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WO2006062544A1 - Administration de medicaments a base de liposomes enrobes de chitosane de composes antioxydants ou anti-inflammatoires - Google Patents

Administration de medicaments a base de liposomes enrobes de chitosane de composes antioxydants ou anti-inflammatoires Download PDF

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Publication number
WO2006062544A1
WO2006062544A1 PCT/US2005/020017 US2005020017W WO2006062544A1 WO 2006062544 A1 WO2006062544 A1 WO 2006062544A1 US 2005020017 W US2005020017 W US 2005020017W WO 2006062544 A1 WO2006062544 A1 WO 2006062544A1
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WIPO (PCT)
Prior art keywords
stilbene
antioxidant
pharmaceutical composition
lipid
nutraceutical
Prior art date
Application number
PCT/US2005/020017
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English (en)
Inventor
Milton B. Yatvin
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Oradel Medical Ltd.
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Publication date
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Publication of WO2006062544A1 publication Critical patent/WO2006062544A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1277—Processes for preparing; Proliposomes
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin

Definitions

  • This invention relates to delivery of nutraceuticals, particularly antioxidant or anti-inflammatory drugs, nutrients and other compounds to a biological organism.
  • the invention relates to liposomes and formulations of nutraceuticals, particularly antioxidant or anti-inflammatory drugs, nutrients and other compounds, particularly polycyclic, aromatic, antioxidant or anti-inflammatory compounds into liposomes to improve or effect delivery of such beneficial compounds to cells and tissues in an organism.
  • the invention provides such liposome compositions of antioxidant or anti-inflammatory drugs, nutrients and other compounds in formulations advantageously administered orally to an animal, wherein the formulation comprises a chitosan coating.
  • nutraceutical is a compound that is a food or a part of a foodstuff that provides medical or health benefits, including the prevention or treatment of disease.
  • Nutraceuticals are also known as functional foods, and include dietary supplements, health foods, phytochemicals and botanical products. They are becoming increasingly more important components of health and nutrition, as the U.S. population ages, diseases have emerged that are chronic and life-style related, and as conventional faith in traditional medicine decreases. In the U.S., nutraceuticals are part of an $18 billion dollar industry. Serigado Antunes, 2002, "Permeability of Cystatin across CaCO2 Cells," (htt p ://etd.lsu.edu/docs/available/etd-l 1 13102-
  • nutraceutical, plant-derived compounds have been recognized as being beneficial both as anticancer and anticardiovascular disease agents.
  • This class of compounds is generally recognized to include polycyclic, aromatic compounds having antioxidant or anti-inflammatory activity, and include the flavonoids (such as flavone, quercetin and chrysin) and derivatives of stilbenes, such as resveratrol.
  • flavonoids such as flavone, quercetin and chrysin
  • stilbenes such as resveratrol
  • Resveratrol is also a component of a traditional oriental medicine, Ko-jo-kon, used to treat ailments of the heart, blood vessels and liver. Soleas et al, 1997, Clin. Biochem. 3_0j 91-113. Resveratrol is found in red wine due to its presence in grape skin, and is thought to be a phytoalexin that provides protection against fungi. Celotti et al., 1996, J. Chromatog. 730: 47 '-52. It is also found (at much lower concentrations) in eucalyptus, spruce, lily, mulberry and peanuts.
  • Resveratrol has also been the subject of several scientific studies.
  • the Copenhagen Heart Study (1995) showed that the relative risk of mortality from coronary artery disease was reduced by 20% when red wine was consumed once a month, by 30% when red wine was consumed once or twice weekly, and by 40% when red wine was consumed 3-5 times per week.
  • Other researchers investigated the physiologic basis for these results.
  • Pendurthi et al. (1999, Arterioscherosis Thrombosis and Vascular Biol. 19: 419-426) showed that resveratrol, dose- dependently, inhibited transcription and expression of tissue factor in endothelial cells.
  • Resveratrol has been shown to have antioxidant (Chanvitayapongs et al, 1997, Neuroreport 8: 1499-1502; Belguendouz et al, 1998, Biochem. Pharmacol. 55: 811-816; Frankel et al, 1993, Lancet 341.: 1 103-1 104), platelet aggregation- inhibiting (Bertelli et al, 1996, Drugs Exp. Clin. Res. 22: 61-63; Rotondo et al,
  • Chrysin (5,7-dihydroxyflavone) is a naturally-occurring flavone found in passion flower (Passiflora coerulea) extracts. Chrysin has activity as an anxiolytic agent (Wolfman et al, 1994, Pharmacol. Biochem. Behav. 47: 1-4; Paladini et al,
  • Chrysin is believed to act by inhibiting aromatase, an enzyme responsible, inter alia, for converting testosterone to estrogen.
  • Quercetin (3,3', 4', 5,7-pentahydroxyflavone) is a natural substance found in apples, onions, tea and red wine (like resveratrol, it is derived from grape skins). Quercetin has been shown to be an antioxidant. Cai et al., 1999, Free Radical Biol. Med. 27: 822-829.
  • Quercetin has been shown to be an efficacious agent for preventing and treating prostate cancer by workers at the Mayo Clinic. Xing et al., American Association for Cancer Research, 26 th Annual Meeting, March 26, 2001. Prostate cancer is the second leading cause of death in men, with 31,500 fatalities and 200,000 diagnoses per year. Quercetin is currently in therapeutic use for treating inflammatory diseases and disorders.
  • a major goal in the pharmacological arts has been the development of reagents and methods that reduce the necessity of administering therapeutic compounds, drugs and other agents invasively (i.e., such as by injection). Most preferably, it has been a consistent goal in the art to develop therapeutic compounds, drugs and agents and formulations thereof that permit oral administration (see, for example U.S. Patent No. 4,963,526 to Ecanow issued October 16, 1990), although other reduced-invasiveness formulations such as suppositories have also been developed.
