WO2001049268A1 - Formulations pharmaceutiques pour l'administration de medicaments ayant une faible solubilite aqueuse - Google Patents

Formulations pharmaceutiques pour l'administration de medicaments ayant une faible solubilite aqueuse Download PDF

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Publication number
WO2001049268A1
WO2001049268A1 PCT/US2000/035322 US0035322W WO0149268A1 WO 2001049268 A1 WO2001049268 A1 WO 2001049268A1 US 0035322 W US0035322 W US 0035322W WO 0149268 A1 WO0149268 A1 WO 0149268A1
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Prior art keywords
formulation
drug
peg
group
polyethylene glycol
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PCT/US2000/035322
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English (en)
Inventor
Evan C. Unger
Marek J. Romanowski
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Imarx Therapeutics, Inc.
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Priority to EP00988371A priority Critical patent/EP1246608A4/fr
Priority to CA002395132A priority patent/CA2395132A1/fr
Priority to AU24585/01A priority patent/AU2458501A/en
Priority to JP2001549636A priority patent/JP2003520210A/ja
Publication of WO2001049268A1 publication Critical patent/WO2001049268A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • A—HUMAN NECESSITIES
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6905—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
    • A61K47/6907—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a microemulsion, nanoemulsion or micelle
    • A—HUMAN NECESSITIES
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
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    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
    • A61K47/6935—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
    • A61K47/6937—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol the polymer being PLGA, PLA or polyglycolic acid
    • 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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A—HUMAN NECESSITIES
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    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
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    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A—HUMAN NECESSITIES
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus

Definitions

  • the present invention relates generally to pharmaceutical formulations, and more particularly relates to pharmaceutical formulations for the delivery of water-insoluble or sparingly water-soluble drugs.
  • the invention additionally relates to methods for using the novel formulations to administer such drugs in the treatment of disease.
  • the invention has utility in the fields of pharmaceutical formulation, drug delivery, and medicine.
  • paclitaxel available commercially as Taxol from Bristol-Myers Squibb. Although paclitaxel has been shown to exhibit powerful antineoplastic efficacy, particularly for cancers of the breast, ovaries and prostate gland, its use is limited in large part by the side effects of the solvent generally used for clinical administration, a mixture of Cremophor EL
  • Liposomes are vesicles comprised of concentrically ordered lipid bilayers that encapsulate an aqueous phase. Liposomes form when phospholipids, amphipathic compounds having a polar (hydrophilic) head group covalently bound to a long-chain aliphatic (hydrophobic) tail, are exposed to water. That is, in an aqueous medium, phospholipids aggregate to form a structure in which the long-chain aliphatic tails are sequestered within the interior of a shell formed by the polar head groups.
  • liposomes for delivering many drugs has proven unsatisfactory, in part because liposome compositions are, as a general rule, rapidly cleared from the bloodstream. Finally, even if satisfactory liposomal formulations could be prepared, it may still be necessary to use some sort of physical release mechanism so that the vesicle releases the active agent in the body before it is taken up by the liver and spleen. Encasement of paclitaxel microcrystals in shells of biocompatible polymeric materials is described in U.S. Patent No. 6,096,331 to Desai et al. However, as crystals of hydrophobic drugs may be difficult to dissolve, the rate of drug release in these formulations is hard to control.
  • a pharmaceutical formulation that is suitable for administration of a water-insoluble or sparingly water-soluble drug such as paclitaxel or the like, wherein (1) the formulation is optimized such that the amount of drug administered is maximized while undesirable side effects are minimized, (2) the rate of drug release can be precisely controlled, (3) no surfactants are necessary, (4) no liposomes or other vesicles are required, (5) premedication is unnecessary, and (6) the formulation displays excellent stability over extended storage periods.
  • a water-insoluble or sparingly water-soluble drug such as paclitaxel or the like
  • a pharmaceutical formulation comprises: (a) a matrix of a spatially stabilized hydrophilic polymer that is optionally covalently bound (or "conjugated") to a phospholipid moiety; (b) a drug that is physically entrapped within the matrix but not covalently bound thereto, wherein the drug has greater solubility in polyethylene glycol 400 than in water; (c) an optional stabilizing agent, (d) an optional targeting ligand, and (e) an optional excipient.
  • hydrophilic polymers may be employed, although polyethylene glycol and poly(ethylene oxide-co-propylene oxide) are preferred.
  • Preferred drugs are those for which systemic bioavailability can be enhanced by increasing the solubility of the drug in an aqueous vehicle; generally, although not necessarily, such drugs are hydrophobic, i.e., water insoluble or sparingly water-soluble. Also preferred are drugs for which a sustained release drug delivery system is desirable, i.e., drugs that are administered to patients on an ongoing, scheduled basis.
  • the stabilizing agents are generally polymers containing hydrophobic and hydrophilic areas, proteins are preferred. Suitable excipients include free phospholipids, which may or may not be the same as the phospholipid moieties conjugated to the hydrophilic polymer.
  • the formulation may be in lyophilized form, which is advantageous for storage stability.
  • a pharmaceutical formulation comprises an aqueous suspension of (a) drug-containing particles having an average size in the range of approximately 1 nm to 500 ⁇ m, comprised of (i) a matrix of a spatially stabilized hydrophilic polymer that is optionally covalently bound to a phospholipid moiety, (ii) a drug that is physically entrapped within the matrix but not covalently bound thereto, wherein the drug has greater solubility in polyethylene glycol 400 than in water, optionally (iii) a stabilizing agent, optionally (iv) a targeting ligand, and optionally (v) an excipient, in (b) an aqueous vehicle.
  • the aqueous vehicle may be, for example, water, isotonic saline solution or phosphate buffer, and may be instilled with an acoustically active gas to facilitate ultrasound imaging and ultrasonic cavitation for local drug release with ultrasound.
  • a method for delivering a drug to a mammalian individual to achieve a desired therapeutic effect, wherein the method involves administering to the individual a therapeutically effective amount of a formulation of the invention, e.g., orally or parenterally.
  • a method for treating an individual suffering from cancer comprising parenterally administering to the patient a surfactant-free formulation of: (a) drug-containing particles comprised of (i) a matrix of a spatially stabilized hydrophilic polymer that is optionally covalently bound to a phospholipid moiety, (ii) an anticancer agent that is entrapped by but not covalently bound to the hydrophilic polymer, wherein the anticancer agent is selected from the group consisting paclitaxel, docetaxel, camptothecin, and derivatives and analogs thereof, (iii) a stabilizing agent, optionally (iv) a stabilizing agent; optionally (v) a targeting ligand; and optionally (vi) an excipient selected from the group consisting of a free phospholipid, a saccharide, a liquid polyethylene glycol, propylene glycol, glycerol, ethyl alcohol, other polyhydroxyalcohols
  • an alternative method for treating an individual suffering from cancer comprising orally administering to the individual a pharmaceutical formulation of: (a) drug-containing particles comprised of (i) a matrix of a spatially stabilized hydrophilic polymer that is optionally covalently bound to a phospholipid moiety, (ii) an anticancer agent that is entrapped by but not covalently bound to the hydrophilic polymer, wherein the anticancer agent is selected from the group consisting of paclitaxel, docetaxel, camptothecin, and derivatives and analogs thereof, (iii) an effective amount of a P-glycoprotein inhibitor, optionally (iv) a stabilizing agent, optionally (v) a targeting ligand, and optionally (vi) an excipient selected from the group consisting of a free phospholipid, a saccharide, a liquid polyethylene glycol, propylene glycol, glycerol, ethyl alcohol, other polyhydroxyal
  • an improved method for administering a drug so as to enhance the bioavailability thereof, wherein the improvement comprises administering the drug in a pharmaceutical formulation comprised of (a) a matrix of a spatially stabilized hydrophilic polymer that is optionally covalently bound to a phospholipid moiety, (b) a drug that is physically entrapped within the matrix but not covalently bound thereto, wherein the drug is water insoluble or sparingly water soluble, optionally (c) a stabilizing agent, optionally a targeting ligand, and optionally (e) an excipient selected from the group consisting of a free phospholipid, a saccharide, a liquid polyethylene glycol, propylene glycol, glycerol, ethyl alcohol, other polyhydroxyalcohols, and combinations thereof, wherein the formulation is free of surfactants.
  • a pharmaceutical formulation comprised of (a) a matrix of a spatially stabilized hydrophilic polymer that is optionally covalently bound to a phospholipid
  • the present invention is based on the formation of a noncovalent complex of drug molecules with a hydrophilic polymer and an optional biocompatible stabilizing agent.
  • This drug/polymer complex allows for the formation of an aqueous suspension of nanoparticles of the complex without requiring chemical modification of the drug.
  • This technology can be applied to many drugs having poor solubility in water, e.g., paclitaxel. Problems related to stability, toxicity of the carrier, and large injection volume of currently available formulations of paclitaxel are well documented. Nanoparticle solubilization technology enables the preparation of paclitaxel formulations with decreased toxicity and improved efficacy.
  • nanoparticles ranging from about 1 nm to about 500-1000 ⁇ m, preferably from about 1 nm to about 500 ⁇ m, that can be stabilized with a stabilizing agent to form nanoparticles having diameters ranging from about lnm to about 300 nm, preferably from about 20 nm to about 100 nm.
  • the resulting nanoparticles are biocompatible and highly useful for drug delivery.
  • the drug delivery is preferably via IN injection but the technology has applications for oral, subcutaneous, e.g., sustained release, and pulmonary delivery.
  • the nanoparticles decrease toxicity of the therapeutic agents such as paclitaxel.
  • the nanoparticles improve dispersal of insoluble drugs and increase uptake from the gastrointestinal tract.
  • the nanoparticles can be formulated into gels, powders or suspensions.
  • the nanoparticles' small effective hydrodynamic radii improves delivery of therapeutic agents into the distal airways, such as the alveoli, thereby allowing systemic delivery of bioactive agents via the pulmonary route.
  • the size of the particles within the formulation helps to control dispersal of the drug and drug release.
  • stabilized and unstabilized drug/polymer complexes have improved solubility and drug release properties compared to crystalline forms of the drug.
  • the rate of release of drug/polymer complexes can be fine-tuned by optionally including a stabilizing agent and by varying the nature of the drug complex.
  • branched polyethylene glycol (PEG) is a soluble polymer that is capable of forming complexes with certain hydrophobic drugs. Once in the body, the PEG will eventually dissolve, releasing the complexed drug.
  • the rate of drug release can be modified by varying the conditions and parameters of complex formation, e.g., ratios of PEG to drug, chemical structure of the PEG, and the amount and type of stabilizing agent. Hydrolyzable bonds may also be incorporated into the hydrophilic polymer and/or the stabilizing agent to accelerate drug release, and pH-responsive groups may be used to increase drug release at a desired pH.
  • FIG. 1 schematically illustrates a formulation of the invention in which a drug molecule (paclitaxel) is "entrapped" within a spatially stabilized matrix of phospholipid- conjugated polyethylene glycol (e.g., dipalmitoyl phosphatidylethanolamine [DPPE] conjugated to polyethylene glycol).
