WO2015134543A1

WO2015134543A1 - Pharmacokinetically equivalent nanoparticle compositions

Info

Publication number: WO2015134543A1
Application number: PCT/US2015/018545
Authority: WO
Inventors: Voung Trieu
Original assignee: Sorrento Therapeutics, Inc.
Priority date: 2014-03-05
Filing date: 2015-03-03
Publication date: 2015-09-11

Abstract

The present invention relates to conditionally unstable micellar compositions containing cytotoxic drugs which do not contain albumin which when introduced to mammals have similar or the same pharmacokinetic profile as compositions using albumin.

Description

Pharmacokinetically Equivalent Nanoparticle Compositions

Related Applications

This application claims priority to U.S. Ser. No. 61/966,871 filed March 5, 2014, which is hereby incorporated in its entirety into this application.

Field of the Invention

Background of the Invention

Taxanes (paclitaxel and docetaxel) are highly active chemotherapeutic agents in the treatment of breast cancer. Being hydrophobic, taxanes require solvents (Cremphor EL or polysorbate) to enable parenteral administration. These solvents contribute to the main toxicities seen with taxanes (hypersensitivity, peripheral neuropathy, and myelo-suppression). Cremophor EL can also leach plasticizers from polyvinyl chloride tubing, which can result in severe, sometimes fatal, anaphylactic reactions. To prevent or limit the onset of hypersensitivity reactions, corticosteroids and antihistamines are standard premedication with taxanes. Furthermore, Cremophor EL entraps paclitaxel into circulating micelles, which reduces its availability and delivery into tumors. Micelle formation with solvent-based paclitaxel results in nonlinear kinetics and the absence of a dose-response relationship: increasing the dose increases toxicity without an accompanying enhancement in efficacy.

nob-Paclitaxel is a solvent-free, albumin-bound nanoparticle formulation of paclitaxel that takes advantage of the increased delivery of albumin to tumors through receptor-mediated transport called transcytosis. nob-Paclitaxel binds to gp60, the albumin receptor on endothelial cells, which in turn activates caveolin-1 and the formation of caveolae. Caveolae transport the albumin-paclitaxel to the extracellular space, including the tumor interstitium. In the tumoral interstitium, SPARC (secreted protein, acidic and rich in cysteine) is selectively secreted by the tumors and binds to albumin-bound paclitaxel with the resultant release of paclitaxel in the vicinity of tumor cells. Together the absence of solvents and the receptor-mediated delivery result in decreased toxicity and increased antitumor activity of nob-paclitaxel compared with solvent-based paclitaxel.

Abraxane is the drug of choice in first and second line of treatment in metastatic breast cancer and is approved in majority of markets. Dose-limiting side effects of Abraxane include dose-dependent bone marrow suppression (primarily neutropenia). In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC) and 47% of patients with non-small cell lung cancer (NSCLC). Abraxane also requires tedious reconstitution which may cause foaming or clumping of the reconstituted lyophilized powder.

While there are cytotoxic drug compositions that are useful in the treatment of various cancers there exists a need for methods of treatment and drug administration that reduce side effects, have improved drug stability and/or increase the efficacy of the treatment regimen. In addition, there is a need for cytotoxic drug compositions that can be administered at higher doses and with increased activity, especially for cancers that are resistant to current treatment regimens.

Summary of the Invention

The present invention relates to conditionally unstable micellar compositions containing cytotoxic drugs which do not contain albumin which when introduced to mammals have similar or the same pharmacokinetic profile as compositions using albumin. The compositions of the present invention are able to use receptor-mediated transport, transcytosis, even though the compositions are not bound to albumin or associated with albumin as they are constituted. The present invention also relates to methods of treating various cancers by administering compositions including micelles and/or nanoparticles that contain a cytotoxic drug but that are not associated with albumin prior to and during administration of the treatment.

The present invention relates to compositions comprising a cancer drug in a micelle or a nanoparticle without any albumin wherein the composition is stable in protein-free medium and unstable in a protein containing medium.

The present invention also relates to compositions comprising a cancer drug in a micelle or a nanoparticle without any albumin wherein the composition is stable in protein-free medium and unstable in a protein containing medium and wherein the pharmacokinetic profile of this composition is similar to that of another composition comprising a cancer drug in which the other composition contains albumin.