  • the oral intake of drugs is undoubtedly preferred because of its versatility, safety and patient comfort.
  • Liposomes generically comprise an enclosed lipid droplet having a core, typically an aqueous core, containing the compound.
  • the compound is chemically conjugated to a lipid component of the liposome.
  • the compound is simply contained within the aqueous compartment inside the liposome.
  • U.S. Patent 5,223,263, issued June 29, 1993 to Hostetler et al. discloses conjugates between antiviral nucleoside analogues and polar lipids for inclusion in liposomes.
  • U.S. Patent No. 5,466,468 to Schneider et al. issued November 14, 1995 discloses parenterally administrable liposome formulations comprising synthetic lipids.
  • U.S. Patent No. 5,484,809 issued January 16, 1996 to Hostetler et al. discloses taxol and taxol derivatives conjugated to phospholipids.
  • U.S. Patent No. 5,580,571, issued December 3, 1996 to Hostetler et al. discloses nucleoside analogues conjugated to phospholipids.
  • U.S. Patent No. 5,626,869 to Nyqvist et al. issued May 6, 1997 discloses pharmaceutical compositions wherein the pharmaceutically active compound is heparin or a fragment thereof contained in a defined lipid system comprising at least one amphiphatic and polar lipid component and at least one nonpolar lipid component.
  • U.S. Patent No. 5,744,461, issued April 28, 1998 to Hostetler et al. discloses nucleoside analogues conjugated to phosphonoacetic acid lipid derivatives.
  • U.S. Patent No. 5,744,592, issued April 28, 1998 to Hostetler et al. discloses nucleoside analogues conjugated to phospholipids.
  • U.S. Patent No. 5,756,116 issued May 26, 1998 to Hostetler et al. discloses nucleoside analogues conjugated to phospholipids.
  • U.S. Patent No. 5,843,509 to Calvo Salve et al. issued December 1, 1998 discloses stabilization of colloidal systems through the formation of lipid- polysaccharide complexes comprising a water soluble and positively charged polysaccharide and a negatively charged phospholipid.
  • European Patent Application Publication Number 0350287A2 to Vical discloses conjugates between antiviral nucleoside analogues and polar lipids.
  • liposomes have conventionally been administered parenterally ⁇ see, for example, U.S. Patent No. 5,466,468), reports of oral administration of liposome-related formulations have appeared in the art.
  • U.S. Patent No. 4,921,757 to Wheatley et al. issued May 1, 1990 discloses controlled release of biologically active substances, such as drugs and hormones entrapped in liposomes that are protected from the biological environment by encapsulation within semi-permeable microcapsules or a permeable polymeric matrix.
  • U.S. Patent No. 5,043,165 to Radhakrishnan to August 27, 1991 disclosed a liposome composition for sustained release of steroidal drugs.
  • compositions comprising non-steroid anti-inflammatory drugs (NSAID's) complexed with either zwitterionic or neutral phospholipids, or both, having reduced gastrointestinal irritating effects and enhanced antipyretic, analgesic, and anti- inflammatory activity.
  • NSAID's non-steroid anti-inflammatory drugs
  • Proliposomes are an alternative to conventional liposomal formulations.
  • Proliposomes are dry, free-flowing granular products, which, on addition of water, disperse to form a multi-lamellar liposomal suspension.
  • the stability problems associated with conventional liposomes such as aggregation, susceptibility to hydrolysis and/or oxidation are avoided by using proliposomes.
  • U.S. Pat. No. 5,635,206 to Ganter et al. discloses a process for preparing liposomes or proliposomes.
  • U.S. Pat. No. 5,595,756 to Bally et al. discloses that the bioactive agent concentration in plasma increases when a synergistic effect is induced by lowering the pH (to approximately 2-3) of the solution in which a bioactive agent is entrapped within a liposome and including in the liposomal membrane an amine-bearing lipid.
  • U.S. Pat. No. 6,093,406 to Alving et al. teaches liposomal derived vaccines that use a liposome and a compound that contains a net negative charge, a net positive charge (via stearylamine) or is neutral in conjunction with liposomes adsorbed to aluminum hydroxide.
  • Proliposomes of indomethacin were prepared using effervescent granules, which upon hydration yielded liposomes of high encapsulation efficiency and increased anti-inflammatory activity with decreased ulcerogenic index (see, for example, Katare et al., 1991, J. Microencapsulation 81.: 1-7).
  • proliposomal concept has been extended to administer drugs through various routes and also to the food industry wherein enzyme immobilization is essential for various food processing regimes.
  • a typical example is the immobilization of the enzyme, chymotrypsin, in liposomes obtained from proliposomes.
  • Advantageous embodiments of such delivery means are formulated to efficiently deliver such compounds to the appropriate portion of the gastrointestinal tract for efficient absorption.
  • the present invention is directed to an improved method for delivering nutraceuticals, particularly polycyclic, aromatic, antioxidant or anti-inflammatory compounds to an animal by oral administration.
  • This delivery system achieves specific delivery of nutraceuticals such as polycyclic, aromatic, antioxidant or antiinflammatory compounds through associating the compounds with liposomes and proliposome components.
  • a nutraceutical is formulated as a proliposomal composition that can be reconstituted in vivo to provide a liposomal preparation.
  • the nutraceutical is a polycyclic, aromatic, antioxidant or anti- inflammatory compound.
  • the invention thus also provides pharmaceutical compositions comprising a nutraceutical, particularly the polycyclic, aromatic, antioxidant or anti-inflammatory compound and a lipid formulated as a proliposomal preparation.
