US20120202890A1 - Polymer-carbohydrate-lipid conjugates - Google Patents

Polymer-carbohydrate-lipid conjugates Download PDF

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US20120202890A1
US20120202890A1 US13/354,726 US201213354726A US2012202890A1 US 20120202890 A1 US20120202890 A1 US 20120202890A1 US 201213354726 A US201213354726 A US 201213354726A US 2012202890 A1 US2012202890 A1 US 2012202890A1
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hydroxyl
amino
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carboxylic group
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Nian Wu
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Priority to US13/354,726 priority Critical patent/US20120202890A1/en
Priority to PCT/US2012/023273 priority patent/WO2012109052A1/en
Priority to PCT/US2012/023844 priority patent/WO2012109112A2/en
Priority to ES12704348.7T priority patent/ES2674885T3/es
Priority to JP2013552690A priority patent/JP5934255B2/ja
Priority to CN201280007922.4A priority patent/CN104704023B/zh
Priority to CA2826468A priority patent/CA2826468C/en
Priority to MX2013009128A priority patent/MX352252B/es
Priority to EP12704348.7A priority patent/EP2673000B1/en
Priority to BR112013019628A priority patent/BR112013019628B8/pt
Publication of US20120202890A1 publication Critical patent/US20120202890A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
    • A—HUMAN NECESSITIES
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
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    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/25—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids with polyoxyalkylated alcohols, e.g. esters of polyethylene glycol
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
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    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2203/00—Applications
    • C08L2203/02—Applications for biomedical use

Definitions

  • the present invention relates to polymer-carbohydrate-lipid conjugates, detailed and specific disclosures are given for synthetic polyethyleneglycol (PEG)-lipid conjugates preferably having substantially monodisperse PEG chains if used for intravenous drug administration. More particularly, the present invention relates to new polymer-carbohydrate-lipid conjugates and their use for drug delivery, cosmetics and other purposes.
  • PEG polyethyleneglycol
  • PEG Polyethylenglycol
  • PEG possesses several beneficial properties: very low toxicity [Pang, S. N. J., J. Am. Coil. Toxicol, 12 (1993), 429-456], excellent solubility in aqueous solutions [Powell, G. M., Handbook of Water Soluble Gums and Resins , R. L. Davidson (Ed.), Ch. 18 (1980), MGraw-Hill, New York], and extremely low immunogenicity and antigenicity [Dreborg, S, Crit. Rev. Ther. Drug Carrier Syst., 6 (1990), 315-365].
  • the polymer is known to be non-biodegradable, yet it is readily excretable after administration into living organisms.
  • the drugs may be administered repeatedly as needed.
  • systemic administration requires large dosages with relatively high vehicle contents which may cause side effects such as allergic reactions [“Cremophor-based paclitaxel ‘chemo’ drug triggers fatal allergic reactions,” The Medical News, 9 Jun. 2009].
  • sugar-lipids are composed of materials that occur naturally in the human body suggests potential advantages over some other polymer-based controlled-release terms of biocompatibility [Kohane D S, Lipp M, Kinney R, Anthony D, Lotan N, Langer R., J. Biomed. Mat. Res. 59 (2002) 450-459; Menei P, Daniel V, Montero-Menei C, Brouillard M, Pouplard-Barthelaix A, Benoit J P., Biomaterials, 14 (1993) 470-478].
  • Lipid-sugars have a good biocompatibility as shown by the results of the in vitro and in vivo studies [Kohane D S, Lipp M, Kinney R, Anthony D, Lotan N, Langer R., J. Biomed. Mat. Res. 59 (2002) 450-459].
  • Narrow molecular weight distribution of drug delivery polymers is crucially important for biomedical applications, especially if used for intravenous injections.
  • PEG-8 Caprylic/Capric Glycerides are mixtures of monoesters, diesters, and triesters of glycerol and monoesters and diesters of polyethylene glycols with a mean relative molecular weight between 200 and 400.
  • PEG-8 CCG Partially due to allergic reactions observed in animals, the application of PEG-8 CCG for many water-insoluble drugs was restricted and a dose limit of approximately 6% of PEG-8 CCG was used for human oral drug formulations.
  • the invention comprises compounds having a backbone and three appended functional groups: one lipid, one hydrophilic polymer, and one carbohydrate.
  • Specific functional groups may be selected for specific applications in formulating pharmaceuticals, cosmetics, nutriceuticals, and the like.
  • a variety of linkers between the backbone and functional groups may also be selected to optimize performance.
  • FIG. 1 shows a representation of the conjugates of the present invention.
  • FIG. 2 shows stability profiles of a sample peptide in a) 2% ODL-15 in 50 mM sodium phosphate buffer (pH 7.0), b) 2% ODL-15 in 50 mM sodium phosphate buffer (pH 8.0) and c) 50 mM sodium phosphate buffer (pH 7.0). The plots were the % recovery vs. time.
  • FIG. 3 shows Lapatinib mouse PK profiles of (a) 5% Cremophor EL® plus 5% methanol in 10 mM sodium phosphate buffer (pH 7.0), b) 1% ODL-15 in 10 mM sodium phosphate buffer (pH 7.0), (b) 2% ODL-15 in 10 mM sodium phosphate buffer (pH 7.0) and the drug was administered intravenously and the dosing strength was 10 mg/kg.
  • FIG. 4 shows pharmacokinetic profiles of Propofol formulations with (a) a commercial product of 1% Propofol (emulsified suspension) and (b) 1% of Propofol solution consisting of 2.3% of OAPDL-11 in saline after intravenous dosing.
  • FIG. 5 shows that the HPLC-FL chromatograms of 1% Propofol solution (a) no filtration and (b) after filtered through a 0.2 ⁇ m Acrodisc® PF filter.
  • Embodiments of the present invention are described herein in the context of varying polymer-carbohydrtae-lipid conjugates for drug delivery. Those of ordinary skill in the art will realize that the following detailed description of the present invention is illustrative only and is not intended to be in any way limiting. Other embodiments of the present invention will readily suggest themselves to such skilled persons having the benefit of this disclosure. Reference will now be made in detail to implementation of the present invention.
  • the invention comprises compounds having a backbone and three appended functional groups: one lipid, one hydrophilic polymer, and one carbohydrate. By combining these three functionalities all into one compound, it is possible to achieve improved formulations of many active agents.
  • the general structure of the family of compounds is shown as FIG. 1 , where B indicates the backbone, P indicates the polymer, L indicates the lipid, and C indicates the carbohydrate.
  • the new conjugates act as a solubility enhancer of poor water soluble agents resulting in either a true solution or a very stable emulsified suspension with those of active agents.
  • polyethyleneglycol PEG
  • PEG polyethyleneglycol
  • the backbone may be selected from glycerol or glycerol-like analogues, polyamines (tri- or tetra-amines), amino acids having three available binding sites, and triols and triacids such as glucoheptonic acid and tartaric acid.
  • the lipid is selected from fatty acids or bile acids.
  • the carbohydrate is a sugar including monosaccharides or disaccharides or oligosaccharides.
  • X 1 , X 2 and X 3 are the same or different linkers. Each linker may be as simple as an oxygen or other single atom. Alternatively, each linker may be single or replicate linkers selected from Table 1 or Table 2.
  • the linker may be co-extensive with or a part of the backbone or functional group component used to synthesize the conjugate.
  • the invention also includes compounds in which the carbohydrate is in the center position of the backbone. However, it is more practical to have carbohydrates at the terminus instead of the center of the backbones due to the routes of synthetic chemistry.
  • the general structure is meant to include all racemers or structural isomers of the structure, as they can be functionally equivalent.
  • the PEG chain preferably consists of between about 5 and 45 subunits, and is preferably substantially monodisperse.
  • R is the terminal group on the PEG chain can be selected from a wide variety of chemical moieties. R preferably has a molecular weight of less than about 650.
  • the terminal group on the PEG chain can be selected from a wide variety of chemical moieties.
  • Such moieties preferably have a molecular weight of less than 650.
  • Such moieties include —NH 2 , —COOH, —OCH 2 CH 3 , —OCH 2 CH 2 OH, —COCH ⁇ CH 2 , —OCH 2 CH 2 NH 2 , —OSO 2 CH 3 , —OCH 2 C 6 H 6 , —OCH 2 COCH 2 CH 2 COONC 4 H 4 O 2 , —CH 2 CH 2 —CH 2 , C 10 H 16 N 2 O 3 S and —OC 6 H 6 .
  • the terminal group may be a functional group that facilitates linking therapeutic or targeting agents to the surface of lipid vesicle aggregates.
