“PC”), phosphatidyl glycerol ( “ PG”), phophatidylethanolamine phophatidylinositol ( " Pr), and phosphatidylserine ( " PS”), sphingomyelin (including brain sphingomyelin), lecithin, lysolecithin, lysophosphatidylethanolamine, cerebrosides, diarachidoylphosphatidyl choline (“DAPC”), didecanoyl-L-alpha-phosphatidyl choline (“DDPC”), dielaidoylphosphatidylcholine (“DEPC”), dilauroylphosphatidylcholine (“DLPC”), dilinoleoylphosphatidylcholine, dimyristoylphosphatidyl choline (“DMPC
  • DMPE dimyristoylphosphatidylethanolamine
  • DOPE dioleoylphosphatidylethanolamine
  • DPPE dipalmitoylphosphatidylethanolamine
  • DSPE distearoylphosphatidylethanolamine
  • POPE dipalmitoy 1 -2-oleoyl-phosphatidylethanolamine
  • POPE diarachidoylphosphatidylinositol
  • DAPI didecanoyl-L-alpha-phosphatidylinositol
  • DEPI dielaidoylphosphatidylinositol
  • DEPI dilauroylphosphatidylinositol
  • DMPI dimyristoylphosphatidylinositol
  • DMPI diolcoylphosphatidylinosito
  • encapsulate or “encapsulation” is understood to be the process of incorporating an active agent into liposomes or liposomal vesicles.
  • the encapsulated active agent can remain in the aqueous interior or associate with membranes.
  • the term “enhance” or “enhancing, “when used in connection with the solubility of a compound, means that the methods provided herein result in the increased solubility of the compound as compared to the solubility of the same compound in water.
  • the term “enhance” or “enhancing” means that, when the methods provided herein are used, the solubility of a compound increases about 20 percent or more, about 40 percent or more, about 60 percent or more, about 80 percent or more, about 100 percent or more, or about 200 percent or more of the solubility of the same compound in a reference solvent.
  • the reference solvent is water.
  • hydrophobic compound means a compound with little or no water solubility.
  • a hydrophobic compound means a compound with little or no water solubility.
  • hydrophobic compound has an intrinsic water solubility (i.e., water solubility of the unionized form) of less than about 20 percent by weight, about 15 percent by weight, about 10 percent by weight, about 5 percent by weight, about 1 percent by weight, about 0.1 percent by weight or about 0.01 percent by weight.
  • a hydrophobic compound has an intrinsic water solubility of less than about 10 mg/mL, about 7 mg/mL, about 5 mg/mL, about 3 mg/mL, about 1 mg/mL or about 0.1 mg/mL.
  • aqueous medium or "aqueous media” include any water based medium, e.g., water, saline solution, a sugar solution, a transfusion solution, a buffer, and any other readily available water-based medium. Further, an aqueous medium may contain one or more water soluble organic solvents. In the case of a parenteral solution, an aqueous medium is preferably sterile and suitable for use as a carrier of an active agent. Examples of aqueous media include, but are not limited to, water for injection, saline solution, Ringer's solution, D5W, or other solutions of water-miscible substances such as dextrose and other electrolytes.
  • fatty acid means acompound whose structure is a carboxylic group attached to a hydrocarbon chain having one or more carbon atoms.
  • the hydrocarbon chain may be saturated or unsaturated (i.e., alkyl, alkenyl or alkynyl hydrocarbon chains). Also, the hydrocarbon chain may be straight or branched. Moreover, in some embodiments, hydrogens in the hydrocarbon chain may be substituted.
  • fatty alcohol means acompound whose structure is an alcohol group attached to a hydrocarbon chain having one or more carbon atoms.
  • the hydrocarbon chain may be saturated or unsaturated (i.e., alkyl, alkenyl or alkynyl hydrocarbon chains). Also, the hydrocarbon chain may be straight or branched. Moreover, in some embodiments, hydrogens in the hydrocarbon chain may be substituted.