  • the pharmaceutical compositions of the invention are formulated for oral administration.
  • nutraceutical formulations and pharmaceutical compositions of the invention are formulated for oral administration to preferably comprise an enteric coating sufficient to prevent dissolution of the composition in the stomach of an animal.
  • the pharmaceutical compositions also comprise a protective coating between the enteric coating and the core of the composition comprising the proliposomal components thereof.
  • Additional advantageous components of said orally-administrable pharmaceutical compositions further comprise the pharmaceutical compositions as will be understood by those with skill in the art, including inter alia excipients, adjuvants, buffers, lubricants, and plasticizers.
  • the pharmaceutical compositions of the invention further comprise a protective coating that is most preferably a chitosan layer, in certain embodiments wherein the chitosan layer is in between the proliposomes and the enteric coating.
  • FIGS IA through 1C depict thermograms produced by differential scanning calorimetry as set forth in Example 1.
  • Figures 2 and 3 depict transfer rates of glyburide through a Caco-2 cellular monolayer using the liposomal compositions of the invention, as set forth in Example 2.
  • Figures 4 and 5 depict total accumulation of glyburide in the receiving chamber of a transwell comprising a Caco-2 cellular monolayer using the liposomal compositions of the invention, as set forth in Example 2.
  • the present invention provides compositions of matter and methods for facilitating the delivery of nutraceuticals, particularly polycyclic aromatic antioxidant or anti-inflammatory compounds, to the tissues of an animal after oral administration.
  • the terms “nutraceuticals” and “functional foods” include but are not limited to carotenoids, fish oils and omega-fatty acids, green tea, beta- carotene, carnitine, glucosamine, chondroitin sulfate, ginseng, ginko biloba, genistein, saw palmetto, curcumin, lycopene, Echinacea, lipoic acid, calcitonin, hyperforin, flavinoids, and Vitamins A, C and E, and in particular polycyclic, polyaromatic compounds, especially said compounds derived from plant sources such as resveratrol, quecertin and chrysin.
  • polycyclic aromatic antioxidant or anti-inflammatory compound is intended to encompass naturally-occurring, most preferably plant-derived, or synthetic compounds having antioxidant or anti- inflammatory properties and comprising c/s-stilbene; trans-s ⁇ lbene; 3-, 4-, or 4'- hydroxy, or (3,4')- or (4', 5)-dihydroxy c/s-stilbene; 3-, 4-, or 4'-hydroxy, or (3,4')- or (4', 5)-dihydroxy /r ⁇ «.s-stilbene; carboxylated derivatives of c/s-stilbene or trans- stilbene; halogenated derivatives of cw-stilbene or /r ⁇ w-stilbene; and resveratrol (f/ww-3,5,4'-trihydroxystilbene); or flavonoids, most preferably chrysin (5,7- dihydroxyflavone) or quercetin (3,3',4',5,7- pentahydroxyflavon
  • Formulations, compositions and pharmaceutical compositions comprising nutraceuticals, particularly polycyclic aromatic antioxidant or anti-inflammatory compounds, are preferably provided as proliposomal compositions that can be reconstituted, most preferably in vivo, to produce liposomal compositions of nutraceuticals, especially polycyclic, aromatic, antioxidant or anti-inflammatory compounds.
  • said formulations, compositions and pharmaceutical compositions comprise one or a plurality of nutraceutical compounds.
  • proliposome and “proliposomal” are intended to encompass calcium-free, dry, free-flowing granular products, which, on addition of water, disperse to form multi-lamellar liposomal suspensions comprising one or a plurality of nutraceuticals, particularly polycyclic, aromatic, antioxidant or antiinflammatory compounds of the invention.
  • the liposomes and preliposomes of the instant invention are not adsorbed to aluminum hydroxide.
  • the stability problems associated with the conventional liposomes (such as aggregation, susceptibility to hydrolysis and oxidation) are avoided by using proliposomes.
  • the proliposomal compositions provided by the invention are reconstituted, particularly in vivo, to provide liposomal compositions wherein one or a plurality of nutraceuticals, particularly polycyclic, aromatic, antioxidant or anti-inflammatory compounds of the invention are encapsulated in said liposomes. Even more preferably, the proliposomal composition is reconstituted in the intestines of the animal.
  • the proliposomes of the instant invention form liposomes in the intestines
  • the liposomes will be in an environment with a pH of approximately 6.4 (in humans.) This precludes the synergistic effect between the stearylamine and the biologically active component in a low pH (approximately 2-3) that is disclosed and claimed in U.S. Patent No. 5,595,756.
  • lipid components including neutral lipids, positively-charged lipids or species, negatively- charged lipids or species, amphoteric lipids such as phospholipids, and cholesterol are advantageously used.
  • the "lipid component" of the proliposomal compositions of the invention are intended to encompass a single species of lipid (such as a particular phospholipid) or combinations of such lipids, either of one type such as combinations of phospholipids (for example, a phosphatidylcholine plus a phosphatidylethanolamine) or of different types (such as a phospholipid plus a charged lipid, charged species, a neutral lipid or neutral species).
  • Combinations comprising a multiplicity of different lipid types are also advantageously encompassed by the proliposomal compositions of the invention (see, Lehninger, 1975, Biochemistry, 2d ed., Chapters 11 & 24, Worth Publishers: New York; and Small, 1986, “From alkanes to phospholipids," Handbook of Lipid Research: Physical Chemistry of Lipids, Volume 4, Chapters 4 and 12, Plenum Press: New York).
  • the "lipid component" of the proliposomal compositions encompasses at least one lipid, and a positively charged species, that is not calcium.
  • a preferred positively charged species is a primary aliphatic amine, such as stearylamine.
  • the lipid component also contains cholesterol.