  • Linked therapeutic and targeting agents may include Fab fragments, cell surface binding agents, and the like. Additionally, the terminal group may include functional cell-targeting ligands such as folate, transferrin and molecules such as monoclonal antibodies, ligands for cellular receptors or specific peptide sequences can be attached to the liposomal surface to provide specific binding sites.
  • functional cell-targeting ligands such as folate, transferrin and molecules such as monoclonal antibodies, ligands for cellular receptors or specific peptide sequences can be attached to the liposomal surface to provide specific binding sites.
  • the terminal group can be neutral or include either negatively or positively charged head-groups such as decanolamine, octadecylolamine, octanolamine, butanolamine, dodecanolamine, hexanolamine, tetradecanolamine, hexadecanolamine, oleylamine, decanoltrimethylaminium, octadecyloltrimethylaminium, octanoltrimethyl-aminium, butanoltrimethylaminium, dodecanoltrimethylaminium, hexanoltrimethylaminium, tetradecanoltrimethylaminium, hexadecanoltrimethylaminium, oleyltrimethylaminium, for example.
  • head-groups such as decanolamine, octadecylolamine, octanolamine, butanolamine, dodecanol
  • R groups include alkyl groups such as alkoxy moieties, amino acids, and sugars including monosaccharides, disaccharides, trisaccharides and the oligosaccharides—containing 1, 2, 3, and 4 or more monosaccharide units respectively.
  • targeting moieties such as antibody fragments and vitamins can also be used as R groups.
  • the R group is highly soluble in water.
  • the molecular weight of the R group is preferably less than about 650, and for most applications the R group is preferably easily polarized, in order to increase the binding and interaction with proteins at the targeted sites.
  • well balanced ionic R groups are advantageously employed for certain modes of administrations such as topical gels and oral solutions targeting the mouth and throat.
  • the compounds of the invention may be categorized into several classes. These classes include monoacylglycerol-carbohydrate-polyethylene glycols (MAGC-PEGs); monoacyldiethylenetetramine-carbohydrate-polyethylene glycols (MADC-PEGs); monoacyltriethylenetetramine carbohydrate-polyethylene glycols (MATC-PEGs); monosteroidglycerol-carbohydrate polyethylene glycols (MSGC-PEGs); monosteroid diethylenetetramine-carbohydrate-polyethylene glycols (MSDC-PEGs); and monosteroid triethylenetetramine-carbohydrate polyethylene glycols (MSTC-PEGs).
  • MAGC-PEGs monoacylglycerol-carbohydrate-polyethylene glycols
  • MADC-PEGs monoacyldiethylenetetramine-carbohydrate-polyethylene glycols
  • MATC-PEGs monoacyltriethylenete
  • the present invention includes linking chemical groups that can be selected to optimize and improve PEG-carbohydrate-lipid based formulations. Selecting an appropriate linker between PEG, carbohydrate and backbone can be important for several reasons, as described below.
  • An object of this invention is to develop the polymer-carbohydrate-lipids with unique linkers to help drugs to achieve therapeutic goals.
  • cytochrome P450 enzymes are a super family of proteins found in all living organisms. In humans, as well as all other mammalian species, this enzyme system is found principally in the liver but exists in all other organs and tissues. These enzymes catalyze the following reactions: aromatic hydroxylation; aliphatic hydroxylation; N-, O-, and S-dealkylation; N-hydroxylation; N-oxidation; sulfoxidation and deamination.
  • aromatic hydroxylation aliphatic hydroxylation
  • N-, O-, and S-dealkylation N-hydroxylation
  • N-oxidation N-oxidation
  • sulfoxidation and deamination Of particular importance to the present invention are the breakdown processes that the vesicles formed from news lipids, and the new lipids themselves, are expected to undergo.
  • Methoxyl and methylamine groups are expected to undergo demethylation.
  • Amines are expected to undergo N-oxidation or deamination.
  • Sulfur bonds are expected to undergo S-oxidation.
  • Esters and amides are expected to undergo hydrolysis. Since different organs and tissues have differing abilities to perform these different reactions, it is a further objective of the present invention to provide linkers with optimal degradation properties.
  • carbohydrate and lipid are digestible by humans while PEG is not.
  • PEG is readily excreted. Breaking the linkage among the three components may result in increased clearance for all. It is therefore an object of the invention to use varying biodegradable linkers for optimizing clearance rates of lipid vesicles and lipids used for drug delivery.
  • Retaining power of lipids can be important in drug formulations and preventing drug precipitation in the body fluids.
  • the present invention provides the means of enhancing retaining power by inclusion carbohydrates into PEG-lipids.
  • the sugar groups in the conjugates of the invention have larger surface polarity than PEG chainss or lipids.
  • PEG-carbohydrate-lipid conjugates provide a better drug dispersion for their applications in micro-suspension or nanoparticles, especially for some amphiphatic drugs or other compounds; this provides a better equilibrium for the drug or other compounds to partition into the lipid bilayer of the vesicle.
  • PEG-lipids such as Capmul®, Centrophase®, Cremophor®, Labrafac®, Labrafil®, Labrasol® and Myverol®
  • a taste masking agent must be used which may have additional issues for manufacturing processes and costs.
  • PEG-carbohydrate-lipid conjugates generally taste better than PEG-lipids conjugates, and can eliminate the need for taste making agents.
  • PEG-carbohydrate-lipid conjugates can be formulated into injectable preparations free from sugars that are commonly used to stabilize lyophilized proteins and peptides for injectables. Injectables prepared with PEG-carbohydrate-lipid conjugates are very stable even under high temperature and/or high humidity conditions. Reducing or eliminating the use of sugars in pharmaceutical preparation is especially beneficial for patients with diabetes mellitus.
  • the PEG chains in the conjugates of the present invention are preferably monodisperse. Materials and methods for synthesizing such monodisperse PEG chains are disclosed in U.S. patent application Ser. No. 12/802,197, which is hereby incorporated by reference in its entirety.
  • Preferably more than 50% of the PEG chains in a particular conjugate have the same molecular weight. More preferably, more than 75% have the same molecular weight. Most preferably, more than 90% have the same molecular weight.
  • the invention includes compositions and methods for synthesizing PEG-carbohydrate-lipid conjugates comprising a glycerol or a linear polyamine backbone with one PEG chain and one carbohydrate group and one lipid group bonded to the backbone.
  • Selected linkers can be used as spacers between the backbone and the PEG chain or the carbohydrate or the lipid group.
  • Variations of the invention include a variety of compounds as for the backbone with at least three available binding positions.
  • Molecules having two available binding positions such as ethylenediamine, diaminopropane, ethanolamine, and aminopropanol, can be chemically extended to three binding sites.
  • glycerol lipid monoesters may be used to formulate many compounds by linking new moieties to the available positions on the glycerol backbone. While positional isomers may be produced during synthesis, such isomers may be functionally equivalent. However, the choice of isomer may have implications in a variety of delivery process such as intracellular transport of lipophilic molecules as well as their use as vehicles in pharmaceutical applications. For example, isomers may differ in the ability to stabilize a compound during solubilizing and storage.
  • Table 1 describes amino acid linkers (“X”) useful in practicing the invention.
  • the present invention also includes nonstandard amino acid backbones such as beta-amino acids, lanthionine, Ornithine, 2-aminoisobutyric acid, dehydroalanine, selenocysteine, and gamma-aminobutyric acid.
  • nonstandard amino acid backbones such as beta-amino acids, lanthionine, Ornithine, 2-aminoisobutyric acid, dehydroalanine, selenocysteine, and gamma-aminobutyric acid.
  • amino acid linkers are Proline, Glycine, Alanine, Lysine, Cysteine, Valine, Isoleucine, Leucine, Methionine, Phenylalanine, Histidine, Tryptophan, Tyrosine, Selenocysteine, and Arginine, more preferable are Proline, Glycine, Alanine, Lysine, Cysteine, Valine, Isoleucine, Leucine, Methionine, most preferable are Proline, Glycine, Alanine and Lysine.
  • Conjugates of the present invention may comprise the linkers as listed in Table 2.
  • the structures shown in the table were mainly named by ChemDraw (CambridgeS oft, Cambridge, Mass., USA). In the event of minor variations of chemical names, the structures shown are meant to be controlling.
  • X may comprise one or more carbon atoms in addition to the linker.
  • the linker is preferably oriented so that the backbone is coupling to the three carrier groups.
  • the present invention can be practiced using a wide variety of central backbones.
  • Preferable backbones have at least three available positions for carbohydrate or lipid or PEG attachments through esterification or etherification.