  • fatty acid salt means acompound formed from a reaction between a fatty acid and an inorganic/organic base.
  • the term encompasses a compound formed from a reaction between a fatty alcohol and an inorganic/organic acid. Examples of such acids include, but are not limited to, sulfuric and phosphoric acid.
  • the hydrocarbon chain of the fatty acid salt may be saturated or unsaturated (i.e., alkyl, alkenyl or alkynyl hydrocarbon chains). In addition, the hydrocarbon chain may be straight or branched.
  • substituted means a group substituted by one or more substituents including, but not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, aroyl, halo, haloalkyl (e.g., trifluoromethyl), substituted or unsubstituted heterocycloalkyl, haloalkoxy (e.g., trifluoromethoxy), hydroxy, alkoxy, cycloalkyloxy, heterocylooxy, oxo, alkanoyl, aryl, substituted aryl, substituted or unsubstituted heteroaryl (e.g., indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like), arylalkyl, alkylaryl, heteroaryl, heteroaryl, indidyl, alkylaryl, heteroaryl
  • alkyl means a saturated straight chain or branched non cyclic hydrocarbon having 1 20 carbon atoms, preferably 1 10 carbon atoms and most preferably 1 4 carbon atoms.
  • Representative saturated straight chain alkyls include methyl, ethyl, n propyl, n butyl, n pentyl, n hexyl, n heptyl, n octyl, n nonyl and n decyl; while saturated branched alkyls include isopropyl, sec butyl, isobutyl, tert butyl, isopentyl, 2 methylbutyl, 3 methylbutyl, 2 methylpentyl, 3 methylpentyl, 4 methylpentyl, 2 methylhexyl, 3 methylhexyl, 4 methylhexyl, 5 methylhexyl, 2,3 dimethylbutyl,
  • alkyl group can be unsubstituted or substituted.
  • Unsaturated alkyl groups include alkenyl groups and alkynyl groups, which are discussed
  • alkenyl means a straightchain or branched non-cyclic hydrocarbon having 2-20 carbon atoms, preferably 2-10 carbon atoms, most preferably 2-6 carbon atoms, and including at least one carbon-carbon double bond.
  • Representative straight chain and branched (C2-C10) alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl- 1-butenyl, -2-methyl -2-butenyl, -2,3 -dimethyl -2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl, - 1-heptenyl, -2-heptenyl, -3-heptenyl, - 1-octenyl, -2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl , -3-nonenyl, -1-decenyl, -2-decenyl, -3 - decenyl and the like.
  • alkynyl means a straightchain or branched non-cyclic hydrocarbon having 2-20 carbon atoms, preferably 2-10 carbon atoms, most preferably 2-6 carbon atoms, and including at lease one carbon-carbon triple bond.
  • Representative straight chain and branched (C2-C io)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl.
  • the term “pharmaceutically acceptablesalt” refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
  • Suitable pharmaceutically acceptable base addition salts for the compositions provided herein include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Suitable nontoxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,
  • inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,
  • hydrate means a compound provided herein, or a saltthereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • clathrate means a compound provided herein, or a saltthereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.
  • spaces e.g., channels
  • guest molecule e.g., a solvent or water
  • prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound.
  • prodrugs include, but arc not limited to, derivatives and metabolites of a compound that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid.
  • Prodrugs can typically be prepared using well-known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley), and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).
  • stable when used inconnection with a formulation, means that the active agent of the formulation, when prepared using the methods provided herein, remains solubilized for a specified amount of time and does not significantly degrade or aggregate or become otherwise modified (e.g., as determined by HPLC).
  • the term "harmful ingredient,” whenused in connection with pharmaceutical compositions, means an ingredient commonly used in a pharmaceutical composition that may cause clinical side effects such as, but not limited to, hemolysis, hypersensitive reaction, peripheral neuropathies, and/or decrease in the bioavailability of the active ingredient of the composition.