  • the lipid component consists essentially of one, two, or three independently selected lipids, a positively charged species and cholesterol.
  • the lipids are independently a phosphatidylcholine, a phosphatidylethanolamine, sphingosine, or ceramide.
  • the phosphatidylcholine is distearylphosphatidylcholine, dimyristylphosphatidylcholine or a mixture thereof. Even more preferably, the phosphatidylcholine is distearylphosphatidylcholine or dimyristylphosphatidylcholine. It should also be noted that negatively charged species do not work; they decrease the biological availability of drugs in the present invention. See Figures 2 and 4.
  • Nutraceuticals such as polycyclic, aromatic, antioxidant or anti-inflammatory compounds that are unstable in the stomach, or that show reduced absorption incident to transit through the stomach or other portions of the gastrointestinal tract, or nutraceuticals such as polycyclic, aromatic, antioxidant or anti-inflammatory compounds that irritate the stomach, and those nutraceuticals including polycyclic, aromatic, antioxidant or anti-inflammatory compounds that are preferentially absorbed in the small intestine are preferred compounds useful with the liposomal formulations of the invention.
  • said compounds include but are not limited to c/s-stilbene; trans-stilbenc; 3-, 4-, or 4'-hydroxy, or (3,4')- or (4',5)-dihydroxy cz ' s-stilbene; 3-, 4-, or 4'-hydroxy, or (3,4')- or (4',5)-dihydroxy rr ⁇ ns-stilbene; carboxylated derivatives of c/s-stilbene or trans-sulbene; halogenated derivatives of c/s-stilbene or /rara-stilbene; and resveratrol (trans-3,5,4'- trihydroxystilbene); or flavonoids, most preferably chrysin (5,7-dihydroxyflavone) or quercetin (3,3 ',4', 5, 7- pentahydroxyflavone), or biologically-active derivatives thereof.
  • carotenoids fish oils and omega-fatty acids
  • green tea beta-carotene
  • carnitine glucosamine
  • chondroitin sulfate ginseng
  • ginko biloba genistein
  • curcumin lycopene
  • Echinacea lipoic acid
  • calcitonin hyperforin, flavinoids, and Vitamins A, C and E.
  • the proliposomal preparations of the invention comprising one or a plurality of nutraceuticals, particularly polycyclic, aromatic, antioxidant or anti-inflammatory compounds, are preferably provided in a form that can be orally administered, including but not limited to syrups, elixirs, capsules, tablets, and emulsions.
  • Preferred forms are tablets or capsules, most preferably comprising an enteric coating to prevent premature dissolution under the chemically harsh environment of the stomach.
  • Enteric coatings are prepared as will be understood by one having skill in the art, and preferably include coatings including but not limited to eudragit and cellulose acetate phthalate.
  • the tablets or capsules of the invention comprise a protective coating between the enteric coating and the core of the capsule or tablet comprising the proliposomal preparations of the invention.
  • the protective coating is prepared as will be understood by one having skill in the art, and preferably include coatings including but not limited to hydroxypropyl methylcellulose, polyethylene glycol and ethylcellulose.
  • the protective coating further comprises a plasticizing agent, including but not limited to triethylcitrate and polyvinyl pyrrolidone.
  • the tablets, capsules and other like embodiments of the proliposomal preparations and pharmaceutical compositions of the invention further advantageously comprise particle lubricants that minimize the tendency of the granular proliposomal compositions to agglomerate.
  • particle lubricant as used herein is meant the class of materials used in the manufacturing of pharmaceutical tablets as lubricants to improve the flowability and prevent agglomeration of an active agent during the tableting process.
  • particle lubricants include talc, lactose, corn starch, ethyl cellulose, fatty acid salts such as magnesium stearate, agar pectin, fatty acids such as stearic acid, gelatin and acacia.
  • the formulations, compositions and pharmaceutical compositions of the invention in preferred embodiments comprise a chitosan layer between the proliposomes and the enteric coating.
  • chitosan is used to specifically refer to poly(l,4- ⁇ -D-glycopyrano-amine), and to substituted derivatives and analogues thereof having substantially the same properties as the base polymer.
  • the chitosan of the invention is hydrolyzed, deacetylated chitin obtained from, inter alia, shrimp, crab or other crustacean shells.
  • the chitosan layer can be produced on the proliposome formulations of the invention by phase separation of chitosan from an aqueous solution by a counterion (termed simple coacervation; see Chandy and Sharma, 1992, Biomaterials J_3: 949-952).
  • the chitosan layer can be produced on the proliposome formulations of the invention by phase separation of chitosan from an aqueous solution by an oppositely-charged macromolecule (termed complex coacervation; see Polk et al., 1994, Aquacultural Engineer. 13: 31 1-323).
  • the chitosan layer can be produced on the proliposome formulations of the invention by emulsification of the chitosan and proliposomes in a non-solvent (see Akbuga and Durnaz, 1994, J. Intl. Pharmaceutics U V. 217-222; Jameela and Jayakrisnan, 1995, Biomaterials 16: 769-775). Chitosan preparations having varying degrees of deacetylation or average molecular weight are useful in the practice of the invention (see, Chiuo et al., 2001, J. Microencapsul. 18: 613-625).
  • the invention specifically provides methods for preparing and administering the proliposomal compositions of the invention as disclosed in the Examples below, and pharmaceutical compositions comprising the proliposomal preparations of one or a plurality of nutraceuticals, such as polycyclic, aromatic, antioxidant or anti- inflammatory compounds.
  • nutraceuticals such as polycyclic, aromatic, antioxidant or anti- inflammatory compounds.
  • Acceptable formulations preferably are nontoxic to recipients at the dosages and concentrations employed.
