TW200942233A - Compositions of hydrophobic taxane derivatives and uses thereof - Google Patents

Abstract

The present invention provides compositions comprising nanoparticles comprising: (1) a hydrophobic taxane derivative; and (2) a carrier protein. Also provided are methods of treating diseases (such as cancer) using the compositions, as well as kits and unit dosesages.

Description

200942233 IX. INSTRUCTIONS: This application claims the priority of US Provisional Application No. 61/044,006, entitled "Compositions of Hydrophobic Taxane Derivative and Uses Thereof", filed on April 10, 2008, the entire contents of which is hereby incorporated by reference. Incorporated herein by reference, the extent of its citation is as set forth in its entirety. [Prior Art] Taxanes, especially two currently available taxane drugs, paclitaxel ® and paclitaxel, are effective antitumor agents. Pacific paclitaxel is very poorly water soluble (less than 10 pg/mL) and therefore cannot be formulated in an aqueous medium for practical IV administration. Currently, paclitaxel is formulated as a primary solvent/surfactant with polyoxyethylated castor oil (Polyoxyl 35 or Cremophor®) and a high concentration of ethanol as a co-solvent for IV administration to cancer patients. One of the main difficulties in administering Pacific paclitaxel is the emergence of allergic reactions. This specific response includes severe skin treatment, anesthesia, facial redness, dyspnea, tachycardia, and other reactions that can be attributed, at least in part, to the high concentration of ethanol and Cremophor® used as a bismuth solvent in the formulation. European paclitaxel (a derivative of paclitaxel) is produced by semi-synthesis of 10-deacetyl berry gibberellin, and ίο-deacetyl gibberellin m is extracted from the needles of Taxus baccata. And esterification to obtain a chemically synthesized side chain of non-cellular precursors. Like Pacific paclitaxel, European paclitaxel is extremely poorly water soluble. Currently, the most preferred solvent/activator for dissolving European paclitaxel is polysorbate 80 (Tween 80). Like Cremoph〇r®, Tween often causes an allergic reaction in patients. In addition, Tween 8 can not be used for the pvc transfer device 134531.doc 200942233 because it tends to dissolve highly toxic diethyl phthalate. Great efforts have been devoted to developing water-soluble prodrugs and novel taxane derivatives having higher hydrophilic groups such as water-soluble polymers to enhance water solubility. For example, US 2003/0203961 describes a taxane-polyethylene glycol (PEG) conjugate which is a current drug and hydrolyzed under normal physiological conditions to provide a therapeutically active taxane. Although the solubility of the combination of paclitaxel and the high molecular weight PEG polymer is increased, since the high molecular weight PEG © is necessary to achieve sufficient solubility, it also results in a corresponding reduction in drug load. Similarly, W094/1 3324 discloses phospholipid prodrugs that enhance water solubility. Another method of solving the problems associated with poor water solubility of taxanes is to develop various formulations of taxanes, such as nanoparticulates, oil-in-water emulsions, and liposomes. For example, Abraxane® is a combination of Pacific paclitaxel and albumin nanoparticle. The nanoparticle composition of the substantially poorly water-soluble drug and its use are disclosed, for example, in U.S. Patent Nos. 5,91,596, 6,096,331, 6,749,868 and 6,537,579, and PCT Application®. No. W098/14174, No. W099/00113, No. W007/027941 and No. W007/027819. Various taxane derivatives have been disclosed, for example, in Kingston, J.

Prod. 2000, 63, 726-734; Deutsch et al., J. Med. Chem. 1989, 32, 788-792; Mathew# A > J. Med. Chem. 1992, 35, 145-151, European Patent U.S. Patent Nos. 5,059, 699, 4, 942, 184, 6, 482, 850, and 6, 602, 902, pp. 134, 531, doc. The disclosure of all of the publications referred to herein is based on the present invention. The invention provides a composition comprising nanoparticle in a form, wherein the particle comprises a hydrophobic taxane derivative and a carrier protein. In some embodiments the carrier protein is albumin (such as human serum albumin).