  • a drug molecule paclitaxel
  • DPPE dipalmitoyl phosphatidylethanolamine
  • FIG. 2 schematically illustrates an alternative formulation of the invention in which a drug is entrapped within a spatially stabilized matrix of a highly branchedpolyethylene glycol molecule.
  • FIG. 3 schematically illustrates another alternative formulation of the invention in which a drug is entrapped within a spatially stabilized matrix formed by star polyethylene glycol.
  • FIG. 4 schematically illustrates still another alternative formulation of the invention in which a drug is entrapped within a spatially stabilized matrix of lower molecular weight, branched polyethylene glycol.
  • FIG. 5 presents sizing data of paclitaxel nanoparticles stabilized with human serum albumin.
  • FIG. 6 presents the body weights of nude mice treated with nanoparticulate formulations of paclitaxel in an MTD (maximally tolerated dose study).
  • FIG. 7 relates tumor growth in nude mice following single doses at 2/3 rds MTD of Taxol and the formulation of the invention.
  • FIG. 8 relates tumor growth in nude mice following single doses at full MTD of Taxol and the formulation of the invention.
  • FIG. 9 shows a branched PEG molecule with 4 arms stabilizing 4 molecules of a therapeutic agent.
  • the number of therapeutic molecules stabilized per molecule of branched PEG will vary depending upon the molecular weight of each arm the PEG, the molecular weight of the drug, the formulation and the intended application.
  • the numeral “1" refers to a drug molecule
  • the numeral “2" refers to the polymer.
  • FIG. 10 shows a modified branched PEG with 4 arms stabilizing 4 molecules of a therapeutic agent.
  • the core of the branched molecule has been substituted with another polymer more hydrophobic than PEG such as polypropylene glycol.
  • the hydrophobic core favors partitioning of hydrophobic drugs into the core and stabilization of drug within the interior of the branched molecule.
  • the PEG comprised outer arms may be free to move as would a hydrated PEG molecule.
  • a single branched molecule may form a stable association with a plurality of drag molecules, and do not aggregate to form a particle.
  • the numeral "1" refers to a drug molecule
  • the numeral "2" refers to hydrophilic polymer in outer part of arms
  • the numeral "3" refers to the more hydrophobic core polymer.
  • FIG. 11 shows a modified branched PEG molecule similar to Figure 10, except in this case the termini of the outermost PEG groups have been modified to covalently bind targeting ligands.
  • the branched PEG molecule may bind more than one type of targeting ligand.
  • the bound targeting ligands facilitate drug delivery to specific cells bearing receptors for the particular targeting ligands.
  • the numeral "1" refers to a drug molecule
  • the numeral “2” refers to hydrophilic polymer in outer part of arms
  • the numeral “3” refers to the more hydrophobic core polymer
  • the numeral "4" refers to the targeting ligands (two different types are shown here).
  • pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the selected active agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
  • “Pharmaceutically or therapeutically effective dose or amount” refers to a dosage level sufficient to induce a desired biological result. That result can be alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • treat as in "to treat a disease” is intended to include any means of treating a disease in a mammal, including (1) preventing the disease, i.e., avoiding any clinical symptoms of the disease, (2) inhibiting the disease, that is, arresting the development or progression of clinical symptoms, and/or (3) relieving the disease, i.e., causing regression of clinical symptoms.
  • drug active agent
  • therapeutic agent a chemical material or compound which, when administered to an organism (human or animal), induces a desired pharmacologic effect. Included are analogs and derivatives (including salts, esters, prodrugs, and the like) of those compounds or classes of compounds specifically mentioned which also induce the desired pharmacologic effect.
  • the "solubility" of a compound refers to its solubility in the indicated liquid determined under standard conditions, e.g., at room temperature (typically about 25 °C), atmospheric pressure, and neutral pH.
  • hydrophobic is used to refer to a compound having an octanol: water partition coefficient (at room temperature, generally about 23 °C) of at least about 8:1, preferably at least about 10:1, more preferably 20:1 or higher.
  • octanol water partition coefficient (at room temperature, generally about 23 °C) of at least about 8:1, preferably at least about 10:1, more preferably 20:1 or higher.
  • Hydrophilic refers to a material that is not hydrophobic. In referring to chemical compounds herein, the following definitions apply:
  • alkyl refers to a branched or unbranched saturated hydrocarbon group of 1 to 24, typically 1 to 18, carbon atoms, such as methyl, ethyl, w-propyl, isopropyl, ⁇ -butyl, isobutyl, t-butyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like.
  • aryl refers to an aromatic species containing 1 to 3 aromatic rings, either fused or linked, and either unsubstituted or substituted with one or more substituents. Preferred aryl substituents contain one aromatic ring or two fused aromatic rings.
  • acyl refers to a group having the structure R(CO)- wherein R is alkyl or aryl as defined above.
  • the pharmaceutical formulations of the invention are advantageously used to deliver any drug whose systemic bioavailability (including oral bioavailability) can be enhanced by increasing the solubility of the drug in water.
  • the drugs that are preferred for use in conjunction with the present invention are generally hydrophobic in nature, tending toward low aqueous solubility.
  • the invention incorporates such drugs in a composition comprised of a matrix of a spatially stabilized hydrophilic polymer that physically entraps and thereby immobilizes the drug, but does not covalently bind thereto.
  • the composition may additionally comprise a stabilizing agent that further stabilizes the hydrophilic polymer/ drug complex and is useful in forming nanoparticulate-stabilized complexes.
  • the hydrophilic polymer of the present formulations is spatially stabilized so as to facilitate physical entrapment and thus immobilization of the active agent; that is, the "spatially stabilized" hydrophilic polymer forms a matrix or three-dimensional structure in which discrete regions of drug are dispersed.
  • spatially stabilized is meant that the relative orientation of the drug in the polymer matrix is fixed in three-dimensional space without directional specification.
  • the "spatially stabilized” matrix is sterically constrained. Any polymer that can form such a matrix can be used in conjunction with the invention, providing that the polymer is sufficiently hydrophilic to increase the aqueous solubility of the entrapped drug. It is preferred that the polymer is not cross-linked.
  • hydrophilic polymers include, but are not limited to, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, polylactide, poly(lactide-co-glycolide), polysorbate, polyethylene oxide, polypropylene oxide, poly(ethylene oxide-co-propylene oxide), poly(oxyethylated) glycerol, poly(oxyethylated) sorbitol, poly(oxyethylated) glucose), and derivatives, mixtures and copolymers thereof.
  • suitable derivatives include those in which one or more C- H bonds, e.g., in alkylene linking groups, are replaced with C-F bonds, such that the polymers are fluorinated or even perfluorinated.
  • the preferred hydrophilic polymer for use in the present formulations is polyethylene glycol (PEG) or a copolymer thereof, e.g., polyethylene glycol containing some fraction of other monomer units (e.g., other alkylene oxide segments such as propylene oxide), with polyethylene glycol itself most preferred.
  • the polyethylene glycol used is either branched PEG (including "dendrimeric” PEG, i.e., higher molecular weight, highly branched PEG) or star PEG, optionally conjugated to a phospholipid moiety as will be discussed below.
  • Covalent conjugates of linear PEG and phospholipids may also be used, since such conjugates can give rise to a spatially stabilized matrix, as the hydrophobic chains of the phospholipids will tend to associate in an aqueous medium. See FIG. 1, which schematically illustrates a formulation in which a drug is entrapped within a spatially stabilized matrix of phospholipid-conjugated linear PEG.
  • Combinations of different types of PEG e.g., branched PEG and linear PEG, star PEG and linear PEG, branched PEG and phospholipid-conjugated linear PEG, etc. may also be employed.
  • Branched PEG molecules will generally although not necessarily have a molecular weight in the range of approximately 1000 to 600,000 Daltons, more typically in the range of approximately 2000 to 10,000 Daltons, preferably in the range of approximately 20,000 to 40,000 Daltons.
  • Branched PEG is commercially available, such as from Nippon Oil and Fat (NOF Corporation, Tokyo, Japan) and from Shearwater Polymers (Huntsville, Alabama), or may be readily synthesized by polymerizing lower molecular weight linear PEG molecules (i.e., PEG 2000 or smaller) functionalized at one or both termini with a reactive group.
  • a free radical polymerization initiator such as 2,2'-azobisisobutyronitrile (AIBN).
  • Branched PEGs have 2 or more arms but may have as many as 1000 arms.
  • the branched PEGs herein preferably have about 4 to 40 arms, more preferably about 4 to 10 arms, and most preferably about 4 to 8 arms.
  • Higher molecular weight, highly branched PEG, e.g., branched PEG having a molecular weight of greater than about 10,000 and at least about 1 arm (i.e., one branch point) per 5000 Daltons, will sometimes be referred to herein as "dendrimeric" PEG.
  • Such PEG is preferably formed by reaction of a hydroxyl- substituted amine such as triethanolamine with lower molecular weight PEG that may be linear, branched or star, to form a molecular lattice that serves as the spatially stabilized matrix and entraps the active agent to be delivered.
  • Dendrimeric structures including dendrimeric PEG are described, inter alia, by Liu et al. (1999) PSrr2(10):393-401.
  • Formulations of the invention prepared with highly branched, high molecular weight dendrimeric PEG and with lower molecular weight branched PEG are schematically illustrated in FIGS. 2 and 4, respectively.
  • Star molecules of PEG are available commercially (e.g., from Shearwater Polymers, Huntsville, AL) or may be readily synthesized using living free radical polymerization techniques as described, for example, by Gnanou et al. (1988) Makromol Chem. 189:2885-2892 and Desai et al., U.S. Patent No. 5,648,506.
  • Star PEG generally has a central core of divinyl benzene or glycerol.
  • Preferred molecular weights for star molecules of PEG useful herein are typically in the range of about 1000 to 500,000 Daltons, although molecular weights in the range of about 10,000 to 200,000 are preferred.
  • a formulation of the invention that employs star PEG is schematically illustrated in FIG. 3.
  • conjugates of hydrophilic polymers and phospholipids are also useful in the present formulations.
  • the polyethylene glycol in the PEGylated phospholipids may be branched, star or linear.
  • Conjugates of linear PEG and phospholipids, if used, will generally although not necessarily employ PEG have a molecular weight in the range of approximately 1000 to 50,000 Daltons, preferably in the range of approximately 1000 to 40,000 Daltons. It will be appreciated by those skilled in the art that the aforementioned molecular weight ranges correspond to a polymer containing approximately 20 to 1000 ethylene oxide units, preferably about 20 to 2000 ethylene oxide units.
  • the phospholipid moiety that is conjugated to the PEG may be anionic, neutral or cationic, of naturally occurring or synthetic origin, and normally comprises a diacyl phosphatidylcholine, a diacyl phosphatidylethanolamine, a diacyl phosphatidylserine, a diacyl phosphatidylinositol, a diacyl phosphatidylglycerol, or a diacyl phosphatidic acid, wherein each acyl moiety can be saturated or unsaturated and will generally be in the range of about 10 to 22 carbon atoms in length.