  • Effective, non-toxic dosage ranges for nutraceuticals, particularly polycyclic, aromatic, antioxidant or anti-inflammatory compounds, are known in the art.
  • resveratrol is typically administered at dosages of up to 3g/kg/day in rats (Crowell et al., 2004, ToxSci Advance Access), and 4mg/kg/day in rabbits (Zou et al., 2000, Life Sci. 68: 153-163).
  • the administered dose will be affected by the efficiency with which the formulations, compositions and pharmaceutical compositions of the invention deliver one or a plurality of nutraceuticals, particularly polycyclic, aromatic, antioxidant or anti-inflammatory compounds to inter alia the intestine for absorption. Determining a correct concentration of the one or plurality of particular nutraceuticals in the formulation is within the skill of one of skill in the art.
  • the pharmaceutical composition may contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition.
  • Suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); ascorbic acid, sodium sulfite or sodium hydrogen-sulfite; buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides, disaccharides, and other carbohydrates (such as glucose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyr
  • compositions can be determined by one skilled in the art depending upon, for example, the desired dosage. See, for example, REMINGTON'S PHARMACEUTICAL SCIENCES, Id. Such compositions may influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the antibodies of the invention.
  • compositions can comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5, which may further include sorbitol or a suitable substitute therefor.
  • Pharmaceutical compositions of the invention may be prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents (REMINGTON'S PHARMACEUTICAL SCIENCES, Id.) in the form of a lyophilized cake or an aqueous solution.
  • Formulation components are present in concentrations that are acceptable for oral administration. Buffers are advantageously used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from about 5 to about 8.
  • compositions of the invention are preferably delivered through the digestive tract.
  • the preparation of such pharmaceutically acceptable compositions is within the skill of the art.
  • One or a plurality of nutraceuticals, particularly polycyclic, aromatic antioxidants or anti-inflammatory compounds, are administered in this fashion may be formulated with or without those carriers customarily used in the compounding of solid dosage forms such as tablets and capsules.
  • a capsule may be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre- systemic degradation is minimized. Additional agents can be included to facilitate absorption of the one or plurality of nutraceuticals.
  • a pharmaceutical composition comprising one or a pluraility of nutraceuticals, particularly polycyclic, aromatic antioxidants or anti-inflammatory compounds, may involve an effective quantity thereof as disclosed herein or a compound identified in a screening method of the invention in a mixture with non- toxic excipients that are suitable for the manufacture of tablets.
  • solutions may be prepared in unit-dose form.
  • Suitable excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.
  • inert diluents such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate
  • binding agents such as starch, gelatin, or acacia
  • lubricating agents such as magnesium stearate, stearic acid, or talc.
  • sustained-release preparations may include semipermeable polymer matrices in the form of shaped articles, e.g. films, or microcapsules, polyesters, hydrogels, polylactides (U.S. 3,773,919 and EP 058,481), copolymers of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al, 1983, Biopolymers 22: 547-556), poly (2- hydroxyethyl-methacrylate) (Langer et al, 1981, J.
  • Sustained release compositions may also include liposomes, which can be prepared by any of several methods known in the art. See e.g., Eppstein et al, 1985, Proc. Natl. Acad. Sci. USA 82: 3688-3692; EP 036,676; EP 088,046 and EP 143,949.
  • the pharmaceutical composition to be used for in vivo administration typically is sterile. In certain embodiments, this may be accomplished by filtration through sterile filtration membranes. In certain embodiments, where the composition is lyophilized, sterilization using this method may be conducted either prior to or following lyophilization and reconstitution. In certain embodiments, the composition for parenteral administration may be stored in lyophilized form or in a solution. In certain embodiments, parenteral compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
  • compositions of the invention may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder.
  • Such formulations may be stored either in a ready-to-use form or in a form (e.g., lyophilized) that is reconstituted prior to administration.
  • the effective amount of a pharmaceutical composition of the invention to be employed therapeutically will depend, for example, upon the therapeutic context and objectives.
  • One skilled in the art will appreciate that the appropriate dosage levels for treatment, according to certain embodiments, will thus vary depending, in part, upon the molecule delivered, the indication for which the pharmaceutical composition is being used, the route of administration, and the size (body weight, body surface or organ size) and/or condition (the age and general health) of the patient.
  • a clinician may titer the dosage and modify the route of administration to obtain the optimal therapeutic effect.
  • Typical dosages range from about 0.1 ⁇ g/kg to up to about 100 mg/kg or more, depending on the factors mentioned above.
  • the dosage may range from 0.1 ⁇ g/kg up to about 100 mg/kg; or 1 ⁇ g/kg up to about 100 mg/kg; or 5 ⁇ g/kg up to about 100 mg/kg.
  • the dosing frequency will depend upon the pharmacokinetic parameters of a FoxMlB inhibitor disclosed herein or compound identified in a screening method of the invention in the formulation.
  • a clinician administers the composition until a dosage is reached that achieves the desired effect.
  • the composition may therefore be administered as a single dose, or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. Appropriate dosages may be ascertained through use of appropriate dose-response data.
  • Acceptable formulations preferably are nontoxic to recipients at the dosages and concentrations employed.
  • Effective, non-toxic dosage ranges for nutraceuticals, particularly polycyclic, aromatic, antioxidant or anti-inflammatory compounds, are known in the art.
  • resveratrol is typically administered at dosages of up to 3g/kg/day in rats (Crowell et ah, 2004, ToxSci Advance Access), and 4mg/kg/day in rabbits (Zou et ah, 2000, Life Sci. 68: 153-163).
  • the administered dose will be affected by the efficiency with which the formulations, compositions and pharmaceutical compositions of the invention deliver one or a plurality of nutraceuticals, particularly polycyclic, aromatic, antioxidant or anti-inflammatory compounds to inter alia the intestine for absorption. Determining a correct concentration of the one or plurality of particular nutraceuticals in the formulation is within the skill of one of skill in the art.