  • suitable molecules can be used as the backbond including glycerol or glycerol-like analogues or linear amines or amino acids or triols or diols with a carboxy group or amine, and diamines with a hydroxyl or carboxy group.
  • the space between the two closest binding positions on the backbone is between 2 to 8 elements such as single carbon or CH 2 . Most preferable space between the two closest binding positions on the backbone is between 2 and 4 elements.
  • glycerol or glyceride or triols or aminodiols and analogues are suitable to be used as the central backbone including and not limited to 3-amino-1,2-propanediol, 3-bromo-1,2-propanediol, 3-chloro-1,2-propanediol, 3-fluoro-1,2-propanediol, DL-glyceric acid, diaminopropionic acid, tartaric acid, glucoheptonic acid, 2,4-butanetriol, 2,2-bis(hydroxy-methyl)butyric acid, 1,3-diamino-2-propanol and 2-(3-aminopropylamino)-ethanol, 34(3-aminopropyl)-amino)propanol, 2-((3-aminopropyl)amino)ethanol and 3-((3-aminopropyl)-amino)propanol.
  • linear amines are suitable to be used as the central backbones including and not limited to diethylenetriamine, spermidine, triethylenetetramine, spermine, norspermidine, bis(3-aminopropyl)-1,3-propanediamine, bis(hexamethylene)triamine.
  • amino acids with two carboxyl groups or two hydroxyl or two amino groups can be used as the central backbone
  • preferable amino acids are Aspartic Acid, Glutamic Acid, Asparagine, Glutamine, Ornithine, Serine and Threonine
  • more preferable are Aspartic Acid, Glutamic Acid, Ornithine, Serine and Threonine
  • most preferable are Aspartic Acid, Glutamic Acid, Ornithine and Serine.
  • the invention can be practiced using a wide variety of fatty acids or those of diacylglycerols consisting of two fatty acids.
  • Table 3 lists some saturated lipids for use in the invention.
  • Table 4 lists some unsaturated lipids for use in the invention.
  • Suitable lipids for synthesis of PEG-carbohydrate-lipid conjugates include bile acids (steroid acids) as well as alkyl chains. Therefore, the present invention includes a variety of PEG-carbohydrate-lipid conjugates and the steroid acid-carbohydrate-PEG conjugates can be incorporated into liposomes as a targeting moiety for lipid-based drug delivery to specific cells or as self-emulsifying drug delivery systems (SEDDS).
  • SEDDS self-emulsifying drug delivery systems
  • Bile acids constitute a large family of molecules, composed of a steroid structure with four rings, a five or eight carbon side-chain terminating in a carboxylic acid, and the presence and orientation of different numbers of hydroxyl groups.
  • the four rings are labeled from left to right A, B, C, and D, with the D-ring being smaller by one carbon than the other three.
  • An exemplary bile acid is shown in Chemical Structure 1. All bile acids have side chains. When subtending a carboxyl group that can be amide-linked with taurine or glycine, the nuclear hydroxyl groups can be esterified with glucuronide or sulfate which are essential for the formation of water soluble bile salts from bile alcohols.
  • R 1 and R 2 may be hydroxyl or proton
  • the new steroid-carbohydrate-PEGs is bile acid including and not limited to cholic acid, desoxycholic acid, dehydrocholic acid, glycochenodeoxycholic acid and glycodeoxy-cholic acid and the invention can be practiced using a wide variety of bile acids as listed in Table 5 and a steroid-carbohydrate-PEG is meant to include all racemers and structural isomers of the structure, as they can be functionally equivalent.
  • Bile acid (steroid acid) and its analogues for use in the Invention Name Chemical Structure Other Name Cholic acid 3 ⁇ ,7 ⁇ ,12 ⁇ - trihydroxy-5 ⁇ - cholanoic acid Desoxycholic acid 3 ⁇ ,12 ⁇ -Dihydroxy- 5 ⁇ -cholanic acid 5-Cholenic acid-3 ⁇ -ol 3 ⁇ -Hydroxy-5- cholen-24-oic acid Dehydrocholic acid 3,7,12-Trioxo-5 ⁇ - cholanic acid Glycocholic acid N-(3 ⁇ ,7 ⁇ ,12 ⁇ - Trifhydroxy-24- oxocholan-24-yl)- glycine Glycodeoxycholic acid N-(3 ⁇ ,12 ⁇ - Dihydroxy-24- oxocholan-24- yl)glycine Chenodeoxycholic acid 3 ⁇ ,7 ⁇ -dihydroxy-5 ⁇ - cholanic acid Glycochenodeoxycholic acid N-(3 ⁇ ,7 ⁇ -Dihydroxy- 24-oxocholan-24- yl)
  • bile salt fatty acid conjugate in which a bile acid or bile salt is conjugated in position 24 (carboxyl) with a suitable amino acid, and the unsaturated C ⁇ C bond is conjugated with one or two fatty acid radicals having 14-22 carbon atoms. That conjugate is intended to be used as a pharmaceutical composition for the reduction of cholesterol in blood, for the treatment of fatty liver, hyperglycemia and diabetes.
  • Another patent discloses acyclovir-bile acid prodrugs in which a linker group may be used between the bile acid and the compound.
  • Suitable carbohydrates for the Lipid-carbohydrate-PEG conjugates include mono-saccharides or disaccharides or oligosaccharides as listed in Table 6.
  • ketotriose dihydroxyacetone
  • aldotriose charide glycolaldehyde
  • ketotetrose erythrulose
  • aldotetroses erythrose, threose
  • pentoses ketopentose ribulose, xylulose
  • aldopentose ribose, arabinose, xylose, lyxose
  • deoxy carbohydrate deoxyribose
  • hexoses ketohexose (psicose, fructose, sorbose, tagatose)
  • aldohexose allose, altrose, glucose, mannose, gulose, idose, galactose, talose
  • deoxy carbohydrate fucose, fuculose, rhamnose
  • others heptose (sedo
  • the lipid-carbohydrate-PEG conjugates of the present invention may be used for many applications. Formulation and delivery of pharmaceutical and cosmetic agents have been described. Additionally, the Lipid-carbohydrate-PEGs of the present invention may be used in other contexts where water soluble lipids are advantages, for example industrial and food processes.
  • the syntheses used in this invention to form monoacylglycerol-carbohydrate-polyethyleneglycols generally utilizes the reaction of the PEG polymer with a linker that is reactive with hydroxyl groups, typically anhydrides, acid chlorides, chloroformates and carbonates, aldehyde, esters, amides etc ore more efficient functional groups for the conjugation.
  • Preferred end groups include maleimide, vinyl sulfones, pyridyl disulfide, amine, carboxylic acids and succinimidyl (NHS) esters.
  • the invention includes a PEG-carbohydrate-lipid conjugate having the General Structure 2:
  • the backbone is selected from glycerol or glycerol-like analogues or linear amines (tri- or tetra-amines) or amino acids having three available binding sites; where the lipid is selected from carboxylic acids including and not limited to diacylglycerols or fatty acids or bile acids; sugar is a carbohydrate including monosaccharides or disaccharides or oligosaccharides; where the three substitutable groups are covalently bond to the backbone through a etherification or esterification or amidification or similar substitution reactions.
  • the General Structure is meant to include all racemers or structural isomers of the structure, as they can be functionally equivalent. Where the PEG chain may consist of between about 5 and 45 subunits.
  • R is the terminal group on the PEG chain can be selected from a wide variety of chemical moieties.
  • R preferably has a molecular weight of less than about 650.
  • the PEG-carbohydrate-lipid conjugates are useful for applications other than liposomes, e.g., as a solvent.
  • Synthesis of the new lipids may be controlled so that there is a single linker in each Lipid-carbohydrate-PEG molecule. In some situations, however, it may be useful to have multiple copies of the same linker, or combinations of different linkers in a single molecule as the following General Structure 3:
  • lipid is an alkyl group having between 4 and 22 carbons (Tables 3 and 4) or bile acids (Table 5) having a particular steroid structure of 24 carbons; where sugar is a carbohydrate including monosaccharides or disaccharides or oligosaccharides (Table 6); and where X is one or more linkers selected from the Table 1 or 2 or groups consisting of oxy, amino acids, amino, succinylamino, acetamido, aminopentanamido, aminoacetyl, thiopropanoayl, N-(mercaptomethyl)propionamido, mercaptopropylthio)-propanoyl, (1,2-dihydroxy-3-mercaptopropylthio)propanoyl, succinyl, acetyl, oxopentanoyl, carbamoyl, aminoalkyl, glutaramido, aminoethanethiol, mercaptopropanol, (hydroxyprop
  • the invention includes a PEG-carbohydrate-lipid conjugate represented by the following General Structure 4:
  • lipid is a diacylglycerol or a alkyl group having between 4 and 22 carbons (Table 3 and 4) or bile acids having a particular steroid structure of 24 carbons (Table 5); where carbohydrate is a carbohydrate including monosaccharides or disaccharides or oligosaccharides; and where X 1 and X 2 are the same or different linkers that consist of one or more linkers selected from the Table 1 or 2 or the group of oxy, amino, succinylamino, acetamido, aminopentanamido, aminoacetyl, thiopropanoayl, N-(mercaptomethyl)-propionamido, mercaptopropylthio)-propanoyl, (1,2-dihydroxy-3-mercaptopropylthio)-propanoyl, succinyl, acetyl, oxopentanoyl, carbamoyl, aminoalkyl, glutaramido,
  • R i has a molecular weight of less than about 650.