  • Preferred compounds are polymer-conjugated diacyl phosphatidyl-ethanolamines having the structure of formula (I)
  • R 1 and R 2 are the acyl groups
  • R represents the hydrophilic polymer, e.g., a poly alkylene oxide moiety such as poly (ethylene oxide) (i.e., polyethylene glycol), poly(propylene oxide), poly(ethylene oxide-co-propylene oxide) or the like (for linear PEG, R 3 is -O-(CH 2 CH 2 O) n -H), and L is an organic linking moiety such as a carbamate, an ester, or a diketone having the structure of formula (II)
  • Preferred unsaturated acyl moieties are esters formed from oleic and linoleic acids, and preferred saturated acyl moieties are palmitate, myristate and stearate.
  • Particularly preferred phospholipids for conjugation to linear, branched or star PEG herein are dipalmitoyl phosphatidylethanolamine (DPPE) and l-palmitoyl-2-oleyl phosphatidylethanolamine (POPE).
  • DPPE dipalmitoyl phosphatidylethanolamine
  • POPE l-palmitoyl-2-oleyl phosphatidylethanolamine
  • the conjugates may be synthesized using art-known methods such as described, for example, in U.S. Patent No. 4,534,899 to Sears. That is, synthesis of a PEG-phospholipid conjugate or a conjugate of a phospholipid and an alternative hydrophilic polymer may be carried out by activating the polymer to prepare an activated derivative thereof, having a functional group suitable for reaction with an alcohol, a phosphate group, a carboxylic acid, an amino group or the like.
  • a polyalkylene oxide such as PEG may be activated by the addition of a cyclic polyacid, particularly an anhydride such as succinic or glutaric anhydride (ultimately resulting in the linker of formula (II) wherein n is 2 or 3, respectively).
  • the activated polymer may then be covalently coupled to the selected phosphatidylalkanolamine, such as phosphatidylethanolamine, to give the desired conjugate.
  • the hydrophilic polymer may be modified in one or more ways.
  • charged groups may be inserted into the ⁇ hydrophilic polymer in order to modify the sustained release profile of the formulation.
  • negatively charged groups such as phosphates and carboxylates are used for cationic drugs, while positively charged groups such as quaternary ammonium groups are used in combination with anionic drugs.
  • a terminal hydroxyl group of a hydrophilic polymer such as PEG may be converted to a carboxylic acid or phosphate moiety by using a mild oxidizing agent such as chromic (VI) acid, nitric acid or potassium permanganate; a preferred oxidizing agent is molecular oxygen used in conjunction with a platinum catalyst.
  • a mild oxidizing agent such as chromic (VI) acid, nitric acid or potassium permanganate
  • a preferred oxidizing agent is molecular oxygen used in conjunction with a platinum catalyst.
  • Introduction of phosphate groups may be carried out using a phosphorylating reagent such as phosphorous oxychloride (POCl 3 ) (see Example 11).
  • Terminal quaternary ammonium salts may be synthesized, for example, by reaction with a moiety such as
  • R wherein R is H or lower alkyl (e.g., methyl or ethyl), n is typically 1 to 4, and X is an activating group such as Br, Cl, I or an -NHS ester.
  • X is an activating group such as Br, Cl, I or an -NHS ester.
  • such charged polymers may be used to form higher molecular weight aggregates by reaction with a polyvalent counter ion.
  • Other possible modifications to the hydrophilic polymer include, but are not limited to, the following.
  • a terminal hydroxyl group of a PEG molecule may be replaced by a thiol group using conventional means, e.g., reacting hydroxyl-containing PEG with a sulfur- containing amino acid such as cysteine, using a protected and activated amino acid.
  • PEG-SH is also commercially available, for example from Shearwater Polymers.
  • a mono(lower alkoxy)-substituted PEG such as monomethoxy polyethylene glycol (MPEG) may be used instead of polyethylene glycol per se, so that the polymer terminates with a lower alkoxy substituent (such as a methoxy group) rather than with a hydroxyl group.
  • MPEG monomethoxy polyethylene glycol
  • PEG amine may be used in lieu of PEG so that a terminal amine moiety -NH 2 is present instead of a terminal hydroxyl group.
  • the polymer may contain two or more types of monomers, as in a copolymer wherein propylene oxide groups (-CH 2 CH 2 CH 2 O-) have been substituted for some fraction of ethylene oxide groups (-CH 2 CH 2 O-) in polyethylene glycol. Incorporating propylene oxide groups will tend to increase the stability of the spatially stabilized matrix that entraps the drug, thus decreasing the rate at which the drug is released in the body. The more hydrophobic the drag and the larger the fraction of propylene oxide blocks, the slower the drug release rate will be.
  • the hydrophilic polymer may also contain hydrolyzable linkages to enable hydrolytic degradation within the body and thus facilitate drug release from the polymeric matrix.
  • Suitable hydrolyzable linkages include any intramolecular bonds that can be cleaved by hydrolysis, typically in the presence of acid or base. Examples of hydrolyzable linkages include, but are not limited to, those disclosed in International Patent Publication No. WO 99/22770 to Harris, such as carboxylate esters, phosphate esters, acetals, imines, ortho esters and amides.
  • Other suitable hydrolyzable linkages include, for example, enol ethers, diketene acetals, ketals, anhydrides and cyclic diketenes.
  • hydrolyzable linkages within the hydrophilic polymer is conducted using routine chemistry known to those skilled in the art of organic synthesis and/or described in the pertinent texts and literature.
  • carboxylate linkages may be synthesized by reaction of a carboxylic acid with an alcohol
  • phosphate ester linkages may be synthesized by reaction of a phosphate group with an alcohol
  • acetal linkages may be synthesized by reaction of an aldehyde and an alcohol, and the like.
  • polyethylene glycol containing hydrolyzable linkages "X" might have the structure -PEG-X-PEG- or alternatively might be a matrix having the structure
  • the core is hydrophobic molecule such as pentaerythritol
  • the core may be synthesized by reaction of various -PEG-Y molecules with -Core-Z or PEG-Z molecules wherein Z and Y represent groups located at the terminus of individual PEG molecules and are capable of reacting with each other to form the hydrolyzable linkage X.
  • the rate of drug release from the polymeric matrix can be controlled by adjusting the degree of branching of the hydrophilic polymer, by incorporating different types of monomer units in the polymer structure, by functionalizing the hydrophilic polymer with different terminal species (which may or may not be charged), and/or by varying the density of hydrolyzable linkages present within the polymeric structure.
  • the branched PEG molecule may be modified to have a hydrophobic core.
  • the central core is pentaerythritol
  • the innermost arms bound to the pentaerythritol may comprise a polymer more hydrophobic than PEG.
  • Useful polymers to accomplish this include polypropylene glycol and polybutylene glycol.
  • Useful monomers for constructing the inner, hydrophobic core structures of the arms include propylene oxide, butylene oxide, copolymers of the two, lactic acid and copolymers of lactic acid with glycolide (polylactide-co-glycolide and copolymers of the foregoing with poly ethylene glycol).
  • the preferred materials for constructing an inner hydrophobic core include polypropylene glycol and copolymers of propylene oxide with ethylene oxide.
  • Useful polymers for constructing the outer, peripheral parts of the arms include polyethylene glycol, polysialic acid and other hydrophilic polymers, with PEG most preferred. It is possible that a fraction of the monomers in the outer portion of a given arm of the carrier molecule may be replaced with PEG, but in this case, there will be substantially more of the hydrophilic monomer (e.g. ethylene oxide) than the hydrophobic monomer (e.g. propylene oxide).
  • the relative proportion of hydrophobic polymer within the branched polymer may vary from about 10 wt.% to about 90 wt.% on a weight/weight ratio, preferably from about 40 wt.% to about 60 wt.%. When more hydrophobic polymer is used this may increase the drug loading capacity of the branched molecule for hydrophobic drugs.
  • a most preferred ratio is about 50 wt.% weight of hydrophobic polymer, e.g. polypropylene glycol, and 50 wt.% weight ratio of hydrophilic polymer (e.g. PEG) in the outer arms.
  • the branched molecules in the hydrophobic core and peripheral hydrophilic arms are thought to have a number of advantages for drug delivery.
  • the hydrophobic core may better stabilize hydrophobic drugs within the branched molecule and, as the drug is stabilized within the core, the free arms of the PEG may be better able to maintain a random state in which the PEG molecules move freely within solution.
  • the outer, hydrophilic PEG layer may act as a steric barrier, inhibiting or decreasing the aggregation of individual branched molecules into particles. Additionally, in instances when targeting ligands are attached to the termini of the peripheral hydrophilic arms, targeting is facilitated by the unencumbered and exposed nature of the outer PEG arms. As will be discussed further on, a wide variety of targeting ligands can be covalently bound to the free ends of the PEG.
  • the hydrophobic and hydrophilic components of the arms may be linked together by a variety of different.
  • Such linkers include ethers, amides, esters, carbamates, thioesters, disulfide bonds.
  • the linker employed is used to attain the desired drug delivery properties of the pharmaceutical formulation. Metabolizable bonds can be selected to improve excretion of the carrier molecule as well as to improve drug release.
  • the free ends of the hydrophilic portions of the branches can be substituted with one or more targeting ligands per carrier molecule. More than one kind of targeting ligand may be bound to each carrier molecule to facilitate binding to a target cell bearing more than one kind of receptor. A wide variety of ligands may be used in this regard.
  • Exemplary targeting ligands include, for example, proteins, peptides, polypeptides, antibodies, antibody fragments, glycoproteins, carbohydrates, hormones, hormone analogs, lectins, amino acids, sugars, saccharides, vitamins, steroids, steroid analogs, enzyme cofactors, bioactive agents, and genetic material.
  • peptides that are particularly useful as targeting ligands include natural, modified natural, or synthetic peptides that incorporate additional modes of resistance to degradation by vascularly circulating esterases, amidases, or peptidases. While many targeting ligands may be derived from natural sources, some may be synthesized by molecular biological recombinant techniques and other ligands may be synthetic in origin. Peptides may be prepared by a variety of different combinatorial chemistry techniques as are now known in the art. One very useful method of stabilizing a peptide moiety incorporates the use of cyclization techniques.
  • end-to-end cyclization whereby the carboxy terminus is covalently linked to the amine terminus via an amide bond, may be useful to inhibit peptide degradation and increase circulating half-life.
  • Side chain-to-side chain cyclization may also be particularly useful in inducing stability.
  • an end-to-side chain cyclization may be a useful modification as well.
  • the substitution of an L-amino acid for a D-amino acid in a strategic region of the peptide may also provide resistance to biological degradation.
  • Suitable targeting ligands, and methods for their preparation will be readily apparent to one skilled in the art. Although the lengths of the peptides utilized as targeting ligands may vary, peptides having from about 5 to about 15 amino acid residues are generally preferred.
  • Antibodies may be used as whole antibodies or as antibody fragments, e.g., Fab or Fab'2, either of natural or recombinant origin.
  • the antibodies of natural origin may be of animal or human origin, or may be chimeric (e.g., mouse/human). Human recombinant or chimeric antibodies are preferred and fragments are preferred to whole antibodies.
  • Immunoglobulins typically comprise a flexible "hinge” region. See, e.g., "Concise Encyclopedia of Biochemistry," Second Edition, Walter de Gruyter & Co., pp. 282-283 (1988).
  • Antibodies may be linked to the termini of the outer hydrophilic arms using the thiols of this "hinge" region.
  • reducing agents include ethanedithiol, mercaptoethanol, mercaptoethylamine or the more commonly used dithiothreitol, commonly referred to as Cleland's reagent.