  • the pharmaceutical composition may contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition.
  • formulation materials for modifying, maintaining or preserving for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition.
  • Suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); ascorbic acid, sodium sulfite or sodium hydrogen-sulfite; buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides, disaccharides, and other carbohydrates (such as glucose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyr
  • compositions can be determined by one skilled in the art depending upon, for example, the desired dosage. See, for example,
  • compositions may influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the antibodies of the invention.
  • compositions can comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5, which may further include sorbitol or a suitable substitute therefor.
  • Pharmaceutical compositions of the invention may be prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents (REMINGTON'S PHARMACEUTICAL SCIENCES, Id) in the form of a lyophilized cake or an aqueous solution.
  • Formulation components are present in concentrations that are acceptable for oral administration. Buffers are advantageously used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from about 5 to about 8.
  • compositions of the invention are preferably delivered through the digestive tract.
  • the preparation of such pharmaceutically acceptable compositions is within the skill of the art.
  • One or a plurality of nutraceuticals, particularly polycyclic, aromatic antioxidants or anti-inflammatory compounds, are administered in this fashion may be formulated with or without those carriers customarily used in the compounding of solid dosage forms such as tablets and capsules.
  • a capsule may be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre- systemic degradation is minimized. Additional agents can be included to facilitate absorption of the one or plurality of nutraceuticals.
  • a pharmaceutical composition comprising one or a pluraility of nutraceuticals, particularly polycyclic, aromatic antioxidants or anti-inflammatory compounds, may involve an effective quantity thereof as disclosed herein or a compound identified in a screening method of the invention in a mixture with nontoxic excipients that are suitable for the manufacture of tablets.
  • solutions may be prepared in unit-dose form.
  • Suitable excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.
  • inert diluents such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate
  • binding agents such as starch, gelatin, or acacia
  • lubricating agents such as magnesium stearate, stearic acid, or talc.
  • Additional pharmaceutical compositions are evident to those skilled in the art, including formulations involving one or a plurality of nutraceuticals, particularly polycyclic, aromatic antioxidants or anti-inflammatory compounds.
  • sustained-release preparations may include semipermeable polymer matrices in the form of shaped articles, e.g.
  • Sustained release compositions most preferably comprise liposomes, which can be prepared by any of several methods known in the art. See e.g., Eppstein et al, 1985, Proc. Natl. Acad. ScL USA 82: 3688-3692; EP 036,676; EP 088,046 and EP 143,949.
  • the pharmaceutical composition to be used for in vivo administration typically is sterile. In certain embodiments, this may be accomplished by filtration through sterile filtration membranes. In certain embodiments, where the composition is lyophilized, sterilization using this method may be conducted either prior to or following lyophilization and reconstitution. In certain embodiments, the composition for parenteral administration may be stored in lyophilized form or in a solution. In certain embodiments, parenteral compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
  • compositions of the invention may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder.
  • Such formulations may be stored either in a ready-to-use form or in a form (e.g., lyophilized) that is reconstituted prior to administration.
  • a pharmaceutical composition of the invention to be employed therapeutically will depend, for example, upon the therapeutic context and objectives.
  • the appropriate dosage levels for treatment will thus vary depending, in part, upon the molecule delivered, the indication for which the pharmaceutical composition is being used, the route of administration, and the size (body weight, body surface or organ size) and/or condition (the age and general health) of the patient.
  • a clinician may titer the dosage and modify the route of administration to obtain the optimal therapeutic effect.
  • Typical dosages range from about 0.1 ⁇ g/kg to up to about 100 mg/kg or more, depending on the factors mentioned above. In certain embodiments, the dosage may range from 0.1 ⁇ g/kg up to about 100 mg/kg;
  • the dosing frequency will depend upon the pharmacokinetic parameters of one or a plurality of nutraceuticals, particularly polycyclic, aromatic antioxidants or anti-inflammatory compounds according to the invention, or compound identified in a screening method of the invention in the formulation.
  • a clinician administers the composition until a dosage is reached that achieves the desired effect.
  • the composition may therefore be administered as a single dose, or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. Appropriate dosages may be ascertained through use of appropriate dose-response data.
  • compositions of the invention can be administered alone or in combination with other therapeutic agents.
  • Animals to be treated with the proliposomal preparations and pharmaceutical compositions of the invention are intended to include all vertebrate animals, preferably domesticated animals, such as cattle, horses, goats, sheep, fowl, fish, household pets, and others, as well as wild animals, and most preferably humans.
  • orally-administered liposomal formulations over parenterally-administered formulations is that oral administration reduces uptake of liposomes by the liver, thus reducing liver toxicity (which is a particular liability of parenterally-administered liposomal formulations).
  • Oral formulations are targeted to deliver nutraceuticals, including polycyclic, aromatic, antioxidant or anti- inflammatory compounds, to the intestine, which is a large surface for absorption and results in slow release of the administered compound.
  • oral administration avoids transport-mediated saturation of nutraceutical absorption, particularly with regard to polycyclic, aromatic, antioxidant or anti-inflammatory compounds of the invention.
  • EXAMPLE 1 Proliposomal formulations useful for oral administration were developed using an in vitro model system.
  • Human Caco-2 cells colon adenocarcinoma cells
  • semipermeable filters provide a simple and reliable in vitro model for studying drug transport across the intestinal mucosa.
  • Caco-2 cells are recognized in the art for yielding useful predictions on oral absorption of new drug formulations.