The present invention also relates to methods of treating a cancer patient having a tumor by administering a composition comprising a cancer drug in a micelle without any albumin wherein the micelle disintegrates in the patient's bloodstream and the paclitaxel is released from the micelles and wherein the released cancer drug binds endogenous drug transport protein and is then taken up by the tumor by transcystosis of the protein/cancer drug complex.

Figures

Figure 1 - Schematic of proposed mechanism of action of IG-001 in cancer tumor treatment.

Figure 2A - Plot of particle size versus paclitaxel concentration for nab-paclitaxel in phosphate buffered saline (PBS) and O.lx serum and lx serum; Figure 2B - Plot of particle size versus paclitaxel concentration for IG-001 in phosphate buffered saline (PBS) and O.lx serum and lx serum

Figure 3 - Plot of the concentration of IG-001 and nab-paclitaxel versus time after a 30mg/kg bolus injection of each into mice

Figure 4 - Plot of the concentration of IG-001 and nab-paclitaxel versus time after a thirty minute intravenous infusion (21.7mg/kg) into each monkey.

Detailed Description of the Invention

The present invention relates to compositions comprising cancer drugs in a micelle or nanoparticle wherein the composition is stable in protein-free medium, and less stable or unstable in a protein containing medium and where the composition does not contain albumin. The present invention relates to paclitaxel compositions wherein the paclitaxel is contained within a micelle or nanoparticle which is stable in protein-free medium and unstable in a protein containing medium. The present invention relates to conditionally unstable micellar compositions containing cytotoxic drugs which do not contain albumin which when introduced to mammals have similar or the same pharmacokinetic profile as compositions using albumin. The compositions of the present invention are able to use receptor-mediated transport, transcytosis, even though the compositions are not bound to albumin or associated with albumin as they are constituted. The present invention also relates to methods of treating various cancers by administering compositions including micelles and/or nanoparticles that contain a cytotoxic drug but that are not associated with albumin prior to and during administration of the treatment. The compositions of the present invention have the same or similar pharmacokinetic profiles to those compositions containing the same active ingredient but in which the compositions contain albumin.

The micelles or nanoparticles of the present invention are formulated such that they disintegrate in the patient's bloodstream and the cancer treating agent is released from the micelles/nanoparticles. The released agent then may bind to endogenous drug transporter protein which then may bind to gp60 albumin receptors in the caveolae of the tumor capillary endothelial cells which induces transcystosis of the albumin/paclitaxel complex. Enrichment of the agent-loaded albumin in the tumor is in part mediated by tumor-associated albumin-binding proteins and the enhanced catabolism of albumin by the tumor. The uptake of the agent by the tumor induces cell death and tumor mass reduction. Moreover, the ability of the micelles or nanoparticles of the present invention to utilize the transcytosis mechanism to enter the tumor enables the compositions of the present invention to the have the same or similar pharmacokinetic profiles of that of the same cancer treating agent in a composition that includes albumin. In particular, the micelles or nanoparticles of the present invention which include paclitaxel as a cancer treating agent have the same or similar pharmacokinetic metrics as nab-paclitaxel. These pharmacokinetic metrics include but are not limited to the peak plasma concentration of a drug after administration (C_max) and area under the curve, the integral of the concentration-time curve (AUC). A pharmacokinetic metric is considered to be similar if the measurement of a metric for one drug or drug composition is between 80% and 125% that of another drug or drug composition.

The micelle compositions of the present invention include amphiphilic block copolymers which may contain a hydrophilic block (A) and a hydrophobic block (B) linked with each other in the form of an A-B, A-B-A, or B-A-B structure. Addiitonally, the amphiphilic block copolymer may form core-shell type polymeric micelles in its aqueous solution state, wherein the hydrophobic block forms the core and the hydrophilic block forms the shell.

In one embodiment, the hydrophilic block (A) of the amphiphilic copolymer may be polyethylene glycol (PEG) or monomethoxypolyethylene glycol (MPEG). The hydrophilic block (A) may have an average molecular weight of about 500-20,000 daltons, or between about 1,000 to about 5,000 daltons or about 1,000-2,500 daltons.