  • Antibody fragments such as F(ab')2 may be prepared by incubating the antibodies with pepsin (60 ⁇ g/ml) in 0.1 M sodium acetate (pH 4.2) for 4 h at 37°C. Digestion may be terminated by the addition of 2 M Tris (pH 8.8) to a final concentration of 80 mM. The fragments may then be obtained by centrifugation. The supernatant may be dialyzed at 4°C against 150 mM NaCl, 20 mM phosphate at pH 7.0. Undigested IgG may be removed by chromatographic methods. The antibody fragments may then be extensively degassing the solutions and purging with nitrogen prior to use.
  • the F(ab')2 fragments may be provided at a concentration of 5 mg/ml and reduced under argon in 30 mM cysteine.
  • cysteamine may be employed; 100 mM Tris, pH 7.6 may be used as a buffer for 15 min at 37°C.
  • the solutions may then be diluted 2-fold with an equal volume of the appropriate experimental buffer and spun through a 0.4 ml spin column of Bio-Gel P-6DG.
  • the resulting antibody fragments may be more efficient in their coupling to the outer arms.
  • peptides may be utilized, especially if they contain a cysteine residue. If the peptides have not been made fresh and there is a possibility of oxidation of cysteine residues within the peptide structure, it may be necessary to regenerate the thiol group using the approach outlined above.
  • the attached targeting ligands may be directed toward lymphocytes that may be T-cells or B-cells, with T-cells being the preferred target.
  • a targeting ligand having specific affinity for that class may be preferably employed.
  • an anti CD-4 antibody may be used for selecting the class of T-cells harboring CD-4 receptors
  • an anti CD-8 antibody may be used for selecting the class of T-cells harboring CD-8 receptors
  • an anti CD-34 antibody may be used for selecting the class of T-cells harboring CD-34 receptors, and so on.
  • a lower molecular weight ligand may preferably be employed, e.g., Fab or a peptide fragment.
  • an OKT3 antibody or OKT3 antibody fragment may be used.
  • IL-2 is a T-cell growth factor generally produced following antigen- or mitogen- induced stimulation of lymphoid cells.
  • Cell types that typically produce IL-2 include, for example, CD4+ and CD 8+ T-cells and large granular lymphocytes, as well as certain T-cell tumors.
  • IL-2 receptors are glycoproteins that are expressed on responsive cells. They are notable in connection with the present invention because they are generally readily endocytosed into lysosomal inclusions when bound to IL-2.
  • preferred targets include the anti-IL-2 receptor antibody, natural IL-2 and an IL-2 fragment of a 20-mer peptide or smaller generated by phage display that binds to the IL-2 receptor.
  • IL-2 may be conjugated to stabilizing materials, for example, in the form of vesicles, and thus may mediate the targeting of cells bearing IL— 2 receptors. Endocytosis of the ligand-receptor complex may then deliver the compound to be delivered to the targeted cell.
  • an IL-2 peptide fragment which has binding affinity for IL-2 receptors may be incorporated, for example, by attachment to the termini of a different outer arm either directly to a reactive moiety or via a spacer or linker molecule with a reactive end such as an amine, hydroxyl, or carboxylic acid functional group.
  • linkers are well known in the art and may comprise from 3 to 20 amino acid residues.
  • D-amino acids or derivatized amino acids may be used which avoids proteolysis in the target tissue.
  • Still other systems which may be used in the present invention include IgM- mediated endocytosis in B-cells or a variant of the ligand-receptor interactions described above wherein the T-cell receptor is CD2 and the ligand is lymphocyte function-associated antigen 3 (LFA-3), as described, for example, in Wallner et al. (1987) J Experimental Med. 166:923-932.
  • Targeting ligands derived or modified from human leukocyte origin, such as CDl la/CDl 8 and leukocyte cell surface glycoprotein (LFA-1), may also be used as these may bind to the endothelial cell receptor ICAM-1.
  • NCAM-1 The cytokine inducible member of the immunoglobulin superfamily, NCAM-1, which is mononuclear leukocyte-selective, may also be used as a targeting ligand.
  • NLA-4 derived from human monocytes, may be used to target NCAM-1.
  • Preferred targeting ligands in accordance with the present invention include, for example, Sialyl Lewis X, mucin, hyaluronic acid, LFA-1, ⁇ -formal peptide, C5a, leukotriene B4, platelet activating factor, IL-8/ ⁇ AP-1, CTAP-III, RANTES, and 1-309.
  • the integrins may be used as targeting ligands for targeting NLA-4, fibrinogen, von Willebrand factor, fibronectin, vitronectin, NCAM-1 and CD49d/CD29.
  • a particularly preferred targeting ligand may be Sialyl Lewis X which binds to P-selectin and which has the following sequence: ⁇ eu5Ac(2->3) ⁇ Gal(l- 4)[ ⁇ Fuc(l-»3)]- ⁇ Glc ⁇ Ac-OR wherein R is an aglycone having at least one carbon atom.
  • P-selectin may be a preferred target because it typically localizes on the luminal side of endothelium during inflammation, but generally not in noninflammatory synovia where it is generally cytoplasmic only.
  • T- and B-cell receptors include, for example, antibodies directed to autoantigens on T-cell receptors.
  • Peptides having the amino acid sequences Leu Leu He Tyr Phe Asn Asn Asn Nal Pro He Asp Asp Ser Gly Met (SEQ ID NO: 1) and Lys lie Gin Pro Ser Glu Pro Arg Asp Ser Ala Nal Tyr Phe Cys Ala (SEQ ID ⁇ O:2) can be used to produce antibodies that may bind to the autoantigen portions of T-cell receptors.
  • antibodies to additional T-cell and B-cell receptors may be used as targeting ligands. T- and B-cell receptors involved in inflammation and rheumatoid arthritis are described in Strayk et al.
  • Still additional targeting ligands that may be employed in the compositions and methods of the present invention are described in PCT publication WO 96/37194, and include fetuin and asialofetuin, hexamine, spermine and spermidine, N-glutaryl DOPE, IgA, IgM, IgG and IgD, MHC and HLA markers, and CDl, CD4, CD8-11, CD15, Cdwl7, CD18, CD21-25, CD27, CD30-45, CD46-48, Cdw49, Cdw50, CD51, CD53-54, Cdw60, CD61-64, Cdw65, CD66-69, Cdw70, CD71, CD73-74, Cdw75, CD76-77, LAMP-1 and LAMP-2.
  • Exemplary covalent bonds through which the targeting ligands may be covalently linked to the termini of the outer arms include, for example: amide (-CONH-); thioamide (-CSNH-); ether (ROR, where R and R' may be the same or different and are other than hydrogen); ester (-COO-); thioesters (-COS-); -O-; -S-; -Sn-, where n is greater than 1, preferably about 2 to about 8, and more preferably about 2; carbamates; -NH-; -NR-, where R is alkyl, for example, alkyl of from 1 to about 4 carbons; urethane; substituted imidate; and combinations of two or more of these.
  • Covalent bonds between targeting ligands and stabilizing materials may be achieved through the use of molecules that may act as spacers to increase the conformational and topographical flexibility of the ligand.
  • molecules that may act as spacers include, for example, succinic acid, 1,6-hexanedioic acid, 1,8- octanedioic acid, and the like, as well as modified amino acids, such as, for- example, 6- aminohexanoic acid, 4-aminobutanoic acid, and the like.
  • sidechain-to-sidechain crosslinking may be complemented with sidechain-to-end crosslinking and/or end-to-end crosslinking.
  • small spacer molecules such as dimethylsuberimidate, may be used to accomplish similar objectives.
  • agents including those used in Schiff s base-type reactions, such as gluteraldehyde, may also be employed.
  • the Schiff s base linkages which may be reversible linkages, can be rendered more permanent covalent linkages via the use of reductive amination procedures.
  • This may involve, for example, chemical reducing agents, such as lithium aluminum hydride reducing agents or their milder analogs, including lithium aluminum diisobutyl hydride (DIBAL), sodium borohydride (NaBH 4 ) or sodium cyanoborohydride (NaBH 3 CN).
  • chemical reducing agents such as lithium aluminum hydride reducing agents or their milder analogs, including lithium aluminum diisobutyl hydride (DIBAL), sodium borohydride (NaBH 4 ) or sodium cyanoborohydride (NaBH 3 CN).
  • the covalent linking of the targeting ligands to the stabilizing materials in the present compositions may be accomplished using synthetic organic techniques that would be readily apparent to one of ordinary skill in the art in view of the present disclosure.
  • the targeting ligands may be linked to the materials via the use of well-known coupling or activation agents.
  • activating agents are generally electrophilic, which can be employed to elicit the formation of a covalent bond.
  • Exemplary activating agents include, for example, carbonyldiimidazole (GDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), methyl sulfonyl chloride, Castro's Reagent, and diphenyl phosphoryl chloride.
  • GDI carbonyldiimidazole
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • methyl sulfonyl chloride methyl sulfonyl chloride
  • Castro's Reagent diphenyl phosphoryl chloride
  • the covalent bonds may involve crosslinking and/or polymerization.
  • Crosslinking preferably refers to the attachment of two chains of polymer molecules by bridges, composed of an element, a group, or a compound, which join certain carbon atoms of the chains by covalent chemical bonds.
  • crosslinking may occur in polypeptides that are joined by the disulfide bonds of the cysteine residue.
  • Crosslinking may be achieved by any number of methods including the addition of a chemical substance (crosslinking agent) and exposing the mixture to heat, and the exposure of the polymer to high energy radiation.
  • crosslinking agents, or "tethers" of different lengths and/or functionalities are described, for example, in R.L.
  • crosslinkers include, for example, 3,3'- dithiobis(succinimidylpropionate), dimethyl suberimidate, and its variations thereof, based on hydrocarbon length, and bis-N-maleimido-l,8-octane.
  • the targeting ligands may be linked or attached via a linking group.
  • the targeting ligand is attached via a linker that is also attached to the arms of the polymer.
  • linker that is also attached to the arms of the polymer.
  • the linking group comprises a hydrophilic polymer.
  • Suitable hydrophilic linker polymers include, for example, polyalkyleneoxides such as, for example, PEG and polypropylene glycol (PPG), polyvinylpyrrolidones, polyvinylmethylethers, polyacrylamides, such as, for example, polymethacrylamides, polydimethylacrylamides and polyhydroxypropylmethacrylamides, polyhydroxyethyl acrylates, polyhydroxypropyl methacrylates, polymethyloxazolines, polyethyloxazolines, polyhydroxyethyloxazolines, polyhyhydroxypropyloxazolines, polyvinyl alcohols, polyphosphazenes, poly(hydroxyalkylcarboxylic acids), polyoxazolidines, polyaspartamide, and polymers of sialic acid (polysialics).
  • PPG polypropylene glycol
  • polyacrylamides such as, for example, polymethacrylamides, polydimethylacrylamides and polyhydroxypropylmethacrylamide
  • the hydrophilic polymers are preferably selected from the group consisting of PEG, PPG, polyvinylalcohol and polyvinylpyrrolidone and copolymers thereof, with PEG and PPG polymers being more preferred and PEG polymers being even more preferred.