  • harmful ingredients include, but are not limited to: toxic solvents, including organic solvents such as ethanol, methanol, 1-propanol, 2-propanol, acetone, acetonitrile, ethyl acetate, methyl acetate, diethyl ether, dimethyl ether, diisopropyl ether, methyl tert-hutyl ether ("MTBE"), tetrahydrofuran (“THF”), dichloromethane, chloroform, carbon tetrachloride, 1,2-dicholroethane, pentane, hexanes, heptane, petroleum ether, dioxane, ethylene glycol, diethylene glycol, diglyme, 1,2-dimethoxyethane, 1-butanol, 2-butanol, 2-butanone, benzene, toluene, dimethylsulfoxide (“DMSO”), dimethylformamide (“DMF-), hexamethyiphosphor
  • Figure 1A shows a control elution profile for size exclusion HPLC of adalimumab (HUMIRA) antibody without added liposomes.
  • Figure IB shows an elution profile for size exclusion HPLC of liposome-encapsulated traztuzumab (HERCEPTF ) antibody.
  • Figure 1C shows an elution profile for size exclusion HPLC of liposome-encapsulated adalimumab (HUMIRA) antibody.
  • the method further comprises homogenization of the lipids in the aqueous medium.
  • Some embodiments further comprise a step (d), wherein one or more active agents is added to the solution of liposomes.
  • the active agent is a hydrophobic drug.
  • the active agent is added as a solid.
  • the active agent is added in an organic solvent.
  • the active agent is added in organic solvent which further comprises one or more fatty acid salts, fatty acids and/or phospholipids.
  • the active agent is added during formation of the liposome.
  • the resulting liposomes are less than about 1 ⁇ in diameter. In one embodiment, the resulting liposomes are less than about 500 nm in diameter. In one embodiment, the resulting liposomes are less than about 100 nm in diameter.
  • At least one of the lipids is a phospholipid or a mixture of phospholipids.
  • phospholipids include, but are not limited to, phosphatidic acid (“PA”), phosphatidylcholine (“PC”), phosphatidylglycerol (“PG”), phophatidylethanolamine (“PE”), phophatidylinositol (“PI “), and phosphatidylserine (“PS”), sphingomyelin (including brain sphingomyelin), lecithin, lysolecithin, lysophosphatidylethanolamine, cerebrosides, diarachidoylphosphatidylcholine (“DAPC”), didecanoyl L alpha phosphatidylcholine ( DDPC ), dielaidoylphosphatidylcholine (“DEPC”), dilauroylphosphatidylcholine (“DLPC”), dilinol
  • PA
  • DDPE phosphatidylethanolamine
  • DEPE dielaidoylphosphatidylethanolamine
  • DLPE dilauroylphosphatidylethanolamine
  • DMPE dimyristoylphosphatidylethanolamine
  • DOPE dioleoylphosphatidylethanolamine
  • DPPE dipalmitoylphosphatidylethanolamine
  • POPE diarachidoylphosphatidylinositol
  • DAPI didecanoyl L alpha phosphatidylinositol
  • DDPI dielaidoylphosphatidylinositol
  • DEPT dielaidoylphosphatidylinositol
  • the phospholipids provided herein may be chiral or achiral.
  • the chiral phospholipidsprovided herein may be D or L phospholipids, for example, L a phosphatidylcholine or I, 3 phosphatidylcholine.
  • L a phosphatidylcholine is used in the methods provided herein.
  • a method for the preparation of liposomes comprising:
  • the aqueous medium contains one or more active agents
  • active agents include, but are not limited to, lapachone (13-lapachone), taxanes (including, but not limited to, taxol, 7-epitaxol, 7-acetyl taxol, 10-desacetyltaxol, lO-desacetyl-7-epitaxol, 7-xylosyltaxol, lO-desacetyl-7-sylosyltaxol, 7-glutaryltaxol, 7-N,N-dimethylglycycltaxol, 7-L-alanyltaxol, taxotere, and mixtures thereof), paclitaxel, colchicine, transferrin, cyclosporines, cyclosporin A, ketoprofen, propofol, acetylsalicylic acid, acetaminophen, amphotericin,
  • the active agent is a hydrophobic compound, or a compound withpoor solubility in water.