The hydrophobic block (B) of the amphiphilic copolymer may be a water-insoluble, biodegradable polymer. In one embodiment, the hydrophobic block (B) of the amphiphilic copolymer may be polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA). The hydrophobic block (B) may have an average molecular weight of about 500-20,000 daltons, or between about 1,000 to about 5,000 daltons or about 1,000-2,500 daltons. Hydroxyl end groups of the hydrophobic block (B) may be protected by fatty acid groups including but not limited to acetate, propionate, butyrate, stearate, palmitate groups and the like. The amphiphilic block copolymer comprising the hydrophilic block (A) and the hydrophobic block (B) may be present in the composition in an amount of about 20-98 wt%, or from about 65-98 wt% or from about 80-98 wt% based on the total dry weight of the composition. The amphiphilic block copolymer comprising the hydrophilic block (A) and the hydrophobic block (B) may be composed such that the hydrophilic block (A) comprises about 40-70% of the block copolymer. In other embodiments the hydrophilic block (A) comprises about 50-60% of the block copolymer. When the hydrophilic block (A) is present in a proportion less than 40% of the block copolymer the polymer has undesirably low solubility in water, resulting in difficult formation of micelles. When the hydrophilic block (A) is present in a proportion greater than 70% of the block copolymer the polymer becomes too hydrophilic to form stable polymeric micelles and thus a less effective composition for solubilizing less soluble active drug compounds such as taxane.

A preferred paclitaxel formulation is IG-001 (also referred to as Genexol-PM and Cynviloq™) which is a Cremphor-free, polymeric micelle formulation of paclitaxel which utilizes a biodegradable block co-polymer comprised of methoxy poly (ethylene glycol) poly lactide to form nanoparticles with a paclitaxel containing hydrophobic core and a hydrophilic shell. The micellar composition may be made by dissolving an amphipathic co-polymer, monomethoxypolyethylene glycol-polylactide with an average molecular weight of 1766-2000 dalton at 80°C in ethanol. Paclitaxel is added to the dissolved copolymer and the solution cooled to about 50°C where room temperature water is added. Anhydrous lactose may be added and dissolved. The solution may then be filtered and lyophilized.

The compositions of the present invention can be administered alone or as admixtures with conventional excipients, for example, pharmaceutically, or physiologically, acceptable organic, or inorganic carrier substances suitable for enteral or parenteral application which do not deleteriously react with the composition. Suitable pharmaceutically acceptable carriers indue water, salt solutions (such as Ringer's solution), alcohols, oils, gelatins and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, and polyvinyl pyrolidine. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring and/or aromatic substances and the like which do not deleteriously react with the compositions administered to the human. The composition of the invention can be in any suitable dosage form or formulation, (see, e.g., Pharmaceutics and Pharmacy Practice, J. B. Lippincott Company, Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), which is incorporated herein in its entirety by reference). Pharmaceutically acceptable salts of the agents discussed herein include metal salts, such as sodium salt, potassium salt, cesium salt, and the like; alkaline earth metals, such as calcium salt, magnesium salt, and the like; organic amine salts, such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, Ν,Ν'-dibenzylethylenediamine salt, and the like; inorganic acid salts, such as hydrochloride, hydrobromide, sulfate, phosphate, and the like; organic acid salts, such as formate, acetate, trifluoroacetate, maleate, tartrate, and the like; sulfonates, such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts, such as arginate, asparginate, glutamate, and the like.