  • Preferred among the PEG polymers are, for example, bifunctional PEG having a molecular weight of about 1,000 Daltons to about 10,000 Daltons, preferably about 5,000 Daltons.
  • the polymer is bifunctional with the targeting ligand bound to a terminus of the polymer.
  • the targeting ligand may be incorporated into the stabilizing agent at concentrations of from about 0.1 mole % to about 25 mole %, preferably from about 1 mole % to about 10 mole %.
  • the particular ratio employed may depend upon the particular targeting ligand, linker group, and stabilizing agents.
  • Standard peptide methodology may be used to link the targeting ligand to the stabilizing materials when utilizing linker groups having two unique terminal functional groups.
  • Bifunctional hydrophilic polymers, and especially bifunctional PEGs may be synthesized using standard organic synthetic methodologies.
  • many of these materials are available commercially, such as, for example, -amino- ⁇ -carboxy-PEG which is commercially available from Shearwater Polymers (Huntsville, AL).
  • an advantage of using a PEG material as the linking group is that the size of the PEG may be varied such that the number of monomeric subunits of ethylene glycol may be as few as about 5, or as many as about 500 or even greater. Accordingly, the "tether" or length of the linkage may be varied, as desired. This may be important depending on the particular targeting ligand employed. For example, a targeting ligand that comprises a large protein molecule may require a short tether, and thereby simulate a membrane-bound protein. A short tether may also allow for a delivery polymer to maintain a close proximity to the target.
  • vesicles that also comprise a bioactive agent in that the concentration of bioactive agent that may be delivered to the cell may be advantageously increased.
  • Another suitable linking group that may provide a short tether is glyceraldehyde. Glyceraldehyde may be bound to DPPE via a Schiff s base reaction. Subsequent Amadori rearrangement can provide a substantially short linking group. The gamma carbonyl of the Schiff s base may then react with a lysine or arginine of the targeting protein or peptide to form the targeted lipid.
  • the targeting ligands may be incorporated in the present polymers via non-covalent associations.
  • non-covalent association is generally a function of a variety of factors, including, for example, the polarity of the involved molecules, the charge (positive or negative), if any, of the involved molecules, the extent of hydrogen bonding through the molecular network, and the like.
  • Non-covalent bonds are preferably selected from the group consisting of ionic interaction, dipole-dipole interaction, hydrogen bonds, hydrophilic interactions, van der Waal's forces, and any combinations thereof.
  • Non-covalent interactions may be employed to bind the targeting ligand to the stabilizing agent. Additional techniques that may be adapted for incorporating the targeting ligand into the present compositions are disclosed, for example, in U.S. Application Serial No. 09/218,660, filed December 28, 1998.
  • the drug in the formulation is any active agent whose systemic bioavailability can be enhanced by increasing the solubility of the agent in water.
  • such drugs will be at least about one-and-one-half times as soluble in the hydrophilic polymer as in water, and preferably at least about ten times as soluble in the hydrophilic polymer as in water.
  • the latter group of drugs is generally "hydrophobic" as defined in section (A).
  • Any number of drugs may be incorporated into the formulations of the invention, i.e., any compounds that fit the aforementioned solubility criteria and induce a desired systemic effect.
  • Such substances include the broad classes of compounds normally administered systemically.
  • this includes: analgesic agents; antiarthritic agents; respiratory drags, including antiasthmatic agents and drags for preventing reactive airway disease; antibiotics; anticancer agents, including antineoplastic drags; anticholinergics; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihelminthics; antihistamines; antihyperlipidemic agents; antihypertensive agents; antiinflammatory agents; antimetabolic agents; antimigraine preparations; antinauseants; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; antiviral agents; anxiolytics; attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD) drugs; cardiovascular preparations including cardioprotective agents; central nervous system stimulants; cough and cold preparations, including decongestants; diuretics; genetic materials; gonadotropin releasing hormone (GnRH) inhibitors; herbal remedies; hormone,
  • the invention is particularly useful for delivering active agents for which chronic administration may be required, as the present formulations provide for sustained release.
  • the invention is thus advantageous insofar as patient compliance with regard to forgotten or mistimed dosages is substantially improved.
  • Any agent that is typically incorporated into a capsule, tablet, troche, liquid, suspension or emulsion, wherein administration is on a regular (i.e., daily, more than once daily, every other day, or any other regular schedule) can be advantageously delivered using the formulations of the invention.
  • drugs for which a sustained release formulation is particularly desirable include, but are not limited to, the following: analgesic agents—hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone, codeine,, morphine, alfentanil, fentanyl, meperidine and sufentanil, diphenylheptanes such as levomethadyl, methadone and propoxyphene, and anilidopiperidines such as remifentanil; ntiandrogens—bicalutamide, flutamide, hydroxyflutamide, zanoterine and nilutamide; anxiolytic agents and tranquilizers—diazepam, alprazolam, chlordiazepoxide, clonazepam, halazepam, lorazepam, oxazepam and clorazepate; antiarthritic agents—hydroxychloroquine, gold-based compounds such as aura
  • Genetic material may also be delivered using the present formulation, e.g., a nucleic acid, RNA, DNA, recombinant RNA, recombinant DNA, antisense RNA, antisense DNA, hammerhead RNA, a ribozyme, a hammerhead ribozyme, an antigene nucleic acid, a ribooligonucleotide, a deoxyribonucleotide, an antisense ribooligonucleotide, and an antisense deoxyribooligonucleotide.
  • a nucleic acid e.g., a nucleic acid, RNA, DNA, recombinant RNA, recombinant DNA, antisense RNA, antisense DNA, hammerhead RNA, a ribozyme, a hammerhead ribozyme, an antigene nucleic acid, a ribooligonucleotide, a deoxyrib
  • genes include vascular endothelial growth factor, fibroblast growth factor, BC1-2, cystic fibrosis transmembrane regulator, nerve growth factor, human growth factor, erythropoeitin, tumor necrosis factor, interleukin-2 and histocompatibility genes such as HLA-B7.
  • the present formulations preferably include a P-gp inhibitor for oral administration in order to increase intestinal absorption and thus oral bioavailability.
  • P-gp inhibitor is cyclosporin A, although other P-gp inhibitors may also be used.
  • the weight ratio of drug to P-gp inhibitor (e.g., the ratio of paclitaxel to cyclosporin A) will generally be in the range of about 1 :5 to 5:1, preferably in the range of about 1 :2 to 2:1, more preferably in the range of about 1 :1.5 to 1.5:1, and optimally about 1 :1.
  • a folate i.e., a salt or ester of folic acid
  • the amount of drug in the formulation should be such that the weight ratio of drag to all other components of the formulation is in the range of about 1 : 1 to 1 : 50, preferably in the range of about 1 :1 to 1 :20, more preferably in the range of about 1 :2 to 1 :10, and optimally about 1:5.
  • phospholipids i.e., phospholipids not conjugated to PEG or other moieties, may be incorporated into the present formulations as excipients in order to reduce the particle size of the polymer/drug matrix.
  • particle size is critical, and is generally in the range of about 1 nm to 10 ⁇ m, preferably in the range of about 5 nm to 500 nm, most preferably in the range of about 30 nm to 250 nm (the values given are number average).
  • the free phospholipid can be anionic, neutral or cationic, of naturally occurring or synthetic origin, and will generally comprise a diacyl phosphatidylcholine, a diacyl phosphatidylethanolamine, a diacyl phosphatidylserine, a diacyl phosphatidylinositol, a diacyl phosphatidylglycerol or a diacyl phosphatidic acid, wherein each acyl moiety can be saturated or unsaturated and typically contains about 8 to 20 carbon atoms.
  • the preferred unsaturated acyl moieties of the free phospholipids are oleic and linoleic acid esters, and preferred saturated acyl moieties are palmitate, myristate and stearate; particularly preferred phospholipids are DPPE and POPE.
  • the amount of free phospholipid should be just sufficient to reduce the particle size as desired.
  • any free phospholipid that is included in the formulation represents less than about 25% of the total phospholipid present, and optimally represents less than about 10% of the total phospholipid present.
  • Stabilizing agents may also be added to the formulation and are useful for reducing particle size.
  • the polymers may be used in addition or in lieu of free phospholipids.
  • the stabilizing agent acts to stabilize the surface of the complex by virtue of a combination of hydrophilic and hydrophobic interactions.
  • the stabilizing agentpolymer contains both hydrophilic and hydrophobic groups or domains thus allowing this interaction to occur. It is also preferred that the stabilizing agent contain a sufficient amount of hydrophilic surfaces that post stabilization nanoparticles remain suspended within water and avoid clumping.
  • the preferred stabilizing agent is a polymer having a molecular weight ranging from about 400 Daltons to about 400,000 Daltons, more preferably from about 1,000 Daltons to about 200,000 Daltons, and still more preferably from about 3,000 Daltons to about 100,000 Daltons.
  • the stabilizing agent may be derived from natural, recombinant, synthetic or semisynthetic sources. Most preferably the stabilizing agent will be a protein or a peptide.
  • Useful preferred proteins include albumin, collagen, fribrin, immunoglobulins, hemoglobin, vascular endothelial growth factor, vascular permeability factor, epidermal growth factor, fibroblast growth factor, fibronectin, vitronectin, and cytokines such as interleukins (e.g. IL-3 and IL-12).
  • Suitable stabilizing proteins include, but are not limited to: serum proteins, i.e., albumin (especially recombinant and defatted), arnylins, atrial natriuretic peptides, endothelins and endothelin inhibitors, urokinase, streptokinase, staphylokiase, vasoactive intestinal peptide, HDL, LDL, NLDL, etc.; agglutination (antihemophillia) factors, i.e., Factor NIII, Factor IX and subtypes thereof, decorsin, serum thymic factor, etc.; peptide hormones, i.e., ACTH, FSH, LH, parathyroid hormone, thyroxin, insulin, vasopressin, bradykinin and bradykinin potentiators, HGH, CRF (corticotropin releasing factor), oxytocin, gastrins, LH-R
  • the stabilizing protein may also serve as a targeting agent or binding ligand to direct the nanoparticles and drugs therein to a certain site.
  • the preferred protein is albumin, in particular, human serum albumin and even more preferably recombinant derived human albumin.
  • Another preferred protein is defatted albumin, either native or recombinant.
  • the albumin is preferably from the patient's species.
  • the stabilizing albumin is generally added to the nanoparticles at an effective stabilizing concentration, generally in the range of about 0.001% w/v to up to about 10% w/v, more preferably in the range of about 0.01%) to about 5%, in the range of about 0.1 % to about 2.5%, and most preferably in the range of about 0.25% to about 1.5%.
  • an effective stabilizing concentration generally in the range of about 0.001% w/v to up to about 10% w/v, more preferably in the range of about 0.01%) to about 5%, in the range of about 0.1 % to about 2.5%, and most preferably in the range of about 0.25% to about 1.5%.
  • the particles may be formulated with about 1.0% w/v albumin and about 0.1% w/v EGF.
  • the EGF serves as a targeting ligand to help the nanoparticle to bind to tissues with increased expression of the EGF receptor.
  • the protein may be naturally occurring, a protein fragment, e.g. a fragment of the gamma-carboxy terminus of fibrinogen, or chemically modified.