  • the active agent is a non-hydrophobic compound.
  • the active agent is a water soluble membrane impermeant agent such as a peptide, a protein, a nucleic acid, a nucleotide, a nucleoside, a carbohydrate or an analog thereof.
  • the aqueous medium does not contain an active agent.
  • the resulting solution contains 10% by weight trehalose.
  • the active agent is lapachone, or a pharmaceutically acceptable salt, hydrate, clathrate or prodrug thereof.
  • the active agent is transferrin, or a pharmaceutically acceptable salt, hydrate, clathrate or prodrug thereof.
  • the active agent is cyclosporine, or a pharmaceutically acceptable salt, hydrate, clathrate or prodrug thereof
  • the active agents are transferrin and lapachone, or pharmaceutically
  • sugars examples include, but are not limited to, sucrose, glucose, fructose, lactose, maltose, mannose, galactose and trehalose.
  • the sugar is trehalose.
  • the liposomal preparation is suitable for parenteral administration to a patient suffering from one or more diseases or disorders.
  • the patient is a human.
  • the sequence of the addition of active agent(s) results in enhanced solubility of the active agent(s).
  • the conventional method of incorporating hydrophobic drug to liposome is by adding the drug to lipid before liposome preparation. See, e.g., Immordino, M L. et al., Journal of Controlled Release, 2003, 91 : 417 429. By the conventional process, the incorporation of the drug is only 0.3 to 0.7mg,/mL.
  • the solubility of the active agent(s) in liposome is increased by at least about two-fold, five-fold or ten-fold compared to the conventional process. In one embodiment, the solubility of the active agent(s) in liposome is increased to about 5 mg/mL.
  • the activeagent is added to pre made liposome as a solid or in an organic solvent.
  • the pre made liposome comprises one or more fatty acid salts, fatty acids and/or phospholipids to increase the solubility of the active agent.
  • the sequence of the addition of active agent(s) results in greaterefficiency of incorporation of the active agent(s) into liposome.
  • the efficiency of incorporation into liposome is 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99% or 100%. In certain embodiments, the efficiency of incorporation is 90%, 95%, 98%, 99% or 100%.
  • the increase in incorporation of active agent to pre made liposome may be due to increase in surface area of liposome.
  • a liposomal composition prepared by a method comprising: (a) Combining one or more lipids in an aqueous medium at ambient temperature;
  • a liposomal composition prepared by a method comprising:
  • the active agent is a hydrophobic drug.
  • the active agent is added as a solid.
  • the active agent is added in an organic solvent.
  • the active agent in organic solvent further comprises one or more fatty acid salts, fatty acids and phospholipids.
  • the methods provided herein result in stable solutions, compositions or formulations comprising liposomes and one or more active agents.
  • the active agent(s) remain solubilized for a specified amount of time and do not significantly degrade, aggregate or become otherwise modified (e.g., as determined by HPLC).
  • the active agent remains solubilized after a week after dilution with an acceptable diluent at an elevated temperature (e.g., about 35°C. or higher).
  • about 70 percent or greater, about 80 percent or greater or about 90 percent or greater of the active agent remains solubilized after a week after dilution with an acceptable diluent at room temperature.
  • about 70 percent or greater, about 80 percent or greater or about 90 percent or greater of the active agent remains solubilized after a week at a reduced temperature (e.g., about 10°C. or lower).
  • the methods provided herein result in enhanced solubility of an active agent, as compared to the solubility of the same active agent in an aqueous medium. Specifically, when the methods provided herein are used, the solubility of the active agent
  • 2325999V 1/20112-19 increases about 20 percent or more, about 40 percent or more, about 60 percent or more, about 80 percent or more, about 100 percent or more, or about 200 percent or more of the solubility of the same active agent in a reference solvent.