In some embodiments, the nanoparticles in the compositions described herein have an average diameter of no greater than about 150 nm, including, for example, no greater than any of about _, 90 80, 70, or 60 nm. In some embodiments, at least about 5% (eg, at least about (four), 鸠, 8 〇, /, _ 〇 、, 95%, or 99%) of all of the nanoparticles of the composition have no A diameter greater than about 15 ' 'includes, for example, no more than about 1 〇〇, 9 〇, 8 〇, 7 〇, or 6 〇 nm. In some embodiments, at least about 50% of all of the nanoparticles in the composition (eg, at least 60%, 7%, 8%, 9%, (four), or any one of the states) are at about 20 to In the range of about 150 nmi, for example, any of about (10) to about 14 〇 nm, and any of about 40 to about 130, about 50 to about 120, and about 6 〇 to about 1 〇〇 nm. In some embodiments, the carrier protein has a sulfhydryl group that can form a disulfide bond. In some embodiments, at least about 5% (including, for example, at least about 1 Å/Å) of the carrier protein in the nanoparticle portion of the composition. Any of 15% or 2% is cross-linked by a parent (eg, via one or more disulfide bonds). In some embodiments, the nanoparticle comprises a hydrophobic taxane derivative coated with a carrier protein such as albumin (eg, human serum albumin) (eg, any of Compounds 1, 2, 3-23, and Any formula j, n, m, Iv, v 134531.doc 200942233 or νι化合物) In some embodiments, the composition comprises a hydrophobic taxane derivative in the form of a non-nanoparticle, wherein the composition is hydrophobic Any of at least about 50%, 60%, 7%, 8%, 9%, 95% or 990 Å of the taxane derivative is in the form of nanoparticle. In some embodiments, the hydrophobic taxane derivative in the nanoparticle constitutes greater than about 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the nanoparticle by weight. One. In some embodiments the 'nanoparticles have a non-polymeric matrix. In some embodiments the 'nanoparticles comprise a hydrophobic taxane derivative core that is substantially free of polymeric material, such as a polymeric matrix. In some embodiments, the composition is substantially free (e.g., free of) interfacial activators (such as Cremophor®, Tween 80, or other organic solvents used to administer taxanes). In some embodiments, the composition contains less than 2 〇 0 /. An organic solvent of any of 15 ° / 〇, 1 〇〇 / 0, 7.5%, 5%, 2.5% or 1%. In some embodiments, a carrier protein (such as albumin) and a hydrophobic taxane derivative (eg, any of compounds 1, 2, 3-23, and any of formulas I, II, III, IV) in the composition. The weight ratio of the compound of V, VI or VI) is about 18:1 or less, such as about 15:1 or less than 15:1, such as about 10:1 or 1 〇:1 or less. In some embodiments, the weight ratio of carrier protein (such as albumin) to hydrophobic taxane derivative in the composition is from about 1:1 to about 18:1, from about 2:1 to about 15:1, about 3 :1 to about 13:1, from about 4:1 to about 12:1, from about 5:1 to about 10:1. In some embodiments, the weight ratio of the carrier protein to the hydrophobic taxane derivative in the nanoparticle portion of the composition is about U, 1:3, 1:4, 1:5, 1:1, I: 15 or 1:15 or less 0 134531.doc -9- 200942233 In some embodiments, the particulate composition may comprise one or more of the above features. In some embodiments, one of the hydrophobic taxane derivatives is sparsed, such as -c(〇)_C4_ClQ alkyl, such as <(〇)&alkyl. In some embodiments, the hydrophobic group is attached to the 2,-hydroxyl oxime of the taxane. In some embodiments, the hydrophobic taxane derivative is a taxane prodrug. In some embodiments, the hydrophobic taxane derivative (eg, any of Compounds 2, 3-23, and any of Formula 1, II, III, IV, V*VI compounds) has no change compared to the corresponding The taxane is improved (e.g., improved compared to paclitaxel and/or paclitaxel). In one or two embodiments, the hydrophobic taxane derivative in the 'protein nanoparticle composition is shown at an equivalent toxic dose compared to the corresponding unmodified taxane (eg, paclitaxel and/or taxol) The rice granule composition has improved therapeutic efficacy. ^ In some embodiments, the hydrophobic taxane derivative is a beta compound as described herein. In some embodiments, the hydrophobic taxane derivative is a compound of formula η as described herein. In some embodiments, the hydrophobic derivative is a compound of formula m as described herein. In some embodiments, the hydrophobic derivative is a compound of formula 1 described herein. In some embodiments, the hydrophobic derivative is a compound of formula v as described herein. In some embodiments, the hydrophobic derivative is a compound of formula VI as described herein. In some embodiments, the hydrophobic derivative is any one of the compounds described herein. In some embodiments, the hydrophobic derivative is the compound 134531.doc -10. 200942233 2 described herein. Also provided herein are methods of treating diseases, such as cancer, using the compositions described herein, as well as kits and unit dosages for use as described herein. [Embodiment] The present invention provides a taxane derivative formulated in the form of a protein-based nanoparticle. These taxane derivatives have a hydrophobic group attached to the corresponding taxane and have an increased hydrophobicity compared to the unmodified taxane. It has been found that taxane derivatives containing a hydrophobic group such as a thiol group attached to a taxane 2, a hydroxy group, such as a -C(0)-C4_C丨〇alkyl group, especially a _C(0)-C6 alkyl group, are When formulated into a protein nanoparticle composition, nanoparticle having a property that is significantly improved compared to the protein nanoparticle of the unmodified taxane is produced. Such properties may include, but are not limited to, one or more of the following: a small particle size (eg, an average diameter of less than about 100 nm), a narrow particle size distribution, enhanced delivery of the compound to its intended site of action, delayed or sustained release. , delayed clearance and increased anti-cancer efficacy. The compositions described herein are therefore particularly suitable for the treatment of diseases such as cancer. Thus, the present invention provides a composition comprising nanoparticle in one aspect, the nanoparticle comprising: 1) a hydrophobic taxane derivative; and 2) a carrier protein. In some embodiments, the 'hydrophobic taxane derivative is a prodrug. In another aspect, the invention provides a method of treating a disease, such as cancer, using the compositions described herein. The invention also provides kits and unit dosage forms. Abbreviations and Definitions 134531.doc •11- 200942233 The abbreviations used herein have their well-known meanings in chemical and biological techniques. As used herein, "hydrophobic taxane derivative" refers to a taxane-substituted yew-burning. "hydrophobic group" refers to the production of unsubstituted yew when substituted on yew. The increased hydrophobic character can be compared, for example, by reduced water solubility, reduced polarity, reduced hydrogen binding potential, and/or increased oil/water partition coefficient, as compared to portions of the taxane derivative having increased hydrophobicity. OK. As used herein, "taxus" includes Pacific paclitaxel and European paclitaxel. Thus the term "hydrophobic taxane derivative" does not include paclitaxel or paclitaxel unless otherwise stated. The term "four" as part of the other-substituent "picture base" or "quote" means a fluorine, chlorine, bromine or iodine atom. Unless otherwise stated, the term "alternatively or as part of another substituent" "alkyl" means completely saturated linear (linear; unbranched) or branched chain or a combination thereof, if specified, has a defined carbon atom The number (ie, Μ means ❹ one to ten carbons). Examples include, but are not limited to, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, a group of a second butyl group, such as n-pentyl, n-hexyl, n-heptyl, n-octyl homologues and isomers, and the like. If no size is specified, the bases referred to herein are Containing 1-20 carbon atoms, usually uo carbon atoms, or μ carbon atoms 'or 1-6 carbon atoms' or 1_4 carbon atoms. The term "dilute base" means including straight bonds (linear; not branched) ), a branched chain group, and combinations thereof, of an unsaturated aliphatic group, if specified, having a defined number of carbon atoms containing at least one double bond (-OC-). All double bonds can be independently (Fantasy 134531.doc 12 200942233 or (z) geometry and mixtures thereof. Examples of alkenyl groups include (but are not limited to) (H2 (H=CH-CH3, -CH=CH-CH =CH2 and (h2-CH=CH even CH3> CH2 cut to the right unspecified size', the alkenyl group mentioned herein contains 2-20 carbon atoms, usually 2-10 carbon atoms, or 2-8 carbon atoms, or 2-6 Carbon atom, or 2-4 carbon atoms. The term "alkynyl" refers to an unsaturated aliphatic group including straight chain (linear; unbranched), branched chain groups, and combinations thereof, which are specified if specified The number of carbon atoms, which contains at least one carbon-carbon bond (examples of _CsC_" alkynyl include, but are not limited to, -CH2-C formula-ch3, -C3(10)-CH2-C tri-C-CH(CH3)- CH2-CH3. The alkynyl group referred to herein has 2 to 20 carbon atoms, usually 2 to 1 carbon atoms 'or 2 to 8 carbon atoms, or 2 to 6 carbon atoms or 2 to 4 carbon atoms. - Unless otherwise stated, the term "cycloalkyl", alone or in combination with other terms, means a cyclic form of an alkyl, a dilute or alkynyl group, or a mixture thereof. The alkyl group may contain a fused ring, but does not include a fused aryl group and a heteroaryl group. Examples of the fluorenylcycloalkyl group include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a ring group. Anthracenyl, 3-cyclohexenyl, cycloheptyl, descending, and the like. If no size is specified, the ring block referred to herein contains 3-9 carbon atoms, usually 3-7 carbon atoms. The term "heterocyclic base group", alone or in combination with other terms, denotes a ring containing at least one ring carbon atom and at least one hetero atom selected from the group consisting of:, N, p, si and s, and wherein the nitrogen And the sulfur atom may be oxygenated according to the situation, and the hetero atom may be arbitrarily obtained. Often, the ring hetero atom