  • Fatty acid may preferably be selected from the group consisting of oleate, myristate, linoleate and palmitate.
  • Sugar may preferably be selected from Table 6, the group consisting of aldose, ketose, pyranose, furanose, trioses, tetroses, pentoses, hexoses, sucrose, lactose, maltose, trehalose, turanose, cellobiose, raffinose, melezitose, maltotriose, acarbose, stachyose.
  • the PEG chain may consist of between about 6 and 45 subunits. More preferably the PEG chain consists of between about 8 and 24 subunits. Still more preferably the PEG chain consists of between about 12 and 24 subunits.
  • the invention includes a compound represented by the following General Structure 5:
  • Lipid 1 and Lipid 2 may be the same or different alkyl groups having between 4 and 22 carbons (Tables 3 and 4) or bile acids having a particular steroid structure of 24 carbons (Table 5); and where sugar is a carbohydrate selected from Table 6, the group consists of aldose, ketose, pyranose, furanose, trioses, tetroses, pentoses, hexoses, sucrose, lactose, maltose, trehalose, turanose, cellobiose, raffinose, melezitose, maltotriose, acarbose, stachyose.
  • X 1 and X 2 may be the same or different linkers that consist of one or more linkers selected from the Table 1 or 2 or the group of oxy, amino, succinylamino, acetamido, aminopentanamido, aminoacetyl, thiopropanoayl, N-(mercaptomethyl)propionamido, mercaptopropylthio)-propanoyl, (1,2-dihydroxy-3-mercaptopropylthio)propanoyl, succinyl, acetyl, oxopentanoyl, carbamoyl, aminoalkyl, glutaramido, aminoethanethiol, mercaptopropanol, (hydroxypropylthio)propanoayl, 3-((2-propionamidoethyl)-disulfanyl)propanoayl, (((acetamidoethyl)disulfanyl)propanoyl
  • Lipid 1 and Lipid 2 may preferably be selected from the group consists of oleate, myristate, linoleate and palmitate.
  • the PEG chain may consist of between about 3 and 45 subunits. More preferably the PEG chain consists of between about 4 and 24 subunits. Still more preferably the PEG chain consists of between about 4 and 12 subunits.
  • the invention includes a molecule comprising a compound represented by the following General Structure 6:
  • sugar is a carbohydrate selected from Table 6, the group consists of aldose, ketose, pyranose, furanose, trioses, tetroses, pentoses, hexoses, sucrose, lactose, maltose, trehalose, turanose, cellobiose, raffinose, melezitose, maltotriose, acarbose, stachyose; and where lipid is a diacylglycerol or a fatty acid from alkyl groups (Tables 3 & 4) having between 4 and 22 carbons or bile acids having a particular steroid structure of 24 carbons (Table 5); where X 1 and X 2 may be same or different linkers selected from Table 1 or 2 or a group consisting of oxy, amino, succinylamino, acetamido, aminopentanamido, aminoacetyl, thiopropanoayl, N-(mercaptomethyl)propiona
  • R i has a molecular weight of less than about 650.
  • Lipid may preferably be selected from diacylglycerols or a fatty acid the group consisting of oleate, myristate, linoleate and palmitate.
  • PEG 1 and PEG 2 may have the same or a different number of subunits.
  • the PEG chain may consist of between about 3 and 45 subunits. More preferably the PEG chain consists of between about 4 and 24 subunits. Still more preferably the PEG chain consists of between about 4 and 12 subunits.
  • the invention includes a molecule comprising a compound represented by the following General Structure 7:
  • sugar is a carbohydrate selected from Table 6, the group consists of aldose, ketose, pyranose, furanose, trioses, tetroses, pentoses, hexoses, sucrose, lactose, maltose, trehalose, turanose, cellobiose, raffinose, melezitose, maltotriose, acarbose, stachyose; and where lipid is selected from alkyl groups (Tables 3 and 4) having between 4 and 22 carbons or bile acids having a particular steroid structure of 24 carbons (Table 5); and where X 1 , X 2 and X 3 are the same or different linkers selected from Table 1 or 2 or a group consisting of one or more linkers selected from oxy, amino, succinylamino, acetamido, aminopentanamido, aminoacetyl, thiopropanoayl, N-(mercaptomethyl)propionamido
  • R i has a molecular weight of less than about 650.
  • R i may be either —OH or —OCH 3 .
  • the lipid may preferably be selected from diacylglycerols or the group consisting of oleate, myristate, linoleate and palmitate.
  • PEG 1 , PEG 2 and PEG 3 may have the same or a different number of subunits.
  • the PEG chain may consist of between about 3 and 45 subunits. More preferably the PEG chain consists of between about 3 and 24 subunits. Still more preferably the PEG chain consists of between about 4 and 12 subunits.
  • the invention includes a molecule comprising a compound represented by the following General Structure 8:
  • the backbone is selected from glycerol or glycerol-like analogues or linear amines (tri- or tetra-amines) or amino acids having three available binding sites; where the lipid is selected from diacylglycerols or carboxylic acids including and not limited to fatty acids or bile acids; sugar is a carbohydrate including monosaccharides or disaccharides or oligosaccharides; where the three substitutable groups are covalently bond to the backbone through a etherification or esterification or amidification or similar substitution reactions.
  • the General Structure is meant to include all racemers or structural isomers of the structure, as they can be functionally equivalent.
  • bPEG is a branched PEG with 2 or more PEG chains and each PEG chain may consist of between about 5 and 45 subunits.
  • R i is the terminal group on each PEG chain which may be the same or different and that can be selected from a wide variety of chemical moieties.
  • R i preferably has a molecular weight of less than about 650.
  • the PEG-carbohydrate-lipid conjugates are useful for applications other than liposomes, e.g., as a solvent.
  • Another aspect of the invention includes a method of delivering a compound, where the method comprises preparing a PEG-carbohydrate-lipid conjugate based formulation of the compound, where the formulation comprises a PEG-carbohydrate-lipid having an amino acid linker and possible secondary linker(s) selected from the group consisting of amino, succinylamino, acetamido, aminopentanamido, aminoacetyl, thiopropanoayl, N-(mercaptomethyl)propionamido, mercaptopropylthio)-propanoyl, (1,2-dihydroxy-3-mercaptopropylthio)propanoyl, succinyl, acetyl, oxopentanoyl, carbamoyl, aminoalkyl, glutaramido, aminoethanethiol, mercaptopropanol, (hydroxypropylthio)propanoayl, 3-((2-propionamidoethyl
  • the invention is a method of linking the central backbone to any of the three carrier groups via an amino acid linkage.
  • the carrier group may be activated by reacting it with disucccimidylcarbonate (DCS).
  • the activated acyl carrier group may then be directly reacted with an amino acid (AA) having a hydroxy group to produce a conjugate having an ester linkage.
  • AA amino acid
  • the carboxyl group of amnio acid from AA-acylglycerate can react with one of hydroxy group of PEG and then the protection group on the primary amine is removed and reacted with the activated carbohydrate to form the PEG-lipid conjugates as depicted in Chemical Structure 1, where lipid may be a diacylglycerol or monoacyl group or fatty acid or or steroid acid.
  • the general structures shown in the application are meant to include all racemers and structural isomers of the structures, as they can be functionally equivalent.
  • the invention includes Lipid-carbohydrate-PEG conjugates comprised of three carrier groups and a central backbone having at three positions available for the conjugation, and one or more linker(s) between one of the carrier groups and the central backbone.