  • the reference solvent is water.
  • the disease or disorder includes, but is not limited to, oncological disorders, proliferative disorders, central nervous system disorders, autoimmune disorders, and inflammatory diseases or disorders.
  • the methods are directed to the treatment of bacterial, viral or fungal infections.
  • Proliferative disorders that may be treated by the methods provided herein include, but are not limited to, neoplasms, tumors (malignant and benign) and metastases, or any disease or disorder characterized by uncontrolled cell growth.
  • the cancer may be a primary or metastatic cancer.
  • Specific examples of cancers that can be prevented, managed, treated or ameliorated in accordance with the methods of the invention include, but are not limited to, cancer of the head, neck, eye. mouth, throat, esophagus, chest, bone, lung, colon, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, and brain.
  • Additional cancers include, but are not limited to, the following: leukemias (e.g., acute leukemia, acute lymphocytic leukemia), acute myelocytic leukemias (e.g., myeloblastic, promyelocyte, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome), chronic leukemias (e.g., chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia), polycythemia vera, lymphomas (e.g., Hodgkin's disease, non Hodgkin's disease), multiple myelomas (e.g., smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasmacytoma), Walden
  • breast cancer e.g., adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget's disease, and inflammatory breast cancer
  • adrenal cancer e.g., pheochromocytom and adrenocortical carcinoma
  • thyroid cancer e.g., papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer
  • pancreatic cancer e.g., insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin secreting tumor, and carcinoid or islet cell tumor
  • pituitary cancers e.g., Cushing's disease, prolactin secreting tumor, acromegaly, and diabetes insipius
  • eye cancers e.g., ocular melanoma such as iris
  • adenocarcinoma adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma
  • penile cancers oral cancers (e.g., squamous cell carcinoma), basal cancers, salivary gland cancers (e.g., adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma), pharynx cancers (e.g., squamous cell cancer, and verrucous), skin cancers (e.g., basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acral
  • bladder cancers e.g., transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma), myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas, follicular lymphomas, carcinomas with p53 mutations, hormone dependent tumors of the breast, prostate and ovary, precancerous lesions such as familial adenomatous polyposis, and myelodysplastic syndromes.
  • bladder cancers e.g., transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma), myxosarcom
  • diseases and disorders that may be treated by the methods providedherein include, but are not limited to, the following: allergic disorders, inflammation, asthma, arthritis, encephalitis, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, inflammatory osteolysis, chronic or acute obstructive pulmonary disease, chronic or acute pulmonary inflammatory disease, inflammatory bowel disease, Crohn's Disease, gout, Bechet's Disease, Henoch Schonlein purpura ("FISP”), septic shock, sepsis, meningitis, colitis, inflammation due to reperfusion, psoriasis, fibrosis including pulmonary fibrosis, Parkinson's disease, bradykinesia, muscle rigidity, Parkinsonian tremor, Parkinsonian gait, motion freezing, depression; defective long term memory, Rubinstein Taybi syndrome (RTS), dementia, sleep disorders, insomnia, postural instability, hypokinetic disorders, hyperkinetic disorders, synuclein disorders, multiple system atrophies, strial
  • Viral infections that may be treated by the methods provided herein include, but are not limited to, the following: human immunodeficiency virus (“HIV”), herpes simplex virus type 1, herpes simplex virus type 2, influenza viruses, influenza virus type A, influenza virus type B, parainfluenza virus, human papillomavirus (“HPV”), adenoviruses, rhinoviruses, hepatitis A
  • HAV human immunodeficiency virus
  • HPV human papillomavirus
  • adenoviruses adenoviruses
  • rhinoviruses hepatitis A
  • hepatitis B virus hepatitis C virus
  • hepatitis D virus hepatitis E virus
  • dengue fever yellow fever
  • West Nile virus Japanese encephalitis virus
  • GB virus A GB virus B
  • GB virus C bovine viral diarrhea virus (BVDV)
  • classical swine fever virus i.e., hog cholera virus
  • border disease virus varicella zoster virus
  • smallpox, measles, rabies virus arbovirus
  • cytomegalovirus mumps virus
  • poliovirus coxsackie B virus
  • Epstein Barr virus rubella virus
  • parvovirus B19 coronaviruses SARS coronavirus
  • coronaviruses SARS coronavirus astrovirus
  • norovirus rotavirus
  • adenoviruses adenoviruses.