system may be attached to the ring carbon or ring hetero atom at the position of i34531.doc •13 - 200942233 The remainder of the subunit. In addition, heterocycloalkyl groups may contain fused rings, but exclude fused aryl and heteroaryl groups. Examples of heterocycloalkyl groups include, but are not limited to, 1-(1,2,5 , 6-tetrahydrogen ratio, 1-piperidinyl, 2-piperidinyl, 3-sole, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrogen喃-^, tetrahydrothiophen-2-yl, tetrahydrothiophene-3-yl, piperazinyl, 2 piperazinyl and the like. The term "cycloalkyl-alkyl" and "Heterocycloalkyl-alkyl" denotes alkyl-substituted cycloalkyl and alkyl-substituted heterocycloalkyl, respectively, wherein the alkyl moiety is attached to the parent structure. Non-limiting examples include cyclopropyl- Ethyl, cyclobutyl-propyl, cyclopentyl-hexyl, cyclohexyl-isopropyl, fluorene-cyclohexenyl-propyl, 3-cyclohexenyl-tert-butyl, cycloheptyl-g Base, norbornylmethyl, hydrazinyl-ethyl, 4-morpholinylpropyl, 3-morpholinyl-tert-butyl, tetrahydrofuran-2-yl-hexyl, tetrahydrofuranyl-isopropyl Base and its like. Cycloalkyl-alkyl and heterocyclic compound-alkyl groups also include substituents in which at least one carbon atom is present in the alkyl group and wherein another carbon atom of the alkyl group has been replaced, for example, by oxygen, nitrogen or sulfonium protons ( For example, cyclopropoxymethyl, 2-piperidinyloxy-t-butyl and the like. Unless otherwise stated, the term "aryl" means polyunsaturated, aromatic, hydrocarbon substituent 'which may be monocyclic or fused together or covalently linked (eg 1 to 3) ring). Further, the aryl group may contain a fused ring in which one or more of the ring members are a cycloalkyl group or a heterocycloalkyl group. Examples of aryl groups include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, 4-linked. The term "heteroaryl" refers to an aryl group (or ring) containing one to four ring heteroatoms selected from the group consisting of ruthenium, osmium and S, wherein the nitrogen and sulfur atoms are optionally oxidized and nitrogen 134531.doc 200942233 Atoms may be quaternized as appropriate. "Heteroaryl groups may be attached to the remainder of the molecule at a ring carbon or ring heteroatom. Alternatively, the heteroaryl group may contain a fused ring wherein one or more of the rings are optionally a cycloalkyl or heterocycloalkyl group. Non-limiting examples of heteroaryl groups are 1-"pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-oxazolyl, 4-imidazolyl, pyrazinyl, 2- Oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- Sturdy base, 4-saltyl, 5-indolyl, 2-indolyl, 3-β-folyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 -pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, fluorenyl, 2-benzimidyl, 5-indenyl, oximeisoquinolinyl, 5-isoquine Alkyl group, 2 喧 喧 基, 5-5 若 琳 基, 3- quinalyl and 6-quinolinyl. The substituents of the above respective aryl and heterocyclic ring systems may be selected from the group of acceptable substituents as described below. The term "aralkyl" denotes an alkyl-substituted aryl group in which the alkyl moiety is attached to the parent structure. Examples are benzyl, phenethyl and the like. , "heteroarylene" means a heteroaryl moiety attached to the parent structure via an alkyl residue. Examples include furylmethyl, pyridylmethyl, pyrimidinylethyl and the like. Aralkyl and heteroarylalkyl also include substituents wherein at least one carbon atom of the alkyl group is present in the alkyl group and wherein another carbon of the alkyl group has been replaced, for example, by an oxygen atom (e.g., phenoxymethyl, 2_. Biting methoxy, naphthyloxy) propyl and the like. The above terms (eg "burning base","alkenyl","alkynyl","ring base","heterocycloalkyl","cycloalkyl-alkyl";,"heterocycloalkyl-alkyl","aryl",,,heteroaryl,',,,aralkyl" and "heteroarylalkyl") are intended to include Substituted and unsubstituted forms of the indicated group 134531.doc 200942233. "Substituted " or "substituted" means that one or more hydrogen atoms have been replaced by a monovalent or divalent group. The group includes, for example, a hydroxyl group, a nitro group, an amine group, an imido group, a cyano group, a halogen group (such as F, ci, Br, I), a haloalkyl group (such as -CCI3 or -CFO, a thio group, a sulfonyl group). , thioguanamine, fluorenyl, imidino, pendant oxy, oxo, methoxy, fluorenyl, fluorenyl, sulfonyl, carboxy, decyl, alkyl, Alkoxy, alkoxy-alkyl, alkylcarbonyl, alkylcarbonyloxy (_〇c〇R), aminocarbonyl, aryl®carbonyl, aralkylcarbonyl, carbonylamino, heteroarylcarbonyl Heteroaralkyl _Carbonyl, alkylthio, aminoalkyl, cyanoalkyl, aminemethanyl (-NHCOOR- or -OCONHR-), glandyl NHC〇NHR_), aryl and the like. In the present invention In some embodiments, the above group (eg, alkyl) is, for example, an amine group, a heterocycloalkyl group (such as morpholine, piperazine, piperidine, azetidine), a hydroxyl group, a methoxy group, or a hetero group. Substituted by an aryl group such as pyrrolidine. The substituent may be substituted. The group substituted on the substituent may be a thiol, a yl group, a nitro group, an amine group, a cyano group, a hydroxy group, an alkyl group, an alkenyl group, Alkynyl, alkoxy, aminocarbonyl, _SR, thioguanamine, _s〇3h '-s〇2R or cycloalkyl, wherein R is usually hydrogen or alkyl. Substituted substituents include straight-chain groups In the case of a group, the substituent may be present in the chain (for example, 2-hydroxypropyl, 2-aminobutyl, and the like) or at the end of the bond (for example, 2-hydroxyethyl, 3-cyanopropyl) Substituents and their analogous groups. Substituted substituents may be linear, branched or cyclic arrangements of covalently bonded carbon or heteroatoms (N, 〇 or 8) unless otherwise indicated. in "Isomers" as used herein includes all of the guest isomers of the compounds referred to in the formula 134531.doc -16 - 200942233, including enantiomers, diastereomers, and all conformational variants. Construct, rotamer isomer. The invention includes any enantiomers of any of the disclosed palmitic compounds in a substantially pure left- or right-handed form, or in the form of a racemic mixture, or in any ratio of enantiomers. For compounds which are (R)-enantiomers, the invention also includes (S)-enantiomers, and for compounds which are not (8)-enantiomers, the invention also encompasses (8) · Enantiomers. The present invention includes any diastereomer of the compounds of the above formulas in the form of diastereomerically pure forms and mixtures of all ratios. Unless explicitly indicated in a chemical structure or chemical name, a chemical structure or chemical name is intended to encompass all possible stereoisomers of the described compounds as conformational isomers, rotamers and tautomers. For example, a compound containing a palmitic carbon atom is intended to comprise a (r) enantiomer and (8) an enantiomer as well as a mixture of enantiomers, including an external fluorene ring; and two The compounds of palmitic carbon are intended to include all enantiomers and diastereomers (including (R'R), (s, s), (r, ^ (R, S) isomers). In all uses of the compounds of the formulae disclosed herein, the invention also includes any or all of the stereochemical, enantiomeric, diastereomeric, conformational isomerization, rotamer, tautomerism of the compounds described. Use of solvates, gargles, polymorphs, crystalline forms, amorphous forms, salts, pharmaceutically acceptable salts, metabolites, and prodrug forms. Certain compounds of the invention may be in unsolvated form And the solvated form 134531.doc • 17· 200942233 (ie, the composition). The compounds of the invention may also include hydrated forms (ie, hydrates). Typically, for bioavailable purposes, solvation Form and hydrated form are equivalent to unsolvated forms and include Included within the scope of the invention. The invention also includes all polymorphs, including crystalline forms and non-positive forms. Generally, all physical defects are ineffective for the purposes covered by the present invention, and It is intended to be within the scope of the invention. The invention includes all salts of the compounds described herein, and methods of using such salts of the compounds. The invention also encompasses all non-salt forms of any of the salts of the compounds described herein. Other salts of all salts of the compounds mentioned herein. In one embodiment, the salt of the compound comprises a pharmaceutically acceptable salt, a pharmaceutically acceptable salt, to maintain the biological activity of the free compound. And can be administered as a drug or a drug to the salt of the individual (e.g., human). The desired salt of the basic functional group of the compound can be prepared by treating the compound with an acid by methods known to those skilled in the art. Examples include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, capric acid, acetic acid, propionic acid, glycolic acid, and horses. Uric acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acid and salicylic acid The desired salt of the acidic functional group of the compound can be prepared by treating the compound with a base by methods known to those skilled in the art. Examples of inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth metal salts. Such as sodium salt, potassium salt, magnesium salt, and calcium salt; ammonium salt; and aluminum salt. Examples of organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, hydrazine-B Piperidine, hydrazine, hydrazine--dibenzylethylenediamine 134531.doc •18· 200942233 and triethylamine salt. 浯 quot "prodrug" means that it is relatively inactive, but is used in its application. An individual is then converted to a more active compound by in vivo (eg, by hydrolysis and/or enzymatic conversion) by chemical or biological processes. Prodrugs include, for example, compounds wherein a hydroxy, amine or thiol group is bonded to any group which is cleaved upon administration to an individual to form a free radical, amine or thiol group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups. Pharmaceutically acceptable prodrugs of the compounds of the invention include, but are not limited to, esters, carbonates, thiocarbonates, N-mercapto derivatives, N-styloxy derivatives, third amines A fourth derivative, a N-Mannich base, a Schiff base, an amino acid conjugate, a sulphate, a metal salt, and a lactate. T_ Higuchi and V· Stella