The micellar formulations of the present invention are quite stable in protein-free media. Sustained release micelles have been prepared in which polymers with very low CMC (< 0.1 μg/ml) can be used for prolonging the circulation time before the micelle degrades. Upon intravenous injection, the micelles undergo dilution in the body. If the CMC of the micelles is high, the concentration of the polymer or surfactant falls below the CMC upon dilution and hence, the micelles dissociate. Therefore, a higher concentration of the polymer or surfactant has to be used to prepare the micelles so that they withstand the dilution up to 5 L in the blood. However, the use of high concentrations might not be feasible due to toxicity-related dose limitations. If the polymer or surfactant has a CMC lower than O.^g/ml, concentrations as low as 5 mg/ml may be used to prepare a micelle formulation in order to counter the dilution effects in the blood. A variety of polymers including diblock copolymers, triblock copolymers and graft copolymers have been synthesized to be stable even after intravenous administration. The formulations of the present invention, contrary to conventional wisdom, provide methodologies for constructing formulations in which the nanoparticles are less stable once administered such that the drug compound can be released from the nanoparticle and made available to the endogenous drug delivery system. Nanoparticles of the present invention are more stable in protein-free solutions than in solutions containing proteins such as serum. The nanoparticles of the present invention may be at least 20% more stable, or 25% more stable, or 30% more stable, or 35% more stable, or 40% more stable, or 45% more stable, or 50% more stable, or 55% more stable, or 60% more stable, or 65% more stable, or 70% more stable, or 75% more stable, or 80% more stable, or 85% more stable, or 90% more stable, or 95% more stable, or 100% more stable, or 125% more stable, or 150% more stable, or 175% more stable, or 200% more stable, or 500% more stable, or 1000% more stable, or 5000% more stable, or 10000% more stable in a protein free solution than in a solution containing protein. The nanoparticles of the present invention may be between about 10% more stable to about 25000% more stable, or about 10% more stable to about 15000% more stable, or about 10% more stable to about 12500%, more stable or about 10% more stable to about 10000%, more stable, or from about 10% more stable to about 9000% more stable, or from about 10% more stable to about 8000% more stable or from about 10% more stable to about 7000% more stable, or from about 10% more stable to about 6000% more stable, or from about 1000% more stable to about 500% more stable, or from about 10% more stable to about 400% more stable, or from about 10% more stable to about 300% more stable, or about 10% more stable to about 200% more stable, or about 20% more stable to about 125% more stable, or about 20% more stable to about 100% more stable, or from about 20% more stable to about 90% more stable, or from about 20% more stable to about 80% more stable, or from about 20% more stable to about 70% more stable, or from about 20% more stable to about 60% more stable, or from about 20% more stable to about 50% more stable, or from about 20% more stable to about 40% more stable, or from about 50% more stable to about 2500% more stable, or from about 50% more stable to about 1250% more stable, or from about 50% more stable to about 1000% more stable in a protein free solution than in a solution containing protein.

The nanoparticles of the present invention may be at least 20% less stable, or 25% less stable, or 30% less stable, or 35% less stable, or 40% less stable, or 45% less stable, or 50% less stable, or 55% less stable, or 60% less stable, or 65% less stable, or 70% less stable, or 75% less stable, or 80% less stable, or 85% less stable, or 90% less stable, or 95% less stable, or 100% less stable, or 125% less stable, or 150% less stable, or 175% less stable, or 200% less stable, or 500% less stable, or 1000% less stable, or 5000% less stable, or 10000% less stable in a solution containing protein than in a protein free solution . The nanoparticles of the present invention may be between about 10% less stable to about 25000% less stable, or about 10% less stable to about 15000% less stable, or about 10% less stable to about 12500% less stable, or about 10% less stable to about 10000% less stable, or from about 10% less stable to about 9000% less stable, or from about 10% less stable to about 8000% less stable, or from about 10% less stable to about 7000% less stable, or from about 10% less stable to about 6000% less stable, or from about 1000% less stable, to about 500% less stable, or from about 10% less stable, to about 400% less stable, or from about 10% less stable to about 300% more stable, or about 10% less stable to about 200% less stable, or about 20% less stable to about 125% less stable, or about 20% less stable to about 100% less stable, or from about 20% less stable to about 90% less stable, or from about 20% less stable to about 80% less stable, or from about 20% less stable to about 70% less stable, or from about 20% less stable to about 60% less stable, or from about 20% less stable to about 50% less stable, or from about 20% less stable to about 40% less stable, or from about 50% less stable to about 2500% less stable, or from about 50% less stable to about 1250% less stable, or from about 50% less stable to about 1000% less stable in a protein containing-solution than in a solution free of protein.

The methods of the present invention provide methodologies for constructing nanoparticles which ideally release their contents in vivo but are stable in an intravenous (i.v.) bag, or in an infusion solution. IG-001 exhibited significant instability in serum even at high paclitaxel concentrations of 2000 ug/ml.