  • Such lipid-carbohydrate-PEG conjugates are represented by the Chemical Structures 1, where X may comprise a linker selected from Table 1 and 2 or a group consisting of amino, succinylamino, acetamido, aminopentanamido, aminoacetyl, thiopropanoayl, N-(mercaptomethyl)propionamido, mercaptopropylthio)-propanoyl, (1,2-dihydroxy-3-mercaptopropylthio)propanoyl, succinyl, acetyl, oxopentanoyl, carbamoyl, aminoalkyl, glutaramido, aminoethanethiol, mercaptopropanol, (hydroxy
  • ODL-PEG Oleoyldiethylenetriamine- PEG Lactobionate
  • n 6 to 24
  • ODL-bioPEG Oleoyldiethylenetriamine- biotinylated PEG Lactobionate
  • n 6 to 24
  • ODL-ThrPEG Oleoyldiethylenetriamine- threoninyl PEG Lactobionate
  • n 6 to 24
  • ODL-TrpPEG Oleoyldiethylenetriamine- Trypto
  • Embodiments of the present invention are described herein in the context of preparation of pharmaceutical compositions including purified PEG-lipid conjugates for increasing the solubility and enhancing the delivery of active agents.
  • the approximate preferable compositions for formulated drug products are generally described herein, though different drugs typically have differing optimal formulations.
  • the preferable concentration of drug is 0.1% to 30%. More preferable is 0.5 to 10%. Most preferable is 0.5 to 5%.
  • the preferable weight ratio of PEG-lipid to the drug (PEG-Lipid/drug) in the final drug solution for the injection is 1 to 30. More preferable is 1 to 20. Most preferable is 1 to 10.
  • PEG-carbohydrate-lipid conjugates having monodisperse PEG chains for intravenous administration of pharmaceutical agents.
  • the monodisperse PEG chains may consist of one or more PEG oligomers where the total oligomer purity from individual oligomers should be higher than 90%.
  • a monodisperse PEG chain may contain 50% of PEG-12 and 40% of PEG-15.
  • the preferable concentration of drug is 1% to 40%. More preferable is 2.5 to 30%. Most preferable is 5 to 30%.
  • the preferable ratio of PEG-lipid to the drug (PEG-Lipid/drug) is 0.5 to 20. More preferable is 1 to 10. Most preferable is 1 to 5.
  • the preferable concentration of drug is 0.01 to 5%. More preferable is 0.05 to 2%. Most preferable is 0.1 to 2%.
  • the preferable ratio of PEG-lipid to the drug (PEG-Lipid/drug) is 1 to 20. More preferable is 3 to 15. Most preferable is 5 to 10.
  • the preferable concentration of drug is 0.05 to 5%. More preferable is 0.1 to 5%. Most preferable is 0.1 to 2%.
  • the preferable ratio of PEG-lipid to the drug (PEG-Lipid/drug) is 1 to 20. More preferable is 3 to 15. Most preferable is 5 to 10.
  • the preferable capsule content of drug is 10 mg to 250 mg. More preferable is 25 mg to 200 mg. Most preferable is 25 mg to 100 mg.
  • the preferable ratio of PEG-lipid to the drug (PEG-Lipid/drug) is 1 to 10. More preferable is 1 to 5. Most preferable is 2 to 5.
  • the preferable concentration of active is 0.5 to 5%, more preferable is 0.5 to 2%, most preferable is 1 to 2%.
  • the preferable ratio of PEG-lipid to the drug (PEG-Lipid/drug) is 1 to 30, more preferable is 1 to 20, most preferable is 3 to 10.
  • the invention further includes alternate backbones and polymers.
  • 3-amino-1,2-propanediol, 3-bromo-1,2-propanediol, 3-chloro-1,2-propanediol, 3-fluoro-1,2-propanediol, DL-glyceric acid, dimethylol propionic acid (2,2-bis(hydroxymethyl)propionic acid), tartaric acid, glucoheptonic acid and 1,2,4-butanetriol may be used as alternative backbones to synthesize similar PEG-carbohydrate-lipid conjugates.
  • the PEG chain (or alternative polymer chain) is preferable as monodisperse or narrow dispersive, especially for intravenous administration of pharmaceutical products.
  • the polymer-sugar-lipid conjugates having a amino acid central component or backbone including a PEG chain the invention further includes those amino acids with two carboxyl groups or two hydroxyl or two amino groups.
  • Preferable amino acids are Aspartic Acid, Glutamic Acid, Glutamine, Asparagine, Serine, Threonine, Arginine, Histidine, Lysine, Ornithine, Threonine, Tryptophan and Tyrosine, more preferable are Aspartic Acid, Glutamic Acid, Ornithine, Serine and Threonine, and most preferable are Aspartic Acid, Glutamic Acid, Ornithine and Serine.
  • the PEG chain (or alternative polymer chain) is preferable as monodisperse or narrow dispersive, specifically for intravenous administration of pharmaceutical products.
  • the polymer-lipid conjugates having a linear multiamine central component or backbone including a PEG chains further includes those those linear amines are suitable to be used as the central backbones including and not limited to diethylenetriamine (spermidine), triethylenetriamine (spermine), norspermidine, bis(3-aminopropyl)-1,3-propanediamine, bis(hexamethylene)triamine.
  • the PEG chain (or alternative polymer chain) is preferable as monodisperse narrow dispersive, specifically for intravenous administration of pharmaceutical products.
  • N,N′-dicyclohexylurea, N,N′-dicyclohexylcarbodiimide, lactobionic acid, and other chemicals were obtained from Sigma-Aldrich (St. Louis, Mo., USA).
  • Activated PEG or biotinylated PEG were obtained from Quanta BioDesign (Powell, Ohio, USA) or Thermo Fisher Scientific (Rockford, Ill.).
  • Effective reagents for the deprotection of tert-butyl carbamates or tert-butyl esters include phosphoric acid and trifluoroacetic acid. The reactions give high yields and very convenient [Li, B. Kirk, M. etc, J. Org. Chem., 2006; 71, 9045]. Equal volumes of Trifluoroacetic acid was added to a solution of Boc-carbamate (10% of crude product) in CH 2 Cl 2 . The resulting solution was stirred at room temperature for overnight and the solvent was evaporated and the residue was re-dissolved into CH 2 Cl 2 , then washed with saturated NaHCO 3 and dried over MgSO 4 . Solvent was evaporated and was used in next step without further purification.
  • the protection group of tert-butyl carbamate on the amino group was removed according to the method described in Example 2.
  • 0.01 moles of oleoylserinylmonomethoxyl -dodecaethylene glycol (0.01 mmol) from Example 4 was dissolved with 50 mL of anhydrous N-methyl-2-pyrrolidinone, 0.01 moles of Lactobionolactone was added.
  • the resulting mixture was stirred at 50-60° C. for overnight, and allowed to cool to the room temperature.
  • the reaction solution was precipitated into isopropyl alcohol (IPA) and methyl t-butyl ether (MTBE) was added to maximize the isolated yield of precipitate.
  • IPA isopropyl alcohol
  • MTBE methyl t-butyl ether
  • lactobionyldiethylenetriamine 0.01 mole of the starting material from Example 6, lactobionyldiethylenetriamine, was dissolved in 20 mL of dimethylformamide (DMF) at 20 to 30° C. The slightly excess active oleic acid N-hydroxysuccinimide ester (0.011 mol) was dissolved in 20 mL of tetrahydrofuran (THF), then mixed with lactobionyldiethylenetriamine and adding triethylamine (TEA, 3%, v/v) as a base, stirred for 2 hrs at room temperature. An assay was performed to verify the yield and moves to next the step 2 without purification.
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • the active mPEG 24 -NHS (0.01 mol) was dissolved in DMF, then mixed with the above reactants, stirred for overnight at room temperature. After the completion of the reaction, solvents were removed by vacuo and 50 mL of acetone was added to the crude product and filtered and washed with 30 mL of acetone three times. The wet product (60-70%) was further lyophilized to a wax as showed in Chemical Structure 7.
  • the polymer chain can be replaced by other polymer(s) such as polymethylene glycol or polypropylene glycol or a mixture of the repeating units of methylene glycol, ethylene glycol and propylene glycol.
  • Hydrophilic polymers useful in forming the polymer-lipid conjugates of the invention include polyethyleneglycol (PEG) and other polyalkene oxide polymers, polyoxyethylene alkyl ethers, polyvinylpyrrolidone, Poly(Allyl Amine), Poly(1-glycerol methacrylate), Poly(2-ethyl-2-oxazoline), Poly(2-hydroxyethyl methacrylate/methacrylic acid)/poly(2-hydroxyethyl methacrylate), Poly(2-vinylpyridine), Poly(acrylamide/acrylic acid), Poly(acrylic acid), Poly(butadiene/maleic acid), Poly(ethyl acrylate/acrylic acid), Poly(ethylene oxide-b-propylene oxide), Poly(ethylene/acrylic acid
  • Copolymers and block copolymers based on the list above may also be used.