Full discussion is provided in Pro_drugs as Novel Delivery Systems (Vol. 14 of the ACS Symposium Proceedings) and in Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, edited by Edward B. Roche, both references cited The manner is incorporated herein. In some embodiments, the yew scent derivative used in the present invention is itself a prodrug. In some embodiments, the taxane derivatives used in the present invention are not prodrugs. By substantially pure compound is meant that the compound is present in the impurity and/or in a different form that does not exceed about 15% or no more than about 1% or no more than about 5% or no more than about 3% of the total amount of the compound. Or no more than about 1% of the time. For example, a 'substantially pure S, S compound means that the total amount of R, R, S, R and R, S forms is no more than about 15% or no more than about 10% or no more than about 5% or not. Super 134531.doc -19- 200942233 over 3% or no more than about 10/〇. "protective group" means a chemical group that exhibits the following characteristics: 1) stable for the desired reaction requiring protection; 2) removable from the protected substrate to produce the desired functional group; and 3) The reagents compatible with other functional groups present or generated in such expected reactions are removed. The selection of suitable protecting groups for use in the methods described herein is well within the skill of those in the art. Examples of suitable protecting groups can be found in Greene et al. (1991) pr〇teetive

Groups in Organic Synthesis, Third Edition (John Wiley & Sons ❹ Inc. New York), the contents of which are incorporated herein by reference. In some embodiments of the invention, the protecting group is not self-hydrophobic violet The cedar derivative is removed. As used herein, "hydroxy protecting group" means a group capable of protecting a free hydroxy group to give a "protected hydroxy group" which may not interfere with the remainder of the compound after use of the protected reaction Partially removed. Exemplary hydroxy protecting groups include, but are not limited to, ethers (eg, allyl, triphenylsulfonyl (triphenylguanidino or Tr), benzyl, p-oxiranyl (PMB), P-Oxylphenyl (PMP), acetal (eg methoxymethyl (MOM), 3-methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), ethoxylate Ethyl (EE), mercaptothiol (MTM), 2-decyloxy-2-propyl (MOP), 2-trimethyldecyl ethoxymethyl (SEM), esters (eg benzene) Formate (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethyl-stone-ethyl carbonate, decyl (eg, trimethyl sulfonyl (TMS), triethyl decyl (TES), triisopropyl decyl (TI PS), triphenyl decyl (TPS), tert-butyl dimethyl decyl ( TBDMS), TBT (TBDPS) and the like. 134531.doc -20- 200942233 "Treatment" as used herein to obtain beneficial or desired results including clinical results Method. For the purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: reducing one or more symptoms caused by a disease, reducing the extent of the disease, stabilizing the disease (eg, preventing or delaying) Disease progression), delaying or slowing the progression of the disease, improving the disease condition, reducing the dose required to treat the disease - or a variety of other drugs, increasing the quality of life, and / or prolonging survival (including total survival and disease progression free survival). , including, including reducing the pathological consequences of cancer. The method of the invention encompasses any one or more of these aspects of treatment. As used herein, "delay" cancer development means delaying, hindering, slowing down, stabilizing, and/or delaying the progression of the disease. Depending on the disease history and/or the individual being treated, this delay can have different lengths of time. As is apparent to those skilled in the art, a full or significant delay may actually include prevention, as the individual does not develop the disease. The "I-delay" method of cancer development is a method of reducing the probability of disease progression and/or within a given period of time or reducing the extent of disease within a given period of time when compared to not using the method. These comparisons are usually based on clinical studies using a significant number of subjects in the system. Cancer development can be detected using standard methods such as routine physical examination or X-ray. Development can also be a private process that may not be detectable at first and includes both onset and onset. As used herein, "at risk, the individual is an individual at risk of developing a condition, such as cancer. "At risk" individuals may or may not have a defensible disease' and may have or may not show detectable disease prior to the treatments described herein. "at risk" indicates that the individual has one or more so-called risk factors, which are measurable parameters described herein in relation to the development of the disease 13453 丨.doc 21 200942233. Individuals with one or more of these risk factors have a higher chance of developing a condition than individuals who do not have such risk factors. As used herein, pharmaceutically active compounds "therapeutic agents" and the like terms of such terms mean compounds which elicit the desired effect (e.g., to treat, stabilize, prevent, and/or delay cancer). As used herein, the term "additional pharmaceutical agent" and its equivalents are intended to refer to an active agent (eg, a drug) that is administered differently than a taxane derivative to cause a therapeutic effect. The pharmaceutical agent may be directed to a therapeutic effect associated with a condition (eg, cancer) that the taxane derivative is intended to treat or prevent, or the pharmaceutical agent may be intended to treat or prevent a symptom of a potential condition (eg, a tumor) Growth, bleeding, ulcers, pain, swollen lymph nodes, cough, jaundice, swelling, weight loss, cachexia, sweating, anemia, paraneoplastic phenomenon, blood test formation, etc.) or otherwise reduce the side effects of administration of taxane derivatives The occurrence or severity. φ as used herein, "pharmaceutically acceptable" or "pharmacologically compatible" means a material that is not biologically or otherwise inappropriate, for example, the material may be incorporated into a pharmaceutical composition for administration to a patient. Does not cause any significant undue biological effect or interacts in a detrimental manner with any other component of the composition comprising the same. As used herein, the term "pharmaceutically acceptable carrier, <RTIgt; By terminology is meant an adjuvant, binder, diluent, etc., which is known to those skilled in the art to be suitable for administration to an individual, such as a mammal or non-mammal. Two or two combinations of uploading agents are also described.遂 ,, 曲 | in the invention towel. The pharmaceutically acceptable carrier and any additional components as herein incorporated should be suitable for the intended investment route of the special dosage form 13435 丨.doc -22- 200942233 (Example a ^ ''', parenteral h, the suitability will be easily recognized by those skilled in the art, and in particular, the pharmaceutically acceptable carrier or excipient provided herein is preferably a poison. Standards and/or requirements for learning and production Inacti ve Ingredient Guide, as defined by the US Food and Drug Administration. As used herein, the term "medical effective amount", "therapeutically effective amount","effective amount, and these terms By analogy is meant the occurrence of the desired pharmacological and/or physiological effect and/or the complete or partial prevention of a condition or symptom thereof for a particular condition (eg, a disease, condition, etc.) or one or more of its symptoms and/or Partial or complete cure of a condition (eg, cancer) and/or a therapeutic amount attributable to the side effects of the condition. Regarding the condition (eg, cancer), medical or therapeutically effective amount described herein. It may comprise, in particular, sufficient to reduce the number of cancer cells, reduce tumor size; inhibit (i.e., to some extent slow and preferably terminate) cancer cells infiltrating into peripheral organs; inhibition (i.e., to some extent slow and better termination) Tumor metastasis; to some extent inhibit tumor growth, prevent growth and 7 or kill existing cancer cells; have cytostatic and / or cytotoxicity; restore or maintain vasopressor or Inhibiting damage or loss of vascular inhibition; reducing tumor burden; reducing morbidity and/or mortality; and/or reducing the amount of one or more symptoms associated with cancer to some extent. An effective amount prolongs progression-free survival ( For example, by measuring the solid tumor response evaluation criteria, RECIST or CA-125 changes, causing an objective response (package = partial response or complete response), increasing the total survival time, and / or improving one or more symptoms of cancer ( For example, by FOSI.) In certain embodiments, a pharmaceutically effective amount is sufficient to prevent the condition 'as in the case of prophylactic administration to an individual 134531.doc 23· 200942233. ''Medicially effective amount" or "therapy Effective amount " can be regarded as the composition to be administered, the condition to be treated/prevented (for example, the type of cancer), the severity of the condition to be treated or prevented, the age and relative health of the individual, the route and form of administration, and the attending The judgment of the physician or veterinarian and those skilled in the art will vary depending on other factors known to the teachings provided herein. As understood in the art, "effective amount" can be one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. It may be considered in the case of administration of one or more therapeutic agents. An effective amount, and if combined with one or more other agents, may be or result in a desirable or beneficial result, the nanoparticle composition (eg, a composition comprising a taxane derivative and a carrier protein) may be considered effective Unless otherwise clearly indicated 'other' as used herein, "individual" means mammals including but not limited to primates, humans, cows, horses, dogs, dogs and/or rodents. Animals ^ When used in connection with the methods of treatment/prevention of the methods and compounds and their nanoparticle compositions described herein, "needs" may be diagnosed as having a condition to be treated or previously treated The individual being treated for treatment. For prevention, the individual in need may also be one of the risk factors (eg, family history of the condition, lifestyle factors predicting the risk of the disease, etc.) "Combination therapy" as used herein, means a first therapy comprising a nanoparticle comprising a hydrophobic taxane derivative and a carrier protein in combination with a second therapy useful for treating, stabilizing, preventing and/or delaying cancer. (eg surgery or 134531.doc • 24 · 200942233 external therapeutics). "Combination" Another compound administration involves sequential, simultaneous or sequential administration in the same or different compositions. In some embodiments, the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds and/or inert materials. The term "antimicrobial agent" as used herein refers to an agent that is capable of inhibiting (e.g., delaying, reducing, slowing, and/or preventing) the growth of one or more microorganisms. Significant microbial lengths are known by the art. Means measure or indicate 'such as the following - or more: (1) a sufficient amount of microorganisms in the composition to cause an adverse reaction to the individual when the composition is administered to the individual; (π) external contamination (eg, at (9) Microbial growth increased by about 10 times over a certain period of time (eg, over 24 hours) after exposure to 1〇_103 colony forming units at temperatures in the range of 2. The other indications of significant microbial growth are described in still 2〇〇7 The entire disclosure of this patent is incorporated herein by reference. Sugars suitable for use in the compositions described herein include, for example, mannitol, co-, fructose, lactose, maltose, and trehalose. The term "protein" refers to a polypeptide or polymer of any length of amino acid (including full length or sheet &) which may be linear or branched, containing modified amino acids and/or miscellaneous non-amines Base acid. The term also includes amino acids that have been naturally modified or modified by insertion (eg, disulfide bond formation, glycosylation, lipidation, acetylation, moielation, or any other manipulation or modification). Glue. The sputum also includes, for example, one or more of the amino acids 134531.doc 200942233 (including, for example, non-naturally modified polypeptides, amino acids, etc.) and its known in the art. Survival " refers to patients, 壬 壬 ( ( ( ( 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 ' ' ' ' ' ' ' 总 总 总 总 总 总 总 总 总 总 总 总 总 总 总 总 总 总A certain period of time, such as 1 year, 5 car 黧 & 5 years, etc. "No disease progression and survival" means that the patient remains alive in the absence of progression or deterioration of the cancer. "Prolonging survival means increasing the total survival or disease progression of the treated patient relative to an untreated patient (eg, compared to a patient who has not been treated with a yew yam granule composition). * , as used in this article, refers to "not for" a value or parameter usually means and describes a value different from a value or parameter. For example, if you do not administer a taxane, then it means S stomach Investigating a drug different from the Taxi House. The term "about" in this document includes (and describes) a variation of the value or parameter itself. For example, the description relates to "about X" Including the description "X" 0 singular forms "a"" &" &""""" It will be appreciated that aspects and variations of the invention described herein include "consisting of "conforms and variations"""substantially composed of aspects and variations". Unless otherwise defined or clearly indicated by the context, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Nanoparticle composition 134531.doc -26 - 200942233 A composition comprising nanoparticle is provided, wherein the nanoparticle comprises a taxane derivative (for example, any of compounds 1, 2, 3, 23, and ^^, , coffee and carrier proteins such as white peony 'such as human serum albumin). In some embodiments, a package is provided: and (iv) a water-based (four) burn-derived W such as albumin 'eg human serum albumin), and wherein ❹ ❹ = violet has a modified albumin binding capacity (with purple Compared with Sugi). In some embodiments, the composition is a pharmaceutical composition. In some embodiments, 'providing a composition comprising nanoparticle," the nanoparticle comprises a hydrophobic taxoid derivative (eg, any of compounds 2, 2, 3) and any formula or A protein (such as albumin, such as human serum albumin), and wherein the composition exhibits improved therapeutic efficacy compared to the taxane. In some embodiments, a composition comprising nanoparticle is provided, wherein the nano The particles comprise a hydrophobic yewtree street organism and a carrier protein (such as albumin, such as human serum albumin and wherein the hydrophobic taxane derivative is a taxane prodrug. In some embodiments, a nanoparticle comprising nanoparticles is provided. The composition of ten nanometer particles comprising a hydrophobic paclitaxel derivative and a carrier protein, such as albumin, such as human serum albumin. In some embodiments, a composition comprising nanoparticle is provided, wherein the nano The particles comprise a hydrophobic European paclitaxel derivative and a carrier protein (such as albumin, such as human serum albumin, in some embodiments, providing a composition comprising nanoparticle, wherein the nanoparticle The particles comprise a hydrophobic taxane derivative and a carrier protein, wherein the hydrophobic taxane derivative has a hydrophobicity attached to the 2,-hydroxyl position of the corresponding taxane 134531.doc • 27- 200942233. In some embodiments, A composition comprising nanoparticles is provided, wherein the non-rice particles comprise a hydrophobic taxane derivative and a carrier protein, wherein the hydrophobic Taxane derivative has a sulfhydryl group attached to the 2,-hydroxyl position of the corresponding taxane. In some embodiments, a composition comprising nanoparticle is provided, wherein the nanoparticle comprises a compound of formula 1 and a carrier protein. In some embodiments, a composition comprising nanoparticle is provided, wherein the nanoparticle comprises a compound of formula π And a carrier protein. In some embodiments, a composition comprising nanoparticle is provided, wherein the nanoparticle comprises a compound of formula m and a carrier protein. In some embodiments, a composition comprising nanoparticle, wherein The rice granules comprise a compound of formula IV and a carrier protein. In some embodiments, a composition comprising nanoparticle is provided, wherein the nanoparticle comprises a compound of formula V and In some embodiments, a composition comprising nanoparticle is provided wherein the nanoparticle comprises a compound of formula VI and a carrier protein. In some embodiments, 'providing a composition comprising nanoparticle, wherein the naibi particle comprises From compounds of compound 1-23 and carrier proteins. In some embodiments, a composition comprising nanoparticle is provided, wherein the nanoparticle comprises compound 2 and a carrier protein. In some embodiments, the nanoparticle comprises, for example, white A carrier protein coated hydrophobic taxane derivative of a protein (eg, human serum albumin) (eg, any of compounds 1, 2, 3-23, and any formula j, n, ln, IV, v, or VI) The compound described herein has a significantly smaller diameter than the nanoparticle composition comprising a taxane substituted with a hydrophobic group (see Figure 134531.doc -28-200942233 8). Nanoparticles typically have an average diameter (eg, in dry form) of no greater than about 1000 nanometers (nm), such as no greater than about 900 nm, 800 nm, 700 nm '600 nm, 500 nm, 400 nm, 300 nm '200 Any of nm or 100 nm. In some embodiments, the particles have an average diameter of no greater than about 200 nm. In some embodiments, the particles have an average diameter of between about 20 and about 400 nm. In some embodiments, the particles have an average diameter of between about 40 and about 200 nm. In some embodiments, the particles are sterile filtered. In some embodiments, the nanoparticles in the compositions described herein have an average diameter of no greater than about 150 nm, including, for example, no greater than about 100, 90, 80, 70, 60, or 50 nm. . Smaller particle sizes may be beneficial for assisted delivery, as described below. In some embodiments, at least about 50% (eg, at least about 60%, 70%, 80%, 90%, 95%, or 99%) of all of the nanoparticles in the composition have no greater than about 150 The diameter of nm includes, for example, any of no more than 100, 90, 80, 70 or 60 nm. In some embodiments, at least about 50% (eg, at least 60%, 70%, 80%, 90%, 95%, or 99%) of all of the nanoparticles in the composition are at 20-❹ 150 nm Within the scope, for example, any of 30-140 nm, 40-130, 50-120, and 60-100 nm. The nanoparticles described herein can be of any shape (e.g., spherical or non-spherical). In some embodiments, the blood circulation comprises a hydrophobicity at a blood concentration of any of about 25, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, or 400 pg/mL The average diameter of the nanoparticle of the taxane derivative (for example, any of the compounds 1, 2, 3-23 and any compound of the formula I, II, III, IV, V or VI) is not more than about 1000 nm. (nm), such as any of no more than about 900 nm, 800 134531.doc -29-200942233 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, or 100 nm. In some embodiments, at least about 50% (eg, at least about 60%, 70%, 80%, 90%, 95°/〇, or 99%) of all of the nanoparticles in the living body have no greater than A diameter of about 150 nm includes, for example, no more than 100, 90, 80, 70 or 60 nm. In some embodiments, between about 10 pg/ml and 300 gg/ml, between 25 pg/ml and 150 pg/ml, or between 50 pg/ml and 100 pg/ml At the blood concentration of the person, the blood contains a hydrophobic taxane derivative organism (for example, any of compounds 1, 2, 3-23 and any compound of formula I, II, III, IV, V or VI) The average diameter of the rice particles is between about 5 nm and 80 nm, between 10 nm and 70 nm, between 20 nm and 60 nm, between 30 and 50 nm, or about 45 nm. By. In some embodiments, the carrier protein has a sulfhydryl group that can form a disulfide bond. In some embodiments, at least about 5% (including, for example, at least about 10%, 15%, or 20%) of the carrier protein in the nanoparticle portion of the composition is crosslinked (eg, crosslinked by SS)一些 In some embodiments, the composition comprises a hydrophobic taxane derivative in the form of nanoparticles and in the form of non-nanoparticles (eg, any of Compounds 1, 2, 3-23, and any Formula I, A compound of II, III, IV, V or VI) wherein the total hydrophobic taxane derivative is greater than about 50%, 60%, 70%, 80%, 90°/. Any of 95% or 99% is in the form of nanoparticle. In some embodiments, the hydrophobic taxane derivative constitutes more than about 50%, 60%, 70%, 80%, 90%, 95% or 99% by weight of the nanoparticles. In some embodiments, the nanoparticles are substantially free of polymer core material 134531.doc -30-200942233. In some embodiments, the hydrophobic taxane derivative in each of the glutinous particles is non-Japanese. The weight ratio of the carrier protein (such as j, the nanoparticle composition protein) to the hydrophobic taxane derivative in the nanoparticle composition is about 18:1 or 18:1. The following, 4 or 丨 5.1 or less, 14:1 or 14:1 or less, 13:1 or 13:1 or less, 9 ·] + ^ to 1 or 12:1 or less, mi or 11:1 or less, 10: 1 or 10:1 or less, 9:1 ^9.] w πτ δ, 士. ^ .1 or less, 8:1 or 8:1 or less, 75:1 or 7 5:1 〇