Cytotoxic drugs used in the compositions and formulations of the present include but are not limited to paclitaxel, docetaxel, 7-epipaclitaxel, t-acetyl paclitaxel, 10-desacetyl-paclitaxel, 10-desacetyl- 7-epipaclitaxel, 7-xylosylpaclitaxel, 10-desacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L- alanylpaclitaxel, carboplatin, cisplatin, cyclophosphamide, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, methotrexate, topotecan, vincristine and vinblastine.

Cancer types for which the methods and formulations of the present invention may be useful include but are not limited to ovarian cancer, breast cancer, pancreatic cancer, liver cancer, non-small cell lung cancer (NSCLC) and other lung cancers, especially cancers resistant to conventional chemotherapeutic agents delivered as solvent solubilized drug such as, for example, Cremaphor™ EL paclitaxel.

IG-001 is formulated such that it disintegrates in the patient's bloodstream and the paclitaxel is released from the micelles. The released paclitaxel then may bind to endogenous serum albumin which then may bind to gp60 albumin receptors in the caveolae of the tumor capillary endothelial cells which induces transcystosis of the albumin/paclitaxel complex. Enrichment of the paclitaxel-loaded albumin in the tumor is in part mediated by tumor-associated albumin-binding proteins and the enhanced catabolism of albumin by the tumor. The uptake of paclitaxel by the tumor induces cell death and tumor mass reduction.

Examples Example 1

Comparison of Stability Abraxane and IG-001

A comparison of dissolution/instability profiles of nab-paclitaxel and IG-001 was conducted in serum-containing (IX FBS, 0.1 X FBS) and protein-free (IX PBS) matrices at 37°C using Dynamic Light Scattering (DLS) methodology (Malvern's Zetasizer Nano S and Wyatt's Nanostar). The results of the study are displayed in Figures 1 and 2. IG-001 has a 10-fold diminished stability versus Abraxane in serum. IG-001 exhibited significant instability in serum even at high paclitaxel concentrations of 2000 ug/ml. Conversely, Abraxane ceased to exist as a nanoparticle starting at about 200 ug/ml paclitaxel concentrations. This data may explain the observed expanded PK proportionality and the higher maximum tolerated does (MTD) of IG-001 vs. Abraxane.

IG-001 has 10-fold enhanced stability compared to Abraxane in protein-free matrices. IG-001 exhibited remarkable stability (high CMC) in protein-free matrices even at low paclitaxel concentrations of 4ug/ml. Conversely, Abraxane ceased to exist as a nanoparticle starting at 40 ug/ml paclitaxel concentrations. Significance of these findings is the better suitability of IG-001 for intraperitoneal and/or intravesicle modes of drug delivery due to higher nanoparticle residence time and the reduced likelihood of paclitaxel precipitation.

Example 2

Pharmacokinetics of IG-001 and Taxol in Mice

Blood was collected at 0.5, 2, 6, 12, 24, 48, and 96 hours post-dose from groups of 4 tumor bearing male mice/timepoint/dose. Paclitaxel was quantitated using a validated paclitaxel LC/MS assay.

IG-001 exhibited lower dose adjusted AUC₀-_t and C_max than Taxof suggestive of more rapid tissue distribution. This is in agreement with its larger volume of distribution and CL in comparison to Taxof.

Example 3

Pharmacokinetics of IG-001 and Taxol in Dogs

Groups of 2 male and 2 female dogs each were administered IG-001 via a 3-hour intravenous infusion and Taxof via a 30-minute intravenous infusion. For the IG-001 animals, blood samples were collected at 1.5, 3, 3.17, 3.5, 4, 6, 9, 15 and 27 hours post-initiation of dosing and for the Taxof animals, blood samples were collected at 0.25, 0.5, 0.67, 1, 1.5, 3.5, 6.5, 12.5 and 24.5 hours post-initiation of dosing.

There were no differences between males and females. The lower AUC_inf is suggestive of rapid tissue distribution of IG-001 out into tissues.

Example 4

Pharmacokinetics of IG-001 and nab-paclitaxel in Mice nab-Pac and IG-001 were administered as an IV Bolus at 30 mg/kg in mice. Blood was collected at 5, 15, 30 min and 1, 4, 8, 12, 24 hr post dose at 3 animals per timepoint and tested for paclitaxel by LC/MS/MS.