  • albumin or other proteins may be modified with one or more hydrophilic or targeting moieties.
  • the protein may be modified by binding one or more PEG residues per protein molecule, typically between 1 and 100 PEG molecules per protein molecule, but more preferably between 1 and 10 PEG residues.
  • mono or bifunctional PEG groups may be coupled to the protein through linkages such as ethers or biodegradable bonds such as esters, amides, carbamates, thioesters, disulfides, thiocarbamates, phosphate esters and phosphoamides.
  • the resulting "PEGylated” protein enables the protein to stabilize the surface of the nanoparticle while the PEG groups help to protect the nanoparticle surface from nonspecific interaction with serum proteins.
  • the "PEGylated” proteins increase the serum half-lives of the nanoparticles.
  • the polymers may be other natural polymers, such as: cellulose and dextran; semi-synthetic cellulose derivatives such as methylcellulose and carboxymethyl cellulose; and synthetic polymers such as polvinylalcohol polyvinylpyrrolidone and copolymers containing PEG and a second polymer such as polypropylene glycol (PPG) (e.g. those available under the Pluronic trademark).
  • PPG polypropylene glycol
  • Synthetic polymers such as the Pluronics i.e. copolymers of PEG and PPG
  • Preferred block copolymers include, but are not limited to, polyethylene glycol-N-carboxyanhydride of 6-(benzyloxycarbonyl)-l- lysine, polyethylene glycol-poly-1-lysine and polyethylene glycol-polyaspartic acid.
  • Methods for synthesizing the above copolymers are detailed in Harada and Kataoka (1995) Macromolecules 28:5294-5299.
  • One of skill in the art will readily recognize that the same synthetic methods can be used to substitute polypropylene glycols for PEG to make the PPG block copolymer analogs of the above.
  • PEG copolymers may be synthesized from polymerizable aldehydes that optionally contain additives and/or crosslinking elements capable of copolymerization, surfactants or surfactant mixtures, coupling agents, biomolecules or macromolecules bound by these coupling agents, as well as diagnostically or therapeutically effective components.
  • the monomers encompassed herein include, but are not limited to, alphabeta- unsaturated aldehydes, e.g., acrolein, crotonaldehyde, propionaldehyde, alpha-substituted acrolein derivatives, e.g., alpha-methyl acrolein, alpha-chloroacrolein, alpha-phenyl acrolein, alpha-ethyl acrolein, alpha-isopropyl acrolein, alpha-n-butyl acrolein, alpha-n-propyl acrolen; dialdehydes, e.g., glutaraldehyde, succmaldehyde or their derivatives or their mixtures with additives capable of copolymerization (comonomers), e.g., alpha-substituted acroleins, beta- substituted acroleins, ethyl
  • Suitable coupling agents that may be employed in the synthesis of PEG copolymers include, but are not limited to: compounds containing amino groups (e.g., hydroxylamine, butylamine, allylamine, ethanolamine, trishydroxymethylaminomethane, 3-amino-l- propanesulfonic acid, 5 -amino valeric acid, 8-aminooetanoic acid, D-glucosamine hydrochloride, aminogalactose, aminosorbitol, aminomannitol, diethylaminoethylamine, anilines, sulfonyl acid amide, choline, N-methylglucamine, piperazine, 1,6-hexanediamine, urea, hydrazine, glycine, alanine, lysine, serine, valine, leucine, peptides, proteins, albumin, human serum albumin, polylysine, gelatin, polyglycolamines, aminopoly
  • Particularly preferred coupling agents include hydroxylamine, trishydroxymethylammomethane, 3-amino-l-propane sulfonic acid, D- glucosaminohydrochloride, aminomamiitol, urea, human serum albumin, hydrazine, proteins, polyglycolamines, aminopolyalcohols (e.g., HO-PEG-NH 2 or NH 2 -PEG-NH 2 ), and compounds containing acid groups such as PEG-linker-asparaginic acid, PEG-linker- glutaminic acid, PEG-linker-DTPA and PEG-linker-EDTA, wherein the molecular weight of the PEG is less than about 100 kD, preferably less than about 40 kD.
  • the amount of coupling agent is typically present in the range of about 1 % wt. to about 95% wt. of the polyaldehyde in the PEG copolymer.
  • the coupling agents can be condensed by their amino group or on the formyl groups located on the surface of nanoparticles synthesized from polymerized aldehydes and optional surfactants. Also, such formyl groups may also bind those monomers listed above that are polymerizable. However, the acids and alcohols named above are typically coupled on the nanoparticles only after previous conventional conversion of the aldehyde function. Generally the stabilizing agent is added to the complex in aqueous media.
  • the complex and stabilizing agent are then subjected to a mechanical dispersal process that helps to break the complex into nanoparticles that are then stabilized by the stabilizing agent.
  • Useful mechanical dispersal processes include shaking, agitation (e.g., vortexing), sonication, extrusion under pressure, microfluidization, microemulsification and high speed blending.
  • Compounds other than free phospholipids are also useful for reducing particle size, and can be used in addition to or in lieu of free phospholipids; these other compounds include, but are not limited to, cholic acids, cholic acid salts, saccharides (such as sorbitol, sucrose and trehalose), polyhydroxyalcohols (such as glycerol), and liquid polyethylene glycols (i.e., PEG having a molecular weight less than about 1000 Daltons).
  • the formulations of the invention can also contain pharmaceutically acceptable auxiliary agents as required in order to approximate physiological conditions; such auxiliary agents include pH adjusting and buffering agents, tonicity adjusting agents, and the like.
  • Lipid-protecting agents that serve to minimize free radical and peroxidative damage upon storage may also be advantageous.
  • Suitable lipid protective agents include alpha-tocopherol and water-soluble, iron-specific chelators such as deferoxamine and ethylenediaminetetraacetic acid (EDTA).
  • EDTA ethylenediaminetetraacetic acid
  • cryoprotectants or anti-flocculants in order to facilitate rehydration and formation of a substantially homogeneous suspension.
  • one or more conventional anti-bacterial agents be included.
  • Still other additives that may be incorporated into the present formulations include radioactive or fluorescent markers useful for imaging purposes.
  • Radioactive markers include, for example, technitium and indium, while an exemplary fluorescent marker is fluorescein.
  • the excipients can be included in an amount up to about 50 wt.% of the formulation, but preferably represent less than about 10 wt.% of the formulation.
  • the formulations of the invention are manufactured using standard techniques and reagents known to those skilled in the art of pharmaceutical formulation and drug delivery and/or described in the pertinent texts and literature. See Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, PA: Mack Publishing Co., 1995), which discloses conventional methods of preparing pharmaceutical compositions that may be used as described or modified to prepare pharmaceutical formulations of the invention.
  • the hydrophilic polymer, drug, optional free phospholipid and all other components of the final composition are mixed together in an organic solvent or solvent system such as isopropanol, t-butanol, benzene/methanol, ethanol, or an alternative suitable solvent as will be apparent to those of skill in the art and then lyophilizing the mixture.
  • the solvent may also be removed by subjecting the mixture to rotary evaporation to yield a powder or a solid matrix.
  • the material may be ground via ball milling or subjected to other mechanical shear stress to achieve a finely ground powder of nanoparticulate material.
  • the resulting nanoparticles may be stabilized with surfactants, phospholipids, stabilizing agents including albumin, and other stabilizing materials, as discussed above.
  • Another method of manufacturing the formulation is spray drying. In this method, a suitable organic solvent, ideally having a flash point sufficiently above the drying temperature. Formulations made using this method are in the form of a fluffy, dry powder.
  • the components of the final product may be dissolved in a supercritical fluid such as compressed carbon dioxide, and then ejected under pressure and shearing force to form dried particles of the drag-containing formulation.
  • the formulation is preferably stored in lyophilized form, in which case, the lyophilized composition is rehydrated prior to use. Rehydration is carried out by mixing the lyophilized composition with an aqueous liquid (e.g., water, isotonic saline solution, phosphate buffer, etc.) to provide a total solute concentration in the range of about 50 to 100 mg/ml and a drug concentration in the range of about 1 to 20 mg/ml, preferably about 5 to 15 mg/ml.
  • aqueous liquid e.g., water, isotonic saline solution, phosphate buffer, etc.
  • the formulation may, however, be stored in the aqueous state, e.g., in pre-filled syringes or vials.
  • the formulation may also be stored as a liquid in a physiologically acceptable organic solvent such as ethanol, propylene glycol or glycerol, to be diluted with water prior to injection into a patient.
  • the lyophilized and rehydrated formulations may be stored at various temperatures such as freezing conditions (below about 0°C and as low as about -40°C to -100°C), refrigerated conditions generally between about 0°C and 15°C, room temperature conditions generally between about 15°C and 28°C, or at elevated temperatures as high as about 40°C.
  • the particle size of individual particles within the formulation will vary, depending upon the molecular weight and concentration of the hydrophilic polymer, the amount of drug as well as its solubility profile (i.e., its solubility in water and the hydrophilic polymer), the use of stabilizing agents, and the conditions used in manufacturing. That is, as noted in the preceding section, stabilizing agents and various excipients may be used to facilitate rehydration and provide a substantially homogeneous dispersion. Additionally, mechanical processing techniques can be used to adjust particle size to the appropriate diameter for the intended application; for example, after rehydration, the formulation can be subjected to shear forces with microfluidization, sonication, extrusion, or the like.
  • Formulations made with stabilizing agents can have a particle size on the order of about 20 nm to 100 nm. These smaller particles, by virtue of their larger accessible surface-to-volume ratio, tend to release drug quite rapidly, while larger particles, e.g., over 10 ⁇ m in diameter, will provide for far more gradual, sustained release of drug.
  • the preferred particle size herein is in the range of about 1 nm to 500-1000 ⁇ m in diameter.
  • particle size should be in the range of about 1 nm to 500 ⁇ m, preferably in the range of about 10 nm to 300 ⁇ m, and most preferably in the range of about 20 ⁇ m to 200 ⁇ m.
  • particle size is optionally in the range of about 30 nm to 250 nm.
  • particle size can be up to 1000 ⁇ m, while for embolization, particle size will generally be between about 100 ⁇ m and 250 ⁇ m.
  • the formulation can be sterilized using heat, ionizing radiation or filtration.
  • heat sterilization is preferable.
  • Lower viscosity formulations can be filter sterilized, in which case the particle size should be under about 200 nm.
  • Aseptic manufacturing conditions may be employed as well, and lyophilization is also helpful to maintain sterility and ensure long shelf-life.
  • anti-bacterial agents may be included in aqueous formulations in order to prevent bacterial contamination.
  • the present formulations are made with small quantities of an acoustically active gas instilled therein.
  • a headspace of gas preferably an insoluble gas
  • a closed container which is then exposed to mild agitation during rehydration.
  • Microquantities of gas will become entrapped in the interstices of the dispersion.
  • the presence of the acoustically active gas is useful in conjunction with ultrasound imaging, as the gas-instilled dispersion produces an echogenic contrast that allows the drug to be tracked in the body.
  • therapeutic ultrasound can allow the microstructure to unfold at the locus where the ultrasound is applied, releasing the active agent and thus enhancing targeting effectiveness.
  • the acoustically active gas lowers the cavitation threshold, i.e., the energy required for cavitation with ultrasound.