^lower, 7, 1 or 7:1 or less, 6:1 or 6:1 or less, 5:1 or 5:1 or less, 4:1 or less, or 3:1 or 3:1 or less. In some embodiments, the weight ratio of carrier protein (such as albumin) to hydrophobic taxane derivative is from about 1:1 to about 18:1, from about 2:1 to about ΐ5:ι, about Η to Approximately 13:1, from about 4:1 to about 12:1, from about 5:1 to about 10:1. In some embodiments, the weight ratio of the carrier protein to the hydrophobic taxane derivative in the nanoparticle portion of the composition is about 1:2, 1:3, i:4, 15, 1:1, 1, 1: Any of 15 or 1:15. The nanoparticles described herein can be present in a dry formulation (e.g., a lyophilized composition) or suspended in a biocompatible medium. Suitable biocompatible media include, but are not limited to, water, buffered aqueous media, physiological saline, buffered saline, optionally buffered amino acid solution, optionally buffered protein solution, optionally Buffered sugar solution, optionally buffered vitamin solution, optionally buffered synthetic polymer solution, lipid-containing emulsion, and the like. In some embodiments, the composition comprises a hydrophobic taxane derivative (eg, any of the compounds 丨, 2, 3-23, and any compound of Formula I, II, HI, IV, V, or VI) and a carrier protein ( A stable aqueous suspension of granules (e.g., nanoparticulates) such as albumin (e.g., particles of a hydrophobic taxane derivative coated with an albumin) of 134531.doc -31 · 200942233. In some embodiments, the composition is substantially free (e.g., free of) interfacial activators (such as Cremophor®, Tween 80, or other organic solvents used to administer taxanes). The nanoparticle compositions described herein may enhance the delivery of hydrophobic taxanes and/or hydrophobic taxane derivative metabolites to cells (eg, tumor cells) and 7 or enhance hydrophobic taxanes and/or Or the binding of a metabolite of a hydrophobic taxane derivative to a cell, such as a tumor cell. Tumor cells exhibit enhanced absorption of proteins including, for example, albumin and transferrin, as compared to normal cells. Because tumor cells divide at a faster rate, they require an additional source of nutrients compared to normal cells. Tumor studies of the pharmaceutical compositions of the present invention containing paclitaxel and human serum albumin showed high absorbance of the tumor to albumin-paclitaxel. This phenomenon has been found to be due to the phenomenon that the glycoprotein 6 ("gp6" ") receptor that is specific for albumin has not been used to deliver albumin-drugs in the past. p In one aspect, the nanoparticle composition comprises a hydrophobic taxane derivative (eg, any of compounds 1, 2, 3, 23, and any compound of formula J, „, m, IV, V, or VI) and a carrier protein capable of binding to a 60 receptor (eg, albumin). In another embodiment, the nanoparticle composition comprises a hydrophobic taxane derivative (eg, any of compounds 1, 2, 3-23, and any compound of formula I, pi, hi, iv, v or vi) And a carrier protein (eg, albumin) capable of binding to a SPARC receptor. In another aspect, when compared to an underivatized taxane derivative, 134531.doc • 32- 200942233 the nanoparticle composition comprising a hydrophobic taxane derivative described herein has a different Dissolving graphics can produce significant advantages. For example, it has been shown that certain nanoparticles containing hydrophobic taxane derivatives have significantly lower solubility than their underived counterparts (see Example 21; Tables 9 and 10; and Figures 9-11). . The reduced solubility allows the nanoparticles to remain intact for a long period of time during the cycle. Thus, in one embodiment, the nanoparticulate composition comprises a hydrophobic taxane derivative (eg, any of compounds 1, 2, 3-23 and any formula 1, 11, HI, IV, V or VI) a compound) and a carrier protein (e.g., chalk protein) wherein the nanoparticle has a reduced water dissolution rate (including a nanoparticle composition comprising a non-hydrophobic substituted taxane (e.g., paclitaxel) Substantially reduced dissolution rate). In some such embodiments, the nanoparticle composition comprising a hydrophobic taxane derivative is compared to a nanoparticle composition comprising an unmodified taxane (eg, paclitaxel or paclitaxel) Water solubility drops by more than about 2 times, or 3 times, or 5, 7, 10, 12, 15, 17, 20, 25, 30, 35, 40, ❹ 50, 75, 100, 200, 500 or 1 〇〇〇 Any one of the times. In some embodiments, 'measuring by using a Malvern Zetasizer by dynamic light scattering' in a dissolution test at 5% HSA at 37 ° C, at any of about 5, 1 〇, 25 or 50 pg/ml The nanoparticle has about 1〇1^ to 1〇()11111, 20 to 75 nm, 15 to 50 nm, or more than about 2〇nm, 3〇nm, 40nm, 50 nm. The average particle size of either one. In some embodiments, the nanoparticle has about 2〇nrr^75 at any of about 5, 5, 75, or 100 pg/ml in a dissolution test in 5% HSA at 37 °C. Nm, or an average particle size greater than about 30 nm. In some embodiments, the measurement is performed by dynamic light scattering using a Malvern Zetasizer by 134531.doc -33- 200942233, and the nanoparticle exhibits the following dissolution pattern when measured at 5% HSA at 37 °C: (l) a) about 40 nm to 75 nm or more than about 50 nm at 200 pg/ml; b) about 30 nm to 60 nm or more than about 40 nm at 100 pg/ml; and c) about 10 pg/ml 10 nm to 40 nm or greater than about 20 nm; or (2) a) about 50 nm to 100 nm or greater than about 60 nm at about 400 pg/ml; b) about 40 nm to 75 nm at 200 pg/ml Or greater than about 50 nm; c) about 30 nm to 60 nm or greater than about 40 nm at about 100 pg/ml; d) about 10 nm to 40 nm at 10 gg/ml or greater than about ® greater than 20 nm; e) about 10 nm to 40 nm or greater than about 20 nm at about 5 pg/ml. In some embodiments, the nanoparticles exhibit the following dissolution pattern when measured by dynamic light scattering using a Malvern Zetasizer at 5 ° / 〇 HSA at 37 ° C: (1) a) at 200 pg /ml from about 40 nm to 75 nm or greater than about 50 nm; b) about 30 nm to 60 nm at 100 pg/ml or greater than about 40 nm; and c) about 10 nm to 40 nm at 10 pg/ml Or greater than about 20 nm; or (2) a) about 50 nm to 100 nm or greater than about 60 nm at about 400 pg/ml; b) about 40 nm to 75 nm or greater than about 50 nm at 200 pg/ml c) 〇 about 30 nm to 60 nm or greater than about 40 nm at about 100 pg/ml; d) about 10 nm to 40 nm at 10 pg/ml or greater than about 20 nm; and e) at about 5 About 10 nm to 40 nm or greater than about 20 nme at pg/ml. In some embodiments, when measured by dynamic light scattering using a Malvern Zetasizer at 5% HSA at 37 ° C, the nanoparticles exhibit a Dissolve the graphic. In some embodiments, the EC50 (ie, half point) of the dissolution profile is less than about 200 pg/ml, 150 pg/ml when measured by dynamic light scattering using a Malvern Zetasizer at 5% HSA at 37 °C. 120 pg/mL, 100 pg/ml, or 50 134531.doc -34- 200942233 μ§/ιη1. In some embodiments, the EC50 of the dissolution profile when measured at 5% HSA at 37 ° C is less than about 75%, 50%, 25% of the EC50 of the unmodified yew yard in the same nanoparticle formulation. 10% or 5% of the embodiments in some embodiments 'using Malvern by dynamic light scattering