  • glyburide glybenclamide
  • an oral blood-glucose-lowering drug of the sulfonylurea class was used as model drug, because uptake in the CaCo-2 system can be monitored by measuring transport across monolayers formed by this cell line.
  • Proliposomal tablets were prepared as follows. The identities and amounts of each of the reagents used to prepare the tablets of the invention are shown in
  • Phospholipids DMPC and DSPC were obtained from Avanti Polar Lipids (Alabaster, AL); glyburide, cholesterol, stearylamine, dicetylphosphate and all tissue culture reagents were obtained from Sigma Chemical Co. (St. Louis, MO); purified talc and anhydrous lactose were obtained from J.T. Baker (Phillipsburg, NJ) and
  • Glyburide, lipid and cholesterol were dissolved at room temperature in 1OmL chloroform. Lactose (25mg/tablet) was suspended in the organic mixture and the suspension evaporated to dryness at 6O 0 C in a conventional coating pan (pan drying method). The solid residue was collected and sifted through a #60 mesh screen.
  • Table I provides a formulary for preparing proliposomal tablets according to the invention.
  • proliposomal formulations can be prepared by lyophilization.
  • mixtures of lipids and drug are prepared in aqueous solution and then sonicated, causing small unilamellar liposomes to form and resulting in an optically-clear solution.
  • Such a solution is then freeze-dried and mixed with the other components of the tablets as described above.
  • DSPC distearylphosphatidylcholine
  • DMPC dimyristylphosphatidylcholine
  • STA stearylamine (Pos: positively charged species)
  • CHO cholesterol (Neu: neutral lipid)
  • DCP dicetylphosphate (Neg: negatively charged species)
  • proliposomal formulations can be prepared by spray-drying.
  • mixtures of lipids and drug are prepared in aqueous solution.
  • a surfactant such as Tween 80 ®
  • the resulting dried proliposomal preparation is mixed with the other components of the tablets as described above.
  • a mechanical mixer is used instead of using a surfactant.
  • the mechanical mixer produces a proliposomal composition in the absence of a surfactant that can be spray-dried as described above.
  • This embodiment is particularly advantageous because it avoids the use of both surfactants and organic solvents in preparing proliposomal formulations according to the invention.
  • Figure IA shows a thermogram of DMPC alone compared with mixtures of DMPC and cholesterol (DMPC/CHOL), DMPC and glyburide (DMPC/GLYB) and DMPC, cholesterol and glyburide (DMPC/CHOL/GLYB). Peak transition temperatures are shown in the Figure. In contrast to the simple and easily- recognizable peak transition temperature obtained for DMPC, the mixtures are heterogeneous, having more than one localized peak region where a thermal transition occurs.
  • Figure IB shows a thermogram of DSPC alone compared with mixtures of DSPC and cholesterol (DSPC/CHOL), DSPC and glyburide (DMPC/GLYB) and
  • the mixtures are heterogeneous, having more than one localized peak region where a thermal transition occurs.
  • Liposomes were reconstituted from proliposomal tablets by adding one tablet to ImL phosphate buffered saline in a sterile glass vial. The tablet was allowed to stand at 37°C for 1 hour with shaking, which was sufficient to dissolve the tablet and reconstitute the liposomal preparation.
  • Reconstituted liposomes were characterized for size distribution by large- angle dynamic light scattering using a particle size analyzer (Brookhaven Instruments, Model BI-90). Each preparation was diluted with filtered saline to an appropriate concentration to achieve a medium viscosity of 0.089 centipoise and a medium relative refractive index of 1.332 at room temperature. Measurements obtained under these condition are shown in Table II. These results indicated that the particle size of the resulting liposomes varied both with the presence or absence of cholesterol and with the identity of the phospholipid component. The mean diameter of the liposomes was greater in neutral liposome embodiments than in charged liposome embodiments, and can be explained by the greater propensity of neutral liposomes to aggregate or fuse with one another.
  • Encapsulation efficiency defined as the percentage of the glyburide encapsulated in liposomes, was determined using the protamine-induced aggregation method as described in Kulkarni et al. (1995, Pharm. Sci. ⁇ : 359-362). Briefly, each tablet was disintegrated in 1 mL of phosphate-buffered saline (PBS, pH 7.4) to give a concentration of 10 mg/mL of lipid. To lOO ⁇ L of the preparation, equal
  • a protamine solution 50 mg/mL in PBS was added and vortexed for about 1 min. The mixture was then incubated for about 12 hours at room temperature. After incubation, the mixture was centrifuged at about 16,000 x g for about 5 minutes. lOO ⁇ L of the supernatant was removed and the pellet was dissolved in about 1 mL of reagent-grade alcohol (95% ethanol) and sonicated for 5 minutes.
  • the quantity of glyburide in the pellet and the supernatant was determined by HPLC analysis using the Star ® 9010 solvent system and Star 9095 ® variable- wavelength ultraviolet/visible spectrum spectrophotometric detector (Varian Associates, Walnut Creek, CA) and the data analyzed by a Dynamax ® Maclntegrator (Rainin Instrument Co., Woburn, MA). HPLC analysis was performed using a Cl 8 column (Phenominex ® ) packed with 5 ⁇ m particles and having dimensions of 250mm in length and an internal diameter of 4.6mm. The mobile phase was a solution of methanol in 0.1M phosphate buffer, pH 3.5 at a ratio of 75:25 by volume. Column flow rate was 1.0 mL/min and the output was scanned at a wavelength of 225nm.
  • Caco-2 cell cultures were prepared as monolayers on polycarbonate transwells having a membrane pore size of 4nm.