  • Fungal infections that may be treated by the methods provided herein include, but are not limited to, aspergillosis, blastomycosis, coccidioidomycosis, cryptococcosis, fungal sinusitis, histoplasmosis, hypersensitivity pneumonitis, mucormycosis, paracoccidioidomycosis, sporotrichosis, and Valley Fever.
  • Bacterial infections that may be treated by the methods provided herein include, butare not limited to, brucellosis, cholera, leprosy, leptospirosis, shigellosis, trench fever, tularemia, Q fever, Whitmore's disease, yersiniosis, yaws, vibrio vulnificus infections, streptococcus infections, staphylococcus infections and E. coli infections.
  • compositions including liposomes that encapsulate antibodies or other therapeutic proteins and methods of making such liposome-encapsulated antibodies or liposome-encapsulated therapeutic proteins.
  • the inventors have found that immunoglobulins and other therapeutic proteins contain a hydrophobic region or pocket that provides them with an affinity for the hydrophobic core of the lipid bilayer of liposomes.
  • antibodies and other therapeutic proteins can be spontaneously incorporated into liposomes if the lyophilized antibody or other protein is exposed to a suspension of pre-formed liposomes in an aqueous medium.
  • incorporation does not require, and preferably avoids entirely, the use of detergents, surfactants, and organic solvents, and also does not require homogenization, microfluidization, filtration, or other mechanisms that disrupt the lipid bilayer. Such incorporation also does not require, and preferably avoids, any covalent or even non- covalent modification of the immunoglobulin or other therapeutic protein prior to or following its incorporation into the liposomes.
  • the immunoglobulin or other therapeutic protein preferably associates with lipid alkyl chains by non-covalent binding, such as by hydrophobic interactions and/or van der Waals interactions, and does not involve the use of derivatized lipids and derivatized proteins containing high affinity matched binding pairs, such as streptavidin and biotin, or the like.
  • the resulting antibody- or protein-containing lipid vesicles can have a molar
  • the yield of protein or antibody incorporation is at least about 40%, 50%, 60%, 70%, or 80%.
  • the encapsulated antibody or protein is partially or wholly embedded within the hydrophobic portion of the lipid bilayer, and is not substantially entrapped in the vesicle lumen or covalently bound to lipid molecules, or covalently bound to high affinity matched binding molecules such as streptavidin or biotin.
  • the method of encapsulation is gentle, with retention of biological function, and the liposome-encapsulated antibody or protein can be lyophilized and later reconstituted prior to use, such as administration to a patient.
  • Example 1 Preparation of liposomes with no drug: 6% L-a-phosphatidyl choline (Soy) liposome.
  • Example 2 Preparation of liposomes encapsulated with lapachone.
  • Example 4 Preparation of liposomes encapsulated with transferrin.
  • transferrin and 6 g of L a phosphatidylcholine (Soy) were dispersed in 100 mL of water using a magnetic stirrer at 200 rpm for 10 minutes at ambient temperature.
  • the dispersed liposome (multilayer) was passed through a Microfluidic homogenizer at 15,000 psi. Three cycles of passing resulted in a liposome encapsulated with 5 mg/mL transferrin less than lOOnm in diameter. Trehalose was then added to the liposome to a final concentration of 10 %(w/w).