  • the free polymers are water-soluble at room temperature, as well as non-toxic. They do not elicit an appreciable immunogenic response in mammals.
  • Hydrophilic polymers with narrow molecular weight distributions are preferable. Because of already existing acceptance in the pharmaceutical business, PEG is the preferred hydrophilic polymer.
  • a drug substance was charged to a suitable blender (e.g., Bohle bin blender) and mixed for 10 minutes at 10 RPM. Based on the amount of the drug charged, required amounts of a solid PEG-carbohydrate-PEG conjugate was passed through a No. 30 mesh screen and blended with the drug substance for 30 minutes at 10 RPM. Compacting and milling the blend using a suitable compactor and rotating impeller screening mill fitted with a 30-mesh screen. The process was kept until the target tapped density ⁇ 0.50 g/mL was achieved. The final blends were encapsulated into No. 4 white opaque hard gelatin capsule shells at a target fill weight of 100 mg with a suitable capsule machine and the filled capsules were polished with a suitable polisher. A sample formulation is described in Table 8.
  • a suitable blender e.g., Bohle bin blender
  • the solid lipid conjugate may be selected from any of the PEG-carbohydrate-lipid conjugates with a longer PEG chain consisting of between about 18 and 45 subunits.
  • the drug may be modafinil or nifedapine or esomeprazole or rapamycin or a fungicide or another active agent.
  • PEG-lipid was added to a vessel equipped with a mixer propeller.
  • the drug substance was added with constant mixing. Mixing continued until the drug was visually dispersed in the lipids. Pre-dissolved excipients were slowly added to the vessel with adequate mixing. Mixing continued until fully a homogenous solution was achieved.
  • a sample formulation is described in Table 9.
  • the liquid lipid may be any of PEG-carbohydrate-lipid conjugates with a shorter PEG chain consisting of between about 6 and 16 subunits.
  • Sodium hydroxide is used to prepare a 10% w/w solution in purified water.
  • the targeted pH is in a range of 4.0 to 7.0.
  • NaOH is used to adjust pH if necessary.
  • the drug may be modafinil or nifedapine or esomeprazole or rapamycin or a fungicide or another active agent.
  • PEG-lipid was added to a vessel equipped with a mixer propeller.
  • the drug substance was added with constant mixing. Mixing continued until the drug was visually dispersed in the lipids. Pre-dissolved excipients were slowly added to the vessel with adequate mixing. Mixing continued until fully a homogenous solution was achieved.
  • the tank impeller mixing speed was approximately 45-50 RPM and compressed air supply pressure to the mixer was between 10-13 psig.
  • the liquid lipid may be any of PEG-carbohydrate-lipid conjugates with a shorter PEG chain consisting of between about 6 and 16 subunits.
  • Sodium hydroxide is used to prepare a 10% w/w solution in purified water.
  • the targeted pH is in a range of 6.0 to 8.0.
  • NaOH or phosphoric acid is used to adjust pH if necessary.
  • the drug may be modafinil or nifedapine or esomeprazole or rapamycin or fungicide or anticancer agent of tinib or another active agent.
  • PEG-carbohydrate-lipid was added to a stainless steel vessel equipped with propeller type mixing blades.
  • the drug substance was added with constant mixing. Mixing continued until the drug was visually dispersed in the lipids at a temperature to 60°-65° C.
  • Organic acid, Cholesterol and glycerin were added with mixing.
  • Ethanol and ethyoxydiglycol were added with mixing.
  • Carbopol ETD 2020, purified water and triethylamine were added with mixing. Mixing continued until fully a homogenous cream was achieved.
  • the formulation is described in Table 11.
  • the lipid may be any of PEG-carbohydrate-lipid conjugates with a PEG chain consisting of between about 6 and 24 subunits.
  • Organic acid may be lactic acid or pyruvic acid or glycolic acid.
  • Sodium hydroxide is used to adjust pH if necessary. The targeted pH range was between 3.5 and 7.0.
  • the drug may be itraconazole, posaconazole, voriconazole or equaconazole, Terbinafine, Amorolfine, Naftifine, Butenafine, Benzoic acid, Ciclopirox, Tolnaftate, Undecylenic acid, Flucytosine, Griseofulvin, Haloprogin, Sodium bicarbonate or Fluocinolone acetonide or azithromycin.
  • the topical solution was prepared as in Example 11, a sample formulation is described in Table 12.
  • the lipid may be any of PEG-carbohydrate-lipid conjugates with a PEG chain consisting of between about 6 and 16 subunits.
  • Organic acid may be lactic acid or pyruvic acid or glycolic acid.
  • Sodium hydroxide is used to adjust pH if necessary. The targeted pH range was between 3.5 and 7.0.
  • the drug may be itraconazole, posaconazole, voriconazole or equaconazole, Terbinafine, Amorolfine, Naftifine, Butenafine, Benzoic acid, Ciclopirox, Tolnaftate, Undecylenic acid, Flucytosine, Griseofulvin, Haloprogin, Sodium bicarbonate or Fluocinolone acetonide or azithromycin.
  • PEG-carbohydrate-lipid was added to a vessel equipped with a mixer propeller.
  • the azithromycin drug substance was added with constant mixing. Mixing continued until the drug was visually dispersed in the lipids. Pre-dissolved excipients and sterile purified water were slowly added to the vessel with adequate mixing. Mixing continued until fully a homogenous solution was achieved.
  • a sample formulation is described in Table 13.
  • the lipid may be any of PEG-carbohydrate-lipid conjugates with a PEG chain consisting of between about 6 and 16 subunits.
  • Sodium hydroxide is used to prepare a 10% w/w solution in purified water.
  • the targeted pH is in a range of 7.0 to 7.8.
  • NaOH is used to adjust pH if necessary.
  • the active may be azithromycin or itraconazole or posaconazole or voriconazole or another active agent.
  • thermolabile peptide with the following sequence was used as the model compound: Phe-Pro-Lys-Leu-Ser-His-Gly-Cys-Asn-Lys-His-Ser-Arg-Lys-His-Pro-Tyr-Met-Thr-Phe.
  • the peptide was added to selected media and sonicated for 10 minutes.
  • the sample solutions were filtered through passed through 0.22- ⁇ m pore-size filter to remove dust particles before the HPLC assay.
  • the peptide was degraded significantly in 24 hours in a 50 mM of phosphate buffer, in the contrast; more than 97% of the peptide was still remaining in a 2% of PEG-carbohydrate-lipid after the same period of the time.
  • FIG. 2 shows the peptide stability profile of 100 ⁇ g peptide/mL in a) 2% ODL-PEG 15 in 50 mM sodium phosphate buffer (pH 7.0), b) 2% ODL-PEG 15 in 50 mM sodium phosphate buffer (pH 8.0) and c) 50 mM sodium phosphate buffer (pH 7.0).
  • the plots were the % recovery vs. time.
  • FIG. 3 shows Laptinib mouse PK profiles of (a) 5% Cremophor EL® plus 5% methanol in 10 mM sodium phosphate buffer (pH 7.0), b) 1% ODL-15 in 10 mM sodium phosphate buffer (pH 7.0), (b) 2% ODL-15 in 10 mM sodium phosphate buffer (pH 7.0) and the drug was administered intravenously and the dosing strength was 10 mg/kg.
  • the AUC obtained from the IV administrations were, 7741, 8594 and 1477 for 1% of ODL-15, 2% of ODL-15 and Cremophor EL®, respectively.
  • a propofol solution suitable for intravenous delivery is prepared as follows. 5% (w/v) of OAPDL-PEG in Saline was added to a vessel equipped with a mixer propeller and 2% (w/v) of Propofol was added with constant mixing at ambient room temperature. Mixing was continued until the drug was visually dispersed. Equal volume of Saline was added to the vessel with adequate mixing. Mixing continued for another 30 minutes or until a homogenous solution was achieved.
  • a sample formulation is described in Table 15.
  • the PEG-lipid may be any of PEG-carbohydrate-lipid conjugates with a PEG chain consisting of between about 6 and 24 subunits.
  • Sodium hydroxide is used to prepare a 10% w/w solution in purified water.
  • the targeted pH is in a range of 4.5 to 7.5.
  • the NaOH solution is used to adjust pH if necessary.
  • the final concentration of the PEG-carbohydrate-lipid is preferably between about 16 mg/mL and about 30 mg/mL.