  • Caco-2 cells were first grown in T- 150 flasks (Falcon, Lincoln Park, NJ) at 37°C under an atmosphere of 5% CO 2 and 95% air in Dulbecco's modified Eagle's medium (pH 7.2, Sigma Chemical Co., St. Louis, MO), with conventional supplements. The medium was changed every other day until the monolayers reached about 90% confluency. Media was removed and the cells were washed with Hank's balanced salt solution (HBSS, Sigma).
  • HBSS Hank's balanced salt solution
  • the cells were trypsinized by adding 0.5mL of a 0.25% trypsin solution containing ImM EDTA to each flask and incubating the monolayers for 10 min at 37°C.
  • the separated cells were removed from the flasks and collected into centrifuge tubes, centrifuged at 200 x g for 10 min, the supernatant removed and the pellet resuspended in a sufficient amount of Dulbecco's modified Eagle medium to yield a suspension that would produce about 60,000 cells/cm 2 on plating.
  • the Caco-2 cells were then seeded into Transwell semipermeable membrane inserts having 4 ⁇ m pore size. In the transwells, media was changed every other day until the cells were used for the transport studies described below.
  • the medium from the transwell plates was gently removed using a micropipette.
  • 0.5 mL of the reconstituted liposomal suspension was gently added to the donor compartment of the transwell and 1.5 mL of HBSS was added to the receiver compartment.
  • lOO ⁇ L of FITC-Dextran was then added to the donor
  • FITC-Dextran was used as a marker to test for the presence of leaks, if any, on the monolayers covering the semipermeable transwell membranes. Samples (300 ⁇ L) were carefully withdrawn from the receiver side at 50, 120, 180, 240, 300
  • HBSS HBSS each time the sample was taken.
  • Cells were incubated at 37°C in a 5% CO 2 /95% air atmosphere at all times during these assays. Sampling was done under aseptic conditions in a laminar air-flow hood.
  • Figure 2 shows the results of glyburide transit across Caco-2 cell monolayers in formulations containing distearylphosphatidylcholine (DSPC).
  • DSPC distearylphosphatidylcholine
  • FIG. 3 shows the results of parallel experiments using dimyristylphosphatidylcholine (DMPC) as the lipid component.
  • DMPC dimyristylphosphatidylcholine
  • Figures 4 and 5 show the cumulative amount of transported glyburide using DSPC- and DMPC-containing formulations over a five hour period.
  • Figure 4 shows DSPC-containing formulations, wherein the highest accumulation levels were achieve with glyburide formulations containing DSPC and positively-charged lipid (about 27 ⁇ g). Similar formulations additionally containing cholesterol had lower total amounts (about 13 ⁇ g).
  • DSPC formulations containing neutral lipid and cholesterol showed slower kinetics but achieved essentially the same total accumulation as DSPC/positive lipid/cholesterol formulations. Formulations containing DSPC and neutral lipids in the absence of cholesterol showed the same total accumulation as control (about 2.5 ⁇ g), while DSPC formulations with negatively-charged lipid (in the presence or absence of cholesterol) showed lower total accumulation amounts.
  • Figure 5 shows the results of similar experiments performed with DMPC formulations. Total accumulation levels were noticeably higher than control only for formulations containing DMPC, positively-charged lipid and cholesterol (about
  • liposomes can be successfully prepared for oral administration in the form of enteric-coated proliposome tablets.
  • the presence of cholesterol reduces the particle size of the formulation.
  • Proliposomes provide a stable system of production of liposomes for oral administration. Degradation of proliposome contents of the tablet in the stomach can be effectively avoided by administering the proliposomes as enteric-coated tablets. Enhanced transport of glyburide across Caco-2 cells was observed with such liposomal formulations.
  • DSPC formulations are better suited for in vivo conditions because of the rigidity and increased stability of the membrane against the attack of bile salts and enzymes of the intestine. Since in vitro transport across Caco-2 cells is an indication of bioavailability, an increased transport with the liposome formulation suggests an increased bioavailabilty of compounds that are poorly absorbed otherwise. For example, using a suitable polymer coating for the proliposomal tablets of the invention, colonic delivery of drugs, especially peptides may be possible.
  • Proliposomes are ideally suited for lipophilic compounds, since the majority of such a polycyclic, aromatic, antioxidant or anti-inflammatory compound will partition into the lipid phase. These results also have implications for developing formulations that stabilize the encapsulated drug.
  • a 3-5% chitosan layer is produced on the proliposomal formulations of the invention as follows.
  • Chitin is prepared according to conventional methods, for example, as disclosed in Chen et al. (1994, Carbohydrate Polym. 24: 41-46), and chitosan is prepared from chitin, for example, as disclosed in Yamamoto and
  • Proliposomes are prepared as described in Example 1 above.
  • a 3% or 5% chitosan solution is prepared in 1% acetic acid solution, and about 2mg of the proliposomes of the invention are poured into the chitosan solution and stirred until completely mixed.
  • Spherical gels are produced from this mixture by adding a solution of IN sodium hydroxide/26% ethyl alcohol using a small-bore (about 27Ga) syringe and incubated for about 30 min.
  • the chitosan-encased proliposomes are removed and rinsed in distilled water under neutral conditions and then dried for at least 24 h at room temperature.

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Abstract

La présente invention a trait à des compositions pharmaceutiques pour l'administration d'un composé antioxydant ou anti-inflammatoire nutraceutique, notamment polycyclique, aromatique à un animal. Plus particulièrement, l'invention a trait à des compositions liposomales qui sont avantageusement utilisées pour l'administration de composés antioxydants ou anti-inflammatoires nutraceutiques, notamment polycycliques, aromatiques au tractus gastro-intestinal suite à une administration orale.
PCT/US2005/020017 2004-12-03 2005-06-07 Administration de medicaments a base de liposomes enrobes de chitosane de composes antioxydants ou anti-inflammatoires WO2006062544A1 (fr)

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