  • the resulting stable isotonic liposome formulation encapsulated with transferrin was either used as liquid or lyophilized.
  • Example 5 Preparation of liposomes encapsulated with colchicine.
  • hydrophobic portions Many therapeutic proteins, including antibodies, have a hydrophobic portion.
  • antibodies just as other hydrophobic proteins or hydrophobic drugs, can be encapsulated by liposomes by adding the antibodies to preformed liposomes.
  • liposomal membranes were found to be capable of encapsulating the hydrophobic portions of
  • HERCEPTIN is indicated for adjuvant treatment of breast cancer which is HER2 overexpressing and node positive or node negative (ER/PR negative or with one high risk feature).
  • HERCEPTIN is provided as a sterile, white to pale yellow, preservative-free lyophilized powder for intravenous administration.
  • Each multi-use vial of HERCEPTIN contains 440 mg trastuzumab, 400 mgD ⁇ , ⁇ - 1,1 -trehalose dihydrate, 9.9 mg L-histidine HC1, 6.4 mg L-histidine, and 1.8 mg polysorbate 20, USP.
  • the sample was analyzed by size exclusion HPLC by injecting 10 ⁇ of sample onto a Tosoh G3000 SWXL gel filtration column using 100 mM sodium sulfate and 100 mM sodium acetate pH 6.0 as mobile phase.
  • a HUMIRA sample without liposomes was used as control (see Fig. 1 A).
  • composition of the liposomal HERCEPTIN is shown in Table 1 below. Table 1.
  • HUMIRA is a tumor necrosis factor (TNF) blocker indicated for treatment of: rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis, Crohn's Disease and plaque psoriasis.
  • RA rheumatoid arthritis
  • psoriatic arthritis ankylosing spondylitis
  • Crohn's Disease plaque psoriasis.
  • HUMIRA is supplied as a sterile, preservative-free solution of adalimumab for subcutaneous administration.
  • the drug product is supplied as either a single-use, prefilled pen (HUMIRA Pen) or as a single-use, 1 mL prefilled glass syringe.
  • the solution of HUMIRA is clear and colorless, with a pH of about 5.2.
  • Each syringe delivers 0.8 mL of drug product, containing.40 mg adalimumab, 4.93 mg sodium chloride, 0.69 mg monobasic sodium phosphate dihydrate, 1.22 mg dibasic sodium phosphate dihydrate, 0.24 mg sodium citrate, 1.04 mg citric acid monohydrate, 9.6 mg mannitol, 0.8 mg polysorbate 80, and Water for Injection, USP.
  • Sodium hydroxide is added as necessary to adjust the pH.
  • composition of the liposomal HUMIRA is shown in Table 2 below.

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Abstract

L'invention concerne des méthodes de préparation de liposomes et les utilisations de ces derniers. Dans certains modes de réalisation, des liposomes sont préparés sans recours à la chaleur, à des solvants organiques, à des protéines et/ou à des sels inorganiques. Dans certains modes de réalisation, la préparation de liposomes contient un ou plusieurs agents actifs. Dans certains modes de réalisation, les préparations de liposomes sont utilisées dans le traitement de maladies ou de troubles.
PCT/US2017/044865 2016-08-02 2017-08-01 Méthodes de préparation de liposomes Ceased WO2018026794A1 (fr)

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CA3032810A CA3032810A1 (fr) 2016-08-02 2017-08-01 Methodes de preparation de liposomes
EP17837525.9A EP3493790A4 (fr) 2016-08-02 2017-08-01 Méthodes de préparation de liposomes
CN201780047019.3A CN109562067A (zh) 2016-08-02 2017-08-01 制备脂质体的方法
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EP3493790A1 (fr) 2019-06-12
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JP7019201B2 (ja) 2022-02-15
CN109562067A (zh) 2019-04-02
JP2019526619A (ja) 2019-09-19

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