  • the weight ratio of the total PEG-lipid to Propofol is preferably between about 2.0 and 2.5.
  • the average MW of PEG chains in the PEG-lipid is preferably less than about 1000.
  • the aqueous solution of Propofol can be further sterilized by filtration and sealed in sterile containers.
  • Example 16 less concentrated or less purified PEG-sugar-lipid will create a suspension instead of an aqueous solution.
  • the final concentration of the PEG-carbohydrate-lipid is less than 1.5% (w/v), it will form a suspension.
  • the oligomer purity is 80% or less, regardless the concentration of the PEG-carbohydrate-lipid, an emulsified solution will be observed instead of a transparent solution.
  • PK Pharmacokinetics
  • FIG. 4 shows mouse PK profiles of propofol formulations with (a) a commercial product of 1% Propofol (emulsified suspension) and (b) 1% of Propofol in a formulation consisting of 2.3% of OAPDL-11 in saline solution.
  • the drug was administered intravenously and the dosing strength was 20 mg/kg.
  • the AUC were 29.85 ⁇ g ⁇ min/mL with a half-life of 4.96 minutes for the commercial Propofol emulsified suspension (a) and 28.82 ⁇ g ⁇ min/mL with a half-life of 4.93 minutes for the Propofol solution (b) in OAPDL-11-saline, respectively.
  • the invention comprises a method of solubilizing a water-insoluble agent, i.e., a drug compound that, because of low solubility in water, typically requires formulation with a pharmaceutically acceptable carrier for effective delivery to an intended site of action.
  • a water-insoluble agent i.e., a drug compound that, because of low solubility in water, typically requires formulation with a pharmaceutically acceptable carrier for effective delivery to an intended site of action.
  • Such delivery may be intravenous, oral, topical, subdermal, sublingual, or any other mode of drug delivery.
  • the invention also includes compositions for such delivery. Both the methods and the compositions related to delivery of water-insoluble agents employ the PEG-carbohydrate-lipid conjugates of the present invention and the methods and materials described above.
  • the conjugates of the present invention do not have a critical micellar concentration (CMC). Micelles only form when the concentration of surfactant is greater than the CMC, and the temperature of the system is greater than the critical micelle temperature.
  • the present polymer-lipid conjugates form aggregates spontaneously at any given concentration.
  • the present invention discloses a novel polymer-lipid conjugate system having at least one of carbohydrate moiety that can be used as a safe and biocompatible vehicle for drug or molecule delivery.
  • a therapeutic, diagnostic or cosmetic agent may be solubilized or encapsulated in those polymer-lipid conjugates to form a solution or micro-suspension.
  • the invention includes compositions and methods for synthesizing polymer-lipid-carbohydrate conjugates comprising a glycerol backbone or a linear multiamine or amino acid with a polymer (PEG) chain, a sugar (carbohydrate) and a lipid group bonded to the backbone.
  • PEG polymer
  • Spacer or linker groups including amino acids may be included between the backbone and the PEG chains, carbohydrates or and/or lipid groups.
  • the terminal end of PEG chain may be a charged or polar moiety.
  • the compounds of the present invention are effective to formulate compositions of active agents whereby side effects and toxicities associated with therapeutic treatments are reduced.
  • the permeation enhancement properties of PEG-lipid conjugates can increase the in vivo targeted delivery of drugs, reduce toxicity and improve oral bioavailability of various drugs.
  • Solutions comprising conjugates of the present invention with solubilized active agents that can incorporate many active agents, including but not limited to propofol, cisplatin, docetaxel, voriconizole and gemcitabin.
  • Propofol belongs to the group of phenols that can directly irritate the skin, mucous membrane and venous intima and could immediately stimulate nociceptors and free nerve endings [Ambesh S P, Dubey P K, Sinha P K. “Ondansetron pretreatment to alleviate pain on propofol injection: a randomized, controlled, double-blinded study.” Anesth Analg. 1999; 89: 197-9].
  • the concentration of aqueous free propofol is related to injection pain.
  • the pain associated with propofol injection may be due to the sizes of propofol droplets; the free Propofol is in a range of 150 to 300 nm, which can slow down the migration or diffusion of the drug in the body and cause longer interactions between Propofol and free nerve endings.
  • Propofol as the active agent was formulated with various polymer-lipid-carbohydrate conjugates described in the present invention.
  • the formulation is a microemulsion and at a higher OAPDL-11 concentration ( ⁇ 2.2%), it is a true solution.
  • a solution is defined as a homogenous mixture of substances with variable composition.
  • true solutions also have certain other characteristics. For example, components of a solution never separate spontaneously, even when a significant density difference exists between the components. Solutions also pass through the finest filters unchanged.
  • FIG. 5 shows that the HPLC-FL chromatograms of 1%-Propofol formulated with 2.2% of OAPDL-11 in comparison with the same Propofol solution after filtered through a 0.2 ⁇ m Acrodisc® PF filter.
  • X 1 , X 2 and X 3 are linking groups.
  • Still another feature or aspect of an embodiment is believed at the time of the filing of this patent application to possibly reside broadly in a chemical compound or a method of making a compound wherein suitable molecules can be used as the backbone including glycerol or glycerol-like analogues or polyamines or amino acids or triols or diols with a carboxy group or amine or diamines with a hydroxyl or carboxy group and extensible amines or alcohols.
  • a further feature or aspect of an embodiment is believed at the time of the filing of this patent application to possibly reside broadly in a chemical compound or a method of making a compound wherein a variety of compounds can be used as for the backbone with at least three available binding positions or molecules can be chemically extended to three binding sites from two available binding positions including and not limited to ethylenediamine or diaminopropane or ethanolamine or aminopropanol. More preferable the space between the two closest binding positions on the backbone is between 2 to 8 subunits such as single carbon or CH 2 . Most preferable space between the two closest binding positions on the backbone is between 2 and 4 subunits.
  • the PEG chain may consist of between about 3 and 45 subunits. More preferably the PEG chain consists of between about 5 and 24 subunits. Still more preferably the PEG chain consists of between about 8 and 16 subunits.
  • Still another feature or aspect of an embodiment is believed at the time of the filing of this patent application to possibly reside broadly a chemical compound or a method of making a compound wherein the PEG-carbohydrate-lipid is a compound represented by the formulas of the General Structure 1, 2, 3, 4, 5, 6, 7 and 8.
  • a further feature or aspect of an embodiment is believed at the time of the filing of this patent application to possibly reside broadly in a chemical compound or a method of making a compound wherein the lipid group is selected from diacylglycerols and the alkyl groups in Table 3 and Table 4 or steroid acid in Table 5
  • Another feature or aspect of an embodiment is believed at the time of the filing of this patent application to possibly reside broadly in a chemical compound or a method of making a compound wherein the carbohydrate is a carbohydrate including monosaccharides or disaccharides or oligosaccharides selected from Table 6.
  • Another feature or aspect of an embodiment is believed at the time of the filing of this patent application to possibly reside broadly in a chemical compound or a method of making a compound wherein preferable amino acid linkers are Proline, Glycine, Alanine, Lysine, Cysteine, Valine, Isoleucine, Leucine, Methionine, Phenylalanine, Histidine, Tryptophan, Tyrosine, Selenocysteine, and Arginine.
  • central backbone is those glycerol or glyceride or triols or aminodiols and analogues selected from the group consisting of 3-amino-1,2-propanediol, 3-bromo-1,2-propanediol, 3-chloro-1,2-propanediol, 3-fluoro-1,2-propanediol, DL-glyceric acid, diaminopropionic acid, tartaric acid, glucoheptonic acid and, 2,4-butanetriol, 2,2-Bis(hydroxymethyl)butyric acid, 1,3-Diamino-2-propanol and 2-(3-Aminopropylamino)-ethanol.
  • Still another feature or aspect of an embodiment is believed at the time of the filing of this patent application to possibly reside broadly in a chemical compound or a method of making a compound wherein the central backbone is a linear amine including diethylenetriamine, spermidine, triethylenetetramine, spermine, norspermidine, bis(3-aminopropyl)-1,3-propanediamine, bis(hexamethylene)triamine.
  • a further feature or aspect of an embodiment is believed at the time of the filing of this patent application to possibly reside broadly in a chemical compound or a method of making a compound wherein the central backbone is selected from a group consisting of a amino acid with two carboxyl groups or two hydroxyl or two amino groups including aspartic acid, glutamic acid, asparagine, glutamine, ornithine, serine and threonine, more preferable are aspartic acid, glutamic acid, ornithine, serine and threonine.