  • the cavitation energy used will be under about 1.5 MegaPascals, and more preferably under about 1.0 MegaPascals.
  • the gas also effects dB reflectivity, and a gas concentration of about 1 mg per ml of particles will generally have a reflectivity approximately 2 dB higher than that of pure water.
  • the amount of acoustically active gas that is imbibed by the particles of the formulation is approximately equal to the void space within the particles, which can be approximated by their density. For example, particles having a density of 0.10 will imbibe about 90 vol.% gas. Lower density particles will imbibe a higher volume of gas (i.e., 95 vol.% for particles having a density of 0.05), while higher density particles will imbibe a lower volume of gas (i.e., 85 vol.% for particles having a density of 0.15). Gas may also adhere to the surface of the particles, typically up to about two times the volume of the particles. Normally, the amount of acoustically active gas that is employed is such that the gas-instilled formulation will contain at least about 5 vol.% gas, preferably about 10-15 vol.% gas.
  • Typical acoustically active gases are chemically inert gases having 1 to 12 carbon atoms, and particularly preferred acoustically active gases are perfluorocarbons, including saturated perfluorocarbons, unsaturated perfluorocarbons, and cyclic perfluorocarbons.
  • the saturated perfluorocarbons which are usually preferred, have the formula C n F 2 ⁇ +2 , where n is from 1 to 12, preferably 2 to 10, more preferably 4 to 8, and most preferably 5.
  • saturated perfluorocarbons examples include the following: tetrafluoromethane; hexafluoroethane; octafluoropropane; decafluorobutane; dodecafluoropentane; perfluorohexane; and perfluoroheptane.
  • Saturated cyclic perfluorocarbons, wliich have the formula C n F 2n , where n is from 3 to 8, preferably 3 to 6, may also be preferred, and include, e.g., hexafluorocyclopropane, octafluorocyclobutane, and decafluorocyclopentane.
  • gases that can be used include air, nitrogen, helium, argon, xenon and other such gases.
  • a gaseous precursor can be used that is in the liquid state at room temperature and that is either (1) volatilized prior to introduction into the headspace above the lipid- and drug-containing dispersion, or (2) volatilized and instilled into a microemulsion which is then introduced into the lipid- and drag-containing dispersion.
  • Suitable gaseous precursors are described, for example, in U.S. Patent No.
  • 5,922,304 to Unger include, without limitation, hexafluoro acetone, isopropyl acetylene, allene, tetrafluoroallene, boron trifluoride, isobutane, 1,2-butadiene, 2,3 -butadiene, 1,3 -butadiene, l,2,3-trichloro-2-fluoro- 1,3 -butadiene, 2-methyl-l,3-butadiene, hexafluoro- 1,3 -butadiene, butadiyne, 1-fluoro-butane, 2-methyl-butane, decafluorobutane, 1-butene, 2-butene, 2-methyl-l-butene, 3-methyl-l- butene, perfluoro- 1-butene, perfluoro-2-butene, 4-phenyl-3-butene-2-one, 2-methyl-l-butene- 3-yne, butyl n
  • the formulations of the invention are used to treat a mammalian individual, generally a human patient, suffering from a condition, disease or disorder that is responsive to systemic administration of a particular drag.
  • the formulations may be administered orally, parenterally, topically, transdermally, rectally, vaginally, by inhalation, intra-ocularly, in an implanted reservoir (i.e., in a sustained release depot for subcutaneous or intramuscular administration), or as a packing material for wounds and fractures.
  • parenteral as used herein is intended to include subcutaneous, intravenous, intramuscular, intra-arterial, intrathecal and intraperitoneal injection, and the formulation may be injected as either a bolus or an infusion.
  • a conventional dosage— or an increased dosage— can be used to provide substantially higher blood levels of a drag than previously obtained using conventional formulations.
  • a bolus dosage of at least 3.5 mg/kg and even 7.0 mg/kg can be administered using the present formulations, while with continuous infusion, a dosage of at least 140 mg/kg can be administered and with using a stabilized formulation, a dosage of up to 200 mg/kg can be administered.
  • the formulations of the invention may be also be used so that a drag is targeted to a particular cell type or tissue.
  • a targeting agent is employed that is covalently coupled to the hydrophilic polymer such as through a terminal hydroxyl group of polyethylene glycol.
  • Suitable targeting agents are those that are generally used with liposomal formulations, e.g., peptides, peptide fragments, antibodies or peptidomimetics, although other ligands such as saccharides and folates can also be used.
  • Preferred targeting agents are integrins such as the ⁇ 3 integrins ("cytoadhesins"), with cyclized oligopeptides containing the Arg-Gly-Asp (RGD) motif particularly preferred.
  • the present formulations are also useful as packing materials for wounds and fractures, and as coating materials for endoprostheses such as stents, grafts and joint prostheses. It is known that restenosis (narrowing of the blood vessels) may occur after angioplasty, placement of a stent, and/or other coronary intervention procedures, as a result of fibroblast proliferation and smooth muscle hypertrophy. Thus, the formulations of the invention may be used as coating materials for endoprostheses to provide local drug delivery following coronary intervention.
  • a known amount of each compound was placed in a 10 ml scintillation vial.
  • Two or three ml of PEG 400 (Kodak, Catalog # 1369941, Lot # 1156703112) were added to each vial using a micropipettor (a Gilson Pipetman, 1000 ⁇ l).
  • Each vial was gently swirled to determine whether or not the drug had dissolved. If dissolution was less than complete, the vial was vortexed at a low speed. If vortexing failed to effect dissolution, the vial was sonicated in a water bath until the drug had dissolved. The time to dissolution was noted.
  • the relative solubility in PEG 400 and water is indicated in Table 3, below.
  • “+” refers to a solubility in PEG 400 that is at least 1.5 times the solubility in water
  • "++” refers to a solubility in PEG 400 that is at least ten times the solubility in water
  • "+++” refers to a solubility in PEG 400 that is at least fifty times the solubility in water.
  • FORMULATION METHODOLOGY 100 mg of a PEG component (either a PEGylated phospholipid or branched PEG, 40 kD, Shearwater Polymers, Huntsville, AL) is dissolved in 10 ml t-butanol. The solution is heated over a 45-60 °C hot water bath and subjected to sonication until the solution clarifies. The optional next component (free phospholipid or dispersing agent) is added in an amount as in Table 1 and sonication is applied again until the mixture clarifies. 10 mg of paclitaxel (Hauser Laboratories or Natural Pharmaceuticals) is then added, followed by heating and sonication as above.
  • a PEG component either a PEGylated phospholipid or branched PEG, 40 kD, Shearwater Polymers, Huntsville, AL
  • the mixture is flash frozen over liquid nitrogen and lyophilized on an ice-water bath for 4 hours followed by room temperature overnight to remove t-butanol.
  • the final lyophilisate may be optionally microfluidized at about 15,000 psi and then lyophilized again for storage.
  • the dry powder so obtained may be rehydrated in 1.0 ml saline.
  • Example 2 SHEARWATER POLYMERS, HUNTSVILLE, AL
  • the protocol of Example 2 is duplicated using 100 mg of the star-PEG or branched PEG described above. No additional phospholipid is added in this case.
  • ETHANOL INJECTION IN WATER 1.6664 g of branched polyethylene glycol, MW 20,000, 4 branches (bPEG) is first dissolved in 20 ml of ethanol in a round bottom flask at approximately 35°C in a water bath with a rotor stirrer for approximately 15 min or until the bPEG has dissolved. This results in a clear solution to which the 332.7 mg of paclitaxel is added and dissolved under the same conditions. This is then taken up into a syringe and injected into a cold stirring solution of 638.6 mg of albumin and 1.6428 g of sucrose. This results in the instant formation of nanoparticles (less than l ⁇ m). The suspension is immediately lyophilized.
  • CHOLIC SALTS AS STABILIZING AGENTS a) 1.6579 g of branched polyethylene glycol, MW 20,000, 4 branches (bPEG) was first dissolved in 30 mL of t-butanol in a round bottom flask at approximately 55°C in a water bath with a rotor stirrer for approximately 15 min or until the bPEG had dissolved. This resulted in a clear solution to which the 329.5-mg of paclitaxel was added and dissolved under the same conditions. This solution was then freeze-dried and lyophilized. The white flaky powder that resulted was hydrated with a solution of 631.3mg sodium taurocholate and 1.6360 g of sucrose. The suspension was microfluidized for 15 min using the Model 11 OS, Microfluidics International Corp., Newton MA. This resulted in an almost clear (translucent) solution; the particle size was less than 50 nm.
  • TWEEN ® 80 POLYOXYETHYLENE 20 SORBITAN MONOOLEATE
  • Branched polyethylene glycol (1.6429 g) and paclitaxel (330.8 mg) were prepared as described in Example 4 above. After lyophilization the dry material was hydrated with a 1% solution of Tween ® 80 (356.8 mg) and microfluidized. This resulted in particles less than l ⁇ m.
  • Taxol ® (Bristol Myers Squibb) was acquired from the University of Arizona Animal Care Center at 6 mg/ml. This solution was further diluted in saline to reach various concentrations needed in the experiment. Mice were injected with 500 ⁇ l in a slow bolus over 1.5 minutes.
  • the dosages for the experimental groups were as follows: 40 mg/kg; 30 mg/kg; 20 mg/kg; 10 mg/kg; and control saline. These animals were injected once a day for 8 days. The 40 mg/kg group died immediately after receiving the first injection. The 30 mg/kg and 20 mg/kg groups survived a single injection on day one but all of the animals in these groups died after receiving the injection on day two.
  • the 10 mg/kg groups all survived the entire 8 days of dosing and showed a delayed (1.-2 minutes) severe response, i.e., they fell on their side, could not move, and had very labored breathing and occasional gasping for 5-10 minutes after which they slowly recovered.
  • the animals were weighed daily until the final day. On the final day of dosing the animals were sacrificed by CO 2 asphyxiation.
  • a blood sample was collected by heart puncture and split for cell count and liver function assays. The heart, liver, left kidney and spleen were collected and weighed from each animal. These tissues were placed in formalin for histological analysis.
  • the animal weights and tissue weights were analyzed statistically. There was no significant effect of Taxol ® at 10 mg/kg/day on body weight when compared to the saline control. There was a significant increase in spleen weight in the 10 mg/kg/day Taxol ® group. The difference was between a mean spleen weight of 0.074 g for the saline group to 0.094 g for the 10 mg/kg/day Taxol ® group with a p value ⁇ 0.015.
  • a formulation of the invention was prepared with 5.3126 g branched PEG 40,000 (“PEG 40K”), 8 branches (Shearwater Polymers), 1.0022 g paclitaxel, 100 ml t-butanol and 2.6919 g sucrose.
  • Paclitaxel content in the lyophilized material was determined by HPLC analysis as 0.078 mg/mg. Daily stock vials were then prepared each containing 768.5 mg of the aforementioned lyophilized formulation. This was dissolved in a total volume of 6 ml of water, making a 10 mg/ml paclitaxel solution.
  • mice Seven groups of 5 mice were given increasing dosages of diluted paclitaxel solution.