PK parameters were similar between IG-001 and Abraxane.

Example 5

Pharmacokinetics of IG-001 and nab-paclitaxel in monkeys

Cynomolgus monkeys were dosed with IG-001 (N=4) and nab-Pac (N=3) via 30-minute intravenous infusion. Dose level was 21.7 mg/kg. Drug was reconstituted to 5 mg/ml and blood was collected at 0, 15, 30 min into infusion and 5 and 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hr post dose. Paclitaxel was quantitated using LC-MS/MS. Drug Ti (hr) Tmax (hr) Cmax (ng/ml) AUQnf Vz (ml/kg) CL

(ng*hr/mL) (ml/hr/kg)

Nab-Pac#9 12.65 0.5 18200 21765 18190 997

Nab-Pac#10 9.05 0.5 21600 29083 9746 746

Nab-Pac#3 7.42 0.5 23800 32374 7180 670

Mean 9.41 0.5 21200 27741 11705 804

IG-001 #7 17.23 0.5 25000 29089 18545 746

IG-001 #8 8.73 0.5 26400 26295 10396 825

IG-001 #2 9.23 0.5 26000 23851 12113 910

IG-001 #4 8.73 0.5 22300 26493 10313 819

Mean 10.98 0.5 24925 26432 12842 825

BE Criteria 80% 16960 22193

125% 26500 34676

During the course of infusions, no infusion reactions were observed for either IG-001 or nab-Pac. The calculated C_max and AUC_inf of IG-001 met bioequivalence criteria: 80%-125% of nab-Pac.

Example 6

Pharmacokinetics of IG-001 and nab-paclitaxel in humans

Clinical trials using the same dosing regimen for nab-Pac or IG-001 were compared. Patients in both trials had received 3-hour intravenous infusions for the test articles. Blood samples were collected before infusion and up to 48 hours post-infusion. The paclitaxel concentrations in plasma were quantified by reverse-phase high-performance liquid chromatography for IG-001 and by liquid chromatography atmospheric pressure ionization tandem mass spectrometry for nab-Pac.

The results demonstrated that nab-Pac and IG-001 PK parameters reached bioequivalence under the same dosing regimen.

Within this disclosure, any indication that a feature is optional is intended provide adequate support (e.g., under 35 U.S.C. 112 or Art. 83 and 84 of EPC) for claims that include closed or exclusive or negative language with reference to the optional feature. Exclusive language specifically excludes the particular recited feature from including any additional subject matter. For example, if it is indicated that A can be drug X, such language is intended to provide support for a claim that explicitly specifies that A consists of X alone, or that A does not include any other drugs besides X. "Negative" language explicitly excludes the optional feature itself from the scope of the claims. For example, if it is indicated that element A can include X, such language is intended to provide support for a claim that explicitly specifies that A does not include X. Non-limiting examples of exclusive or negative terms include "only," "solely," "consisting of," "consisting essentially of," "alone," "without", "in the absence of (e.g., other items of the same type, structure and/or function)" "excluding," "not including", "not", "cannot," or any combination and/or variation of such language.

Similarly, referents such as "a," "an," "said," or "the," are intended to support both single and/or plural occurrences unless the context indicates otherwise. For example "a dog" is intended to include support for one dog, no more than one dog, at least one dog, a plurality of dogs, etc. Non-limiting examples of qualifying terms that indicate singularity include "a single", "one," "alone", "only one," "not more than one", etc. Non-limiting examples of qualifying terms that indicate (potential or actual) plurality include "at least one," "one or more," "more than one," "two or more," "a multiplicity," "a plurality," "any combination of," "any permutation of," "any one or more of," etc. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.

Where ranges are given herein, the endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that the various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

1. A composition comprising a cancer drug in a micelle without any albumin wherein the composition is stable in protein-free medium and unstable in a protein containing medium.