  • Another feature or aspect of an embodiment is believed at the time of the filing of this patent application to possibly reside broadly in a chemical compound or a method of making a compound wherein the PEG chain is perfectible monodisperse for intravenous administration of pharmaceutical agents and the monodisperse PEG chain may contain a few numbers of oligomers.
  • the preferable number of oligomers is 1 to 5, more preferable is 1 to 3. Most preferable is 1 to 2.
  • Yet another feature or aspect of an embodiment is believed at the time of the filing of this patent application to possibly reside broadly in a chemical compound or a method of making a compound wherein the PEG chains are replaced by polymers selected from the group consisting of polymethylene glycol, polypropylene glycol, and copolymers comprised of a at least two of the monomers selected from the group consisting of methylene glycol, propylene glycol and ethylene glycol.
  • Still another feature or aspect of an embodiment is believed at the time of the filing of this patent application to possibly reside broadly in a chemical compound or a method of making a compound wherein the terminal (R) group is preferably easily polarized or negatively or positively charged head-groups such as alkoxy moieties, amines, amino acids, and oligosaccharides.
  • a further feature or aspect of an embodiment is believed at the time of the filing of this patent application to possibly reside broadly in a chemical compound or a method of making a compound wherein the composition for delivery of an active agent, comprising: a chemical compound is represented by the formula
  • X 1 , X 2 and X 3 are linking groups; and the active agent is a poorly water soluble compound of Biopharmaceutics classification II or IV including but not limited to propofol, docetaxel, paclitaxel, voriconazole and posacanzole.
  • Another feature or aspect of an embodiment is believed at the time of the filing of this patent application to possibly reside broadly in a method of delivering a compound, the method comprising preparing a polymer-carbohydrate-lipid conjugate(s) based formulation of the compound, where the formulation comprises a PEG-carbohydrate-lipid conjugate having the three carrier groups.
  • Another feature or aspect of an embodiment is believed at the time of the filing of this patent application to possibly reside broadly in a chemical compound or a method of making a compound wherein the therapeutic agent is Propofol; and where the weight ratio of the PEG-carbohydrate-lipid to the drug compound is between about 1 and 3.

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014055941A2 (en) * 2012-10-04 2014-04-10 Pappalardo Juan Sabastian Compounds and methods for targeted immune system delivery
US20150157721A1 (en) * 2013-12-05 2015-06-11 Nian Wu Polymer-carbohydrate conjugates for drug delivery technology
WO2016209732A1 (en) 2015-06-23 2016-12-29 Wu Nian Polymer-cyclodextrin-lipid conjugates
WO2017053991A1 (en) * 2015-09-25 2017-03-30 University Of Notre Dame Du Lac Nanoallergens and uses thereof
US10064954B2 (en) 2015-06-23 2018-09-04 Nian Wu Polymer-cyclodextrin-lipid conjugates
WO2020097376A1 (en) * 2018-11-09 2020-05-14 Translate Bio, Inc. Multi-peg lipid compounds
US12016865B2 (en) 2017-12-21 2024-06-25 Cormedix Inc. Methods and pharmaceutical compositions for treating candida auris in blood

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8883177B2 (en) * 2011-06-28 2014-11-11 Nian Wu Pharmaceutical compositions for parenteral administration
JP2016505523A (ja) * 2012-11-13 2016-02-25 アドシア 離散数の糖単位から構成される主骨格から成る置換されたアニオン性化合物
JP6322642B2 (ja) 2012-11-13 2018-05-09 アドシア 置換されたアニオン性化合物を含有する速効型インスリン製剤
US10595527B2 (en) 2017-12-12 2020-03-24 International Business Machines Corporation Antimicrobial polymers capable of supramolecular assembly
US10687530B2 (en) 2017-12-12 2020-06-23 International Business Machines Corporation Hydrophilic polymers with antimicrobial functionalities
US10836864B2 (en) 2017-12-12 2020-11-17 International Business Machines Corporation Chemical compositions with antimicrobial functionality
US10653142B2 (en) 2017-12-12 2020-05-19 International Business Machines Corporation Polymers with antimicrobial functionalities
US10743537B2 (en) 2017-12-12 2020-08-18 International Business Machines Corporation Monomer compositions with antimicrobial functionality
US10687528B2 (en) 2017-12-12 2020-06-23 International Business Machines Corporation Antimicrobial polymers with enhanced functionalities
US10667514B2 (en) 2017-12-12 2020-06-02 International Business Machines Corporation Antimicrobial ionene compositions with a variety of functional groups
WO2020139851A1 (en) * 2018-12-26 2020-07-02 Clear Lake Research, Llc Delivery of health benefits through component formulation

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6309633B1 (en) * 1999-06-19 2001-10-30 Nobex Corporation Amphiphilic drug-oligomer conjugates with hydroyzable lipophile components and methods for making and using the same

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL142650A (en) 1998-04-08 2007-06-03 Galmed Int Ltd Use of bile acid conjugates or bile salts and fatty acids or fatty acids in the preparation of pharmaceuticals for lowering cholesterol, for the treatment of fatty liver and for the treatment of hyperglycemia and diabetes
US20030212051A1 (en) 2001-04-06 2003-11-13 Polli James E Bile acid containing prodrugs with enhanced bioavailabilty
DE10209822A1 (de) * 2002-03-06 2003-09-25 Biotechnologie Ges Mittelhesse Kopplung niedermolekularer Substanzen an ein modifiziertes Polysaccharid
US20030215395A1 (en) * 2002-05-14 2003-11-20 Lei Yu Controllably degradable polymeric biomolecule or drug carrier and method of synthesizing said carrier
JP4723380B2 (ja) * 2003-09-25 2011-07-13 テルモ株式会社 ポリエチレングリコール誘導体及びこれを膜構成成分とする薬物担体
US20090011001A1 (en) * 2004-10-29 2009-01-08 Zafeer Ahmad Manufacturing process for liposomal preparations
WO2008100288A2 (en) * 2006-09-15 2008-08-21 The Burnham Institute High affinity ephb receptor binding compounds and methods of use thereof
BRPI1005293A2 (pt) 2009-01-23 2019-09-24 Brian Charles Keller composição e método para aumentar a solubilidade de uma droga lipofílica e respectivo método de tratamento
WO2010107487A2 (en) 2009-03-18 2010-09-23 Wu Nian Lipid-drug conjugates for drug delivery
KR101800833B1 (ko) * 2009-03-20 2017-11-23 씨엘에스엔 래버러토리스, 인코퍼레이티드 폴리아민 유도체
AU2010257181A1 (en) * 2009-06-02 2012-01-12 Brian Charles Keller Pure PEG-lipid conjugates
WO2011005980A1 (en) 2009-07-09 2011-01-13 Intradigm Corporation Novel heterobifunctional polyethylene glycol reagents, their preparation and uses thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6309633B1 (en) * 1999-06-19 2001-10-30 Nobex Corporation Amphiphilic drug-oligomer conjugates with hydroyzable lipophile components and methods for making and using the same

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014055941A2 (en) * 2012-10-04 2014-04-10 Pappalardo Juan Sabastian Compounds and methods for targeted immune system delivery
WO2014055941A3 (en) * 2012-10-04 2014-07-03 Pappalardo Juan Sabastian Compounds and methods for targeted immune system delivery
US9962448B2 (en) 2012-10-04 2018-05-08 Northeastern University Compounds and methods for targeted immune system delivery
US20150157721A1 (en) * 2013-12-05 2015-06-11 Nian Wu Polymer-carbohydrate conjugates for drug delivery technology
US10835608B2 (en) * 2013-12-05 2020-11-17 Nian Wu Polymer-carbohydrate conjugates for drug delivery technology
WO2016209732A1 (en) 2015-06-23 2016-12-29 Wu Nian Polymer-cyclodextrin-lipid conjugates
US10064954B2 (en) 2015-06-23 2018-09-04 Nian Wu Polymer-cyclodextrin-lipid conjugates
WO2017053991A1 (en) * 2015-09-25 2017-03-30 University Of Notre Dame Du Lac Nanoallergens and uses thereof
US10874751B2 (en) 2015-09-25 2020-12-29 University Of Notre Dame Du Lac Nanoallergens and uses thereof
US11638763B2 (en) 2015-09-25 2023-05-02 University Of Notre Dame Du Lac Nanoallergens and uses thereof
US12016865B2 (en) 2017-12-21 2024-06-25 Cormedix Inc. Methods and pharmaceutical compositions for treating candida auris in blood
WO2020097376A1 (en) * 2018-11-09 2020-05-14 Translate Bio, Inc. Multi-peg lipid compounds

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