  • the groups received either saline, BMS Taxol ® 10 mg/kg, or the branched PEG 40K/paclitaxel solution as prepared above. Dosages were 20 mg/kg, 40 mg/kg, 60 mg/kg, 100 mg/kg and 140 mg/kg paclitaxel.
  • the paclitaxel formulations (BMS Taxol ® or PEG 40K/paclitaxel) were further diluted in saline to reach concentrations needed in the experiment.
  • Mice were injected with 500 ⁇ l in a slow bolus over 1.5 minutes. The mice were injected once a day for 8 days, a Monday through Thursday schedule.
  • mice in the BMS Taxol ® group had no response to injection on day 1 or 2.
  • All mice in the BMS Taxol ® group showed a delayed (1-2 minutes) severe response, i.e., they fell on their side, could not move, and had very labored breathing and occasional gasping for 5-10 minutes after which they slowly recovered on both day 1 and 2.
  • All mice receiving 20, 40, and 60 mg/kg paclitaxel using the branched PEG 40K/paclitaxel formulation prepared above showed no response to the injections on day 1 or 2.
  • 100 mg/kg paclitaxel resulted in slight distress, i.e., movements were slowed for 1-2 minutes but no breathing problems were observed on day 1 or day 2.
  • the 140 mg/kg group showed moderate distress immediately after injection, i.e., they did not move and their breathing was slightly labored. Within this group one mouse died on day 1, one-hour post injection, and one mouse died two hours post injection. On day 2 one mouse died immediately after injection.
  • the average dose tolerance was found to be at least 1 OX in terms of toxicity tolerance for the branched PEG/paclitaxel formulation of the invention compared to Taxol ® .
  • Taxol ® the results of this in vivo study support a ten-fold improvement in acute safety for the branched PEG/paclitaxel formulation of the invention and a six-fold improvement for subacute administration.
  • Example 2 PREPARATION OF PACLITAXEL "MICROBUBBLES"
  • the formulation described in Example 2 is suspended in a 3 ml glass vial volume in a 1.6 ml saline solution, paclitaxel concentration 10 mg per ml, and the vial is sealed with a headspace of perfluorobutane gas.
  • the vial is agitated at 4,500 rpm using a Capmix (ESPE, Morris, IL) dental amalgamator for 60 seconds. This results in microbubbles bearing paclitaxel.
  • EXAMPLE 10 EXAMPLE 10
  • An endorectal ultrasound probe is placed in the patient's rectum and ultrasound, 1.OMHz, 1.0 Watt/cm 2 , is applied across the patient's rectum for 30 minutes.
  • the ultrasound probe is adjusted so that the energy is concentrated on the prostate gland.
  • Ultrasound energy is adjusted so that the microbubbles are ruptured as they circulate within the patient's prostate gland.
  • Increased delivery of paclitaxel to the cancer within the prostate is achieved.
  • the patient is then treated with radiation therapy with a fraction of 300 Rads as part of a multi-dose treatment regiment.
  • the paclitaxel acts as a radiation sensitizer and the ultrasound-mediated delivery enhances cellular uptake of the drag by the cancer.
  • a patient with breast cancer may develop an allergic reaction to Taxol® due to the surfactants in the formulation. Still the patient will need the drag to control her disease and require pre-medication to avoid allergic reaction as well as sustained, slow infusion of the drug.
  • the new formulation described in Example 3 is made available. Because of the absence of surfactants, the paclitaxel can be administered as an IN bolus injection without premedication.
  • Paclitaxel is dissolved in t-butanol at a concentration of 20 mg per ml with 100 mg per ml of branched PEG.
  • the material is lyophilized and reconstituted at a concentration of 25 mg per ml paclitaxel in physiological buffered saline (PBS).
  • PBS physiological buffered saline
  • the material appears as a viscous suspension of particles up to about an average size of 100 to 200 microns.
  • This material is applied as a paste to the peritoneal surfaces of a patient with ovarian cancer following laparotomy and debulking for recurrent tumor.
  • the formulation acts as a sustained release depot within the peritoneal cavity helping to control the patient's cancer.
  • the peptide leuprolide acetate is dissolved in t-butanol at a concentration of 20 mg per ml with 100 mg per ml of branched PEG. This is reconstituted with PBS at a drag concentration of 50 mg per ml. Two cc of this material is injected subcutaneously into a patient with prostate cancer. The sustained release of leuprolide acts to decrease hormonal stimulation and help control his cancer.
  • the reaction mixture was then concentrated in vacuo followed by resuspension/dissolution in 100 ml of water.
  • the product was dialyzed in a 1000 Molecular weight cutoff (MWCO) dialysis bag against deionized water. The solution from the bag was recovered, frozen, and lyophilized; yielding a white product containing mono-phosphorylated branched PEG.
  • MWCO Molecular weight cutoff
  • the reaction may be repeated in the identical manner using twice, three times, four times, five times, etc., the stoichiometric amount of phosphorous oxychloride (POCl 3 ) to yield di-, tri-, terra-, penta-, hexa-, hepta-, and per-phosphorylated branched PEGs. Note that the same procedure can be applied to any terminally hydroxylated branched PEG.
  • a Wallstent ® (Boston Scientific, Quincy, MA, model no. 42054) metallic stent is coated at described above.
  • the coated stent is covered by a hazy white clathrate.
  • the stent is advanced into the iliac artery of a patient with stenotic narrowing due to advanced atherosclerosis.
  • the stent is positioned and deployed at the site of stenosis using a Unistep Plus Delivery System (Boston Scientific).
  • the paclitaxel aids in prevention of restenosis and the formulation releases the drug over a delayed period of time for maximal therapeutic benefit.
  • ALTERNATIVE STENT COATING Another Wallstent ® (same model) is treated with a gold plating process using electrochemistry to deposit a thin film of gold on the surface of the stent.
  • a different branched PEG is prepared by substituting the terminal hydroxyl moieties of the PEG with thiol groups.
  • the branched PEG is mixed with paclitaxel as described above in an organic solvent. The mixture is atomized and sprayed on the stent as described above in Example 12.
  • the thiolated PEG used in this coating provides for a slower release rate, delivering the paclitaxel over a longer period of time.
  • Example 14 The procedure of Example 14 is repeated with a poly(alkylene oxide) comprising 50% ethylene oxide monomers and 50% propylene oxide monomers.
  • a poly(alkylene oxide) comprising 50% ethylene oxide monomers and 50% propylene oxide monomers.
  • the incorporation of propylene oxide groups prolongs the release of the paclitaxel, providing therapy for a longer period of time.
  • Example 2 PREPARATION OF NANOPARTICLES WITH LINEAR PEG STABILIZED IN ALBUMIN The procedure of Example 2 was used. The ratio of paclitaxel to PEG was maintained at 1 :5 for PEG 35K, 20K & 10K. The difference between linear and branched PEG was not apparent without the use of human serum albumin. When the different formulations were suspended in an albumin solution, the difference in particle size was apparent and in the linear PEG the toxicity was greater.
  • Example I The procedure of Example I was repeated (ratio of 1 :5 paclitaxel: PEG) using a 2% albumin solution in a phosphate buffer (pH7.24) to hydrate the dry complex of the PEG and paclitaxel. This suspension was microfluidized for 45 minutes. No crystals were observed. Large particles resulted which appeared to aggregate.
  • PEG paclitaxel
  • the PEG is initially activated using trichloro-s-triazine (TsT), which is a symmetrical heterocyclic compound containing three reactive acyl-like chlorines. PEG activation is necessary to form derivatives that are amine reactive where proteins linkages, in this case albumin, can develop.
  • TsT trichloro-s-triazine
  • the activated PEG is slowly added to a solution of albumin in a 0.1 M sodium borate buffer at a concentration of 2- 10 mg/ml. Note that at least a fivefold molar excess of the activated PEG should be present. This reaction takes 1 hr. at 4°C and the excess PEG can be removed by dialysis or gel filtration using a column of Sephacryl S-300 (Hermanson G.T, (1996) "Bipconjugate Techniques” Academic Press, San Diego).
  • a maximum tolerated dose (MTD) study was designed to test the safety of the stabilized paclitaxel formulation described in Example 16. These experiments were carried out in non-tumor bearing nude mice of between 6 and 8 weeks and an approximate body weight of 25 g. The animals were warmed under a heat lamp for 15 minutes and then placed into a mouse restraint. An injection dose was then administered through the tail vein at a volume not exceeding 20 ml/kg. The maximum tolerated dose was defined to be the highest dose where the animals did not lose more than 10% body weight for two weeks after a single dose of drug.
  • mice were caged in groups of 5 for the holding period and were provided with food and water ad libitum. Animals completing the study were euthanized by CO 2 asphyxiation after the final weighing. A control study was carried out using Bristol-Myers Squibb's TAXOL ® in this strain of mice.
  • mice A group of three nude mice were tested, each receiving different doses of the formulation: 150, 200, and 250 mg/kg. Their body weight was monitored following the injection and results are present in the figure below. In all tested mice, body weight change was approximately proportional to the dose given. The body weight decreased less than 10% of the initial weight, except for the mouse that received 250 mg/kg, (that mouse died on day 4). In the control study, the MTD of BMS TAXOL ® was determined as 20 mg/kg. The single dose MTD for the formulation is 200 mg/kg and exceeds ten times that of BMS TAXOL ® . (See Table 7 below.)
  • the efficacy of the formulation was monitored following single administration at 2/3rd of MTD (maximum tolerated dose, 135 mg/kg) and full MTD (200 mg/kg), and compared to the efficacy of BMS TAXOL ® administered at its MTD, i.e., 20 mg/kg.
  • MTD i.e. 200 mg/kg. Following the single administration, all tumors regressed throughout the duration of experiment. Tumor inhibition as defined above is not applicable here.
  • tumor regression was calculated using the formula (1 - mean tumor weight/initial mean tumor weight) x 100%. A maximum tumor regression of 82% was seen on day 8. The body weight of the animals undergoing efficacy experiment was monitored and is shown in

Abstract

Cette invention se rapporte à des formulations pharmaceutiques qui augmentent la biodisponibilité systémique d'un médicament ayant une faible solubilité aqueuse. Le médicament est encapsulé dans une matrice spatialement stabilisée d'un polymère hydrophile, sans être lié à elle par covalence. Des fractions phospholipidiques sont éventuellement conjuguées avec le polymère hydrophile, et des phospholipides libres, des agents stabilisants et/ou d'autres excipients peuvent être incorporés également dans ces formulations. Cette invention concerne en outre des procédés thérapeutiques, dans lesquels une telle formulation est administrée à un patient, pour traiter un état, un trouble ou une maladie réagissant à un médicament particulier. Généralement, l'administration se fait par voie orale ou parentérale.
PCT/US2000/035322 2000-01-05 2000-12-21 Formulations pharmaceutiques pour l'administration de medicaments ayant une faible solubilite aqueuse WO2001049268A1 (fr)

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AU24585/01A AU2458501A (en) 2000-01-05 2000-12-21 Pharmaceutical formulations for the delivery of drugs having low aqueous solubility
JP2001549636A JP2003520210A (ja) 2000-01-05 2000-12-21 低い水溶性を有する薬物の送達のための薬学的処方物

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EP1246608A4 (fr) 2005-05-18
CA2395132A1 (fr) 2001-07-12

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