2. The composition of claim 1 wherein the cytotoxic compound is selected from the group consisting of: paclitaxel, docetaxel, 7-epipaclitaxel, t-acetyl paclitaxel, 10-desacetyl-paclitaxel, 10-desacetyl-7- epipaclitaxel, 7-xylosylpaclitaxel, 10-desacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L- alanylpaclitaxel, carboplatin, cisplatin, cyclophosphamide, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, methotrexate, topotecan, vincristine, vinblastine and combinations thereof.

3. The composition of claim 2 wherein the cytotoxic compound is paclitaxel.

4. The composition according to claims 1-3, wherein said micelles comprise an amphiphilic block copolymer.

5. The composition of claim 4 wherein said block copolymer is a hydrophilic block (A) and a hydrophobic block (B) chemically linked with each other in the form selected from a group consisting of A-B, A-B-A and B-A-B.

6. The composition of claim 5 wherein the hydrophilic block (A) of the amphiphilic block copolymer is selected from the group consisting of polyethylene glycol (PEG) and monomethoxypolyethylene glycol (mPEG).

7. The composition of claim 6 wherein the hydrophobic block (B) is selected from the group consisting of polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA).

8. The composition according to claims 1-7 wherein the paclitaxel-containing micelles comprise monomethoxypolyethylene glycol-polylactide.

9. The composition of claim 9 wherein the average molecular weight of the monomethoxypolyethylene glycol-polylactide is about 1,766-2000 daltons.

10. A first composition comprising a cancer drug in a micelle without any albumin wherein the composition is stable in protein-free medium and unstable in a protein containing medium and wherein the pharmacokinetic profile of the first composition is similar to that of a second composition comprising a cancer drug in which the second composition contains albumin.

11. The first composition of claim 10 wherein the cancer drug is paclitaxel.

12. The first composition of claim 11, wherein said micelles comprise an amphiphilic block copolymer.

13. The first composition of claim 12, wherein said block copolymer is a hydrophilic block (A) and a hydrophobic block (B) chemically linked with each other in the form selected from a group consisting of A-B, A-B-A and B-A-B.

14. The first composition of claim 13 wherein the hydrophilic block (A) of the amphiphilic block copolymer is selected from the group consisting of polyethylene glycol (PEG) and monomethoxypolyethylene glycol (mPEG).

15. The first composition of claim 13 wherein the hydrophobic block (B) is selected from the group consisting of polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA).

16. The first composition according to claims 11-17 wherein the paclitaxel-containing micelles comprise monomethoxypolyethylene glycol-polylactide.

17. The first composition of claim 16 wherein the average molecular weight of the monomethoxypolyethylene glycol-polylactide is about 1,766-2000 daltons.

18. A method of treating a cancer patient having a tumor by administering a composition comprising a cancer drug in a micelle without any albumin wherein the micelle disintegrates in the patient's bloodstream and the paclitaxel is released from the micelles and wherein the released cancer drug binds endogenous serum albumin and is then taken up by the tumor by transcystosis of the albumin/cancer drug complex.

19. The method of claim wherein the cancer drug is selected from the group consisting of: paclitaxel, docetaxel, 7-epipaclitaxel, t-acetyl paclitaxel, 10-desacetyl-paclitaxel, 10-desacetyl-7-epipaclitaxel, 7- xylosylpaclitaxel, 10-desacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel, carboplatin, cisplatin, cyclophosphamide, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, methotrexate, topotecan, vincristine, vinblastine and combinations thereof.

20. The method of claim 2 wherein the cancer drug is paclitaxel.

21. The method according to claims 18-20, wherein said micelles comprise an amphiphilic block copolymer.

22. The method of claim 21 wherein said block copolymer is a hydrophilic block (A) and a hydrophobic block (B) chemically linked with each other in the form selected from a group consisting of A-B, A-B-A and B-A-B.

23. The method of claim 22 wherein the hydrophilic block (A) of the amphiphilic block copolymer is selected from the group consisting of polyethylene glycol (PEG) and monomethoxypolyethylene glycol (mPEG).

24. The method of claim 23 wherein the hydrophobic block (B) is selected from the group consisting of polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA).

25. The method according to claims 18-24 wherein the paclitaxel-containing micelles comprise monomethoxypolyethylene glycol-polylactide.

26. The method of claim 25 wherein the average molecular weight of the monomethoxypolyethylene glycol-polylactide is about 1,766-2000 daltons.