When Zetasizer is measured at 5% HSA at 37 ° C, the E9 溶解 (ie 90 dissolution point) of the dissolution pattern is less than about 100 μβ/ηι1, 75 μβ/πι1, 5〇yg/ml, 3〇pg/m. Bu 20 pg/nU, i 5 pg/ml or! 〇 gg/ml either. In some embodiments, the nanoparticles are capable of maintaining an average diameter of from about 3 〇 nm to about 50 nm for at least about 5 minutes, 1 minute, or > hour when administered intravenously. The particle size and dissolution of the nanoparticle comprising the hydrophobic taxane derivative as described above can cause the intact nanoparticle to enter the cell membrane cavity to be invaded for delivery of the endothelium into the tumor cell (the opening is about 3 〇 _ 5 〇 nm and an inner diameter of 100 nm; see Westermann et al., (10) Ce " Still 〇/(1999) 111·71-81, the contents of which are incorporated herein by reference. Therefore, the transport of nanoparticle containing a hydrophobic taxane derivative may be more effective than the transport of a yew-containing nanoparticle comprising a non-hydrophobic group. Nanoparticles containing hydrophobic taxane derivatives have improved physical and/or chemical stability compared to nanoparticles of the cedar moon hall, >r crater, such as Pacific purple alcohol and/or European paclitaxel Sex. In some embodiments, the 'nanoparticle composition comprises a hydrophobic beech house derivative (eg, any of the compounds 2, 3-23, and any of the formulas m, IV, V· compounds) and a carrier protein (eg, Albumin), which is at 134531.doc -35- 200942233 4 ° C (or 25 ° C) and about 6, 7, or 8? Store any of 5, ι, 30, 60, 90, 120, 180, 27, 36 days at 1^, or 2, 3, 4, 5, 6, 7, 8, 9, or 1 After any of the leap years, the nanoparticles are in substantially pure form (impurities and/or different forms (such as different forms of taxane/taxane derivatives) not exceeding about 15% of the total composition) Or no more than about 10% or no more than about 5% or no more than about 3% or no more than about 1%). In some embodiments 'at 4. Store any of 5, 10, 30, 6〇, 9〇, 120, 180, 270, 360 days under 〇 (or 25t), or 2, 3, 4, 56, 7 8 9 or 10 years After either, the nanoparticle containing the hydrophobic taxane derivative is suitable for infusion to the human body. In some embodiments, a hydrophobic taxane derivative (eg, any of the compounds 丨, 2, 3-23, and any Formula I, II, is included without additional stabilizer (eg, citrate)) The nanoparticles of the III, IV, V or VI compound are stable. In some embodiments, the nanoparticulate composition has a blood Cmax that is exhibited after administration of the primate for about 0. 05 hours to about 3 hours. In some Q embodiments, the nanoparticle composition has a final half-life of from about 1 hour to about 5 hours after administration of the primate (including, for example, from about 2 hours to about 4 hours, such as about 3 hours to About 3.7 hours) shows decomposition in the blood. In some embodiments, after administration of the primate, the nanoparticulate composition has between about 2% and 20%, between about 3% and 1%, or between about 4% and 7%. Metabolite conversion of either of the compartments to remove the hydrophobic group from the hydrophobic taxane derivative. In some embodiments, the primate is a monkey. In some embodiments the 'primate is a human. Hydrophobic taxane derivative 134531.doc • 36- 200942233 The nanoparticle composition described herein comprises a hydrophobic taxane derivative (e.g., a hydrophobic paclitaxel derivative or a hydrophobic European paclitaxel derivative). Examples of structures comprising paclitaxel of paclitaxel and paclitaxel are shown below using the conventional numbering system as used herein:

Pacific Taxus Yeast: R: European Paclitaxel: R Ph: R · * Ethyl-OtBu; R' = Η To illustrate an example of the nomenclature used herein, the symbol C2, or 2, is indicated by the above indication "2," a carbon atom, and the ring system consists of a ring formed by a minimum number of ring carbons around the letter A (i.e., a ring formed by C1, ci5, C11, C12, C13, and ^4) . Thus, "2, _ hydroxy," refers to a hydroxy moiety attached to a carbon atom labeled "2'". The attached side chain is an atom attached to the cU oxygen atom (eg, Cl, C2', C3) And the like. In some embodiments, the 'hydrophobic taxane derivative is a derivative of paclitaxel. In some embodiments, the hydrophobic taxane derivative is a derivative of paclitaxel.

& Wanfa·measures can be converted to taxanes (eg as described in the example section of the article such as European paclitaxel or Taiping 134531.doc • 37· 200942233 paclitaxel) up to about 1, 2, 3, 4, 5, 8 , 10, 12, 15 18 '20, 25 or 30% (for example, transformed from human liver microsomes). In some embodiments, the hydrophobic taxane derivative contains a hydrophobic group attached to an A ring carbon or an extraring atom directly attached to the A ring carbon. In some embodiments, the 'hydrophobic taxane derivative contains a hydrophobic group attached to a B-ring carbon or an extra-ring atom directly attached to the b-ring carbon. In some embodiments, the hydrophobic taxane derivative contains a hydrophobic group attached to a C-ring carbon or an extra-ring atom directly attached to a c-ring carbon. In some embodiments, the hydrophobic taxane derivative ® contains a hydrophobic group attached to the pendant side chain.

In some such embodiments, the ''hydrophobic taxane derivative contains one or more hydrophobic groups. In some embodiments, the hydrophobic taxane derivative contains a plurality of hydrophobic groups." (4) The derivative contains only one hydrophobic group. In some embodiments, the hydrophobic group is _c(〇)r6; wherein R is selected from the group consisting of an alkyl group, a county, a block group, a cycloalkyl group, a cycloalkyl group, an aryl group, a hydrazine group, and an aromatic group. A substituted or unsubstituted portion of a heterofamily. In some embodiments, r6 is independently a substituted or unsubstituted moiety selected from the group consisting of an alkyl group, a dilute group, a ring-based cycloalkyl-alkyl group, an aryl group, and an aryl group. In some embodiments, R6 is a substituted or unsubstituted moiety selected from the group consisting of an alkyl group, a dilute group, a cyclomorphyl group, a cycloalkyl-alkyl group, an aryl group, and an aralkyl group. In two embodiments, R6 is a substituted or substituted moiety selected from the group consisting of alkyl, aryl and aralkyl. In some embodiments, the pendant, aryl, and aryl groups are not substituted. In some embodiments, r6 is a 6 membered radical substituted with an unsubstituted ~(10) group or a fluorene. In some embodiments, r6 is unsubstituted or unsubstituted phenyl. In some embodiments, Han 6 is not 13453I.doc • 38- 200942233 substituted iCl_ClG alkyl (e.g., a alkyl). In some embodiments, R6 is unsubstituted phenyl. In some such embodiments, the hydrophobic taxane derivative has the formula:

Wherein R1 is phenyl or _0tBu; r2, R3, R4 and R5 are independently H or a hydrophobic group' and wherein at least one of R2, R3, R4 and R5 is not H. In some embodiments, the hydrophobic taxane derivative of Formula I contains the following limitation: when R1 is phenyl and R2, R3, and R5 are each oxime, R4 is not an ethylidene moiety. In some embodiments 'R1 is phenyl. In some embodiments, R1 is -OtBu. In some embodiments, Ri is phenyl and the rule 2 is a hydrophobic group (such as a fluorenyl group such as -C(0)-C4-C1Q alkyl, especially unsubstituted -C(0)-C6 alkyl). In some embodiments, R1 is phenyl and r2 is a hydrophobic thiol group (such as a fluorenyl group, such as -c(〇)-C4-c1G alkyl, especially unsubstituted -C(0)-C6 alkyl). In some embodiments, only one of R2, R3, Ruler 4, and R5 is not Η. In some embodiments, the hydrophobic taxane derivative has the formula:

134531.doc •39· 200942233 wherein R丨 is phenyl or —〇tBu; r2, r3, 4 and r5 are independently h or —c(〇)r6; each _r6 is independently selected from alkylalkenyl a substituted or unsubstituted portion of an alkynyl, cycloalkylcycloalkyl-alkyl, aryl, heteroaryl, aralkyl, and heteroarylalkyl group; and wherein at least one of r2, r3, RW is not Why? In some embodiments, the hydrophobic taxane derivative of the formula contains the following limitations. In the case of a phenyl group and each of R2, R3 and R5 is fluorene, R4 is not a fluorenyl moiety. In some embodiments, Rl is phenyl. In some embodiments, R1 is -OtBu. In some embodiments, each R6 of the formula is independently selected from the group consisting of 4丨-^5 alkyl, _CVC15, _Cl_Ci5, _Ci_Ci5 a substituted or unsubstituted portion of a cycloalkyl, _Ci Ci5 cycloalkyl-alkyl, aryl, 5- to 7-membered heteroaryl, aralkyl, and heteroarylalkyl group. In some embodiments, each hydrazine Independently substituted or unsubstituted moieties selected from alkyl, -Ci-C^alkenyl and aryl. In some embodiments, each R6 is independently substituted or unsubstituted aryl or Substituted or unsubstituted _Ci_Ci5 alkyl. In some embodiments, each R6 is independently unsubstituted aryl or unsubstituted-Ci-Ch alkyl. In some embodiments, each R6 Independently an unsubstituted phenyl or unsubstituted methyl group. In some embodiments, each 尺6 is independently an unsubstituted aryl group. In the examples, each R6 is independently an unsubstituted phenyl group. In some embodiments, each R6 is independently an unsubstituted-Ci-Cu alkyl group. In some embodiments, each R6 is independently Is an unsubstituted -Ci-C^oalkyl group or a -CVCio system. In some embodiments, each R6 is -CH3, -CH2CH3, -(CH2)2CH3, -(〇Η2)3 (: Η3, 13453I.doc · 40· 200942233 -(CH2)4CH3 > -(CH2)5CH3 ' -(CH2)6CH3 > -(CH2)7CH3 and -(CHACH3. In some embodiments, R6 is -(CH2)4CH3. In some embodiments, only one of R2, R3, R4&R5 of Formula II is not deuterium. In some embodiments, R2 is not H. In some embodiments, R3 is not Η. In some embodiments, R4 is not H. In some embodiments, R5 is not Η. In some embodiments, only two of the formulas H2R2, R3, 尺4, and han5 are not In some embodiments, R2 and R3 are not H. In some embodiments, RW is not H. In some embodiments, Η. In some embodiments, R4 is an acetyl group and r2 , "only one of the Han 5 is not Η » In some embodiments, Equation 1 R4 of 1 is an ethylidene moiety D phenyl; and each of R3 and R5 is fluorene. In some embodiments, the acetyl group; R1 is phenyl; R3 and r5 are each Η; and ruler 6 is selected from A substituted or unsubstituted portion of an alkyl group, a -C|_Cl5 alkenyl group, and an aryl group.

In some embodiments, R 4 is an ethyl fluorenyl moiety; R 1 is phenyl; R 3 and R 5 are each deuterium, and R 6 is substituted or unsubstituted aryl or substituted or unsubstituted -CVC 5 burning base. In some embodiments, R4 is an ethylenic moiety; R1 is phenyl; RW is each H; &r6 is an unsubstituted aryl or unsubstituted-CVCW group. In some embodiments, R4 is a B(tetra) moiety; R1 is phenyl HR5 each being H; and "unsubstituted phenyl or unsubstituted _c: 4_Ci. leuco 4 - in some embodiments, R4 Is a brityl moiety; R1 is a stupid group; R3AR5 is each an unsubstituted aryl group of HaR6. In some embodiments, r4 is an acetamidine moiety; r丨 is a phenyl group; r3 134531.doc -41 - 200942233 And R is each a fluorene, and R6 is a phenyl group. In some embodiments, r4 is an ethylenic moiety; R1 is phenyl; R3AR5 is each H; ar6 is unsubstituted -C^-C"5 alkyl In some embodiments, R 4 is an ethyl sulfhydryl moiety; ... is a phenyl group; R 3 and R 5 are each H; and r 6 is an unsubstituted C-poly- hospital group. In some embodiments, R 4 is an ethyl fluorenyl group. a moiety; R1 is phenyl; R3 and R5 are each Η; and R6 is unsubstituted _C4_Cig alkyl. In some embodiments, R4 is ethinyl; R is phenyl; R3 and r5 are each H; and is considered to be -(CH2)4CH3 0 In some embodiments, R 式 of formula π is _〇tBu; R3, ... and 尺5 are each Η; and R6 is substituted or unsubstituted aryl or Replaced or unsubstituted -cvcu entertainment: base. In some embodiments, R^-〇tBu of the formula π; R3, R4, and R5 are each H; and R6 is an unsubstituted aryl group or an unsubstituted-Ci-C丨5 alkyl group. In some embodiments Wherein R is _〇tBu; R, R and R are each Η; and R6 is unsubstituted phenyl or unsubstituted -cvc fluorenyl. In some embodiments, Ri of formula π R_R and R are each Η; and R6 is an unsubstituted aryl group. In some embodiments, R1 of formula II is _〇tBu; R3, R^R5 are each Η; R6 is phenyl. In some embodiments, R1 of the formula is _〇tBu; R3, R4 and R5 are each Η; and R6 is an unsubstituted _Ci_Cl5 alkyl group, in some embodiments 'Formula II R1 is _〇tBu; R3, R4 and R5 are each η; and R6 is unsubstituted-(VCw alkyl. In some embodiments, Ri of the formula π is -OtBu; R3, R4 and R5 are each η And r6 is an unsubstituted _c4-c10 alkyl group. In some embodiments, R1 of formula II is _〇tBu; R3, R4 and R5 are each Η; and R6 is _(CH2)4CH3. Doc-42- 200942233 In some embodiments, the hydrophobic taxane derivative has the formula:

❹ wherein R 2 , R 3 and R 4 are independently mc(〇)R 6 ; each —r 6 is independently 2 alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, heteroaryl a substituted or unsubstituted portion of an aralkyl group and a heteroaralkyl group; and wherein at least one of R2, R3 and R4 is not hydrazine. In some embodiments, each of r6 of formula (1) is independently selected from the group consisting of _c cardinyl, -cvc15, _Ci_Ci5 alkynyl, _Ci Ci5 ring-based (tetra)-based {yl'-aryl, 5 to 7 members a substituted or unsubstituted portion of a heteroaryl, an aramid or a heteroaromatic. In some embodiments, each - R6 is independently selected from the group consisting of 15 groups and aryl groups substituted or not. In some implementations, each _R6 is independently a substituted or unsubstituted, aryl group or substituted or unsubstituted _C1_C15^. In one embodiment of the invention, each R6 is independently unsubstituted aryl or unsubstituted = - 15 filaments. In some embodiments, each is an unsubstituted phenyl or unsubstituted methyl group. In some embodiments, each 2 is an unsubstituted implementation, and each - R6 is independently an unsubstituted phenyl group. In a consistent example of a peptide, such as A ρ Λ , each R6 is independently a substituent: a substituent. In some embodiments, each -r6 is independently unsubstituted W group ' or ^. The phenotype β is in some embodiments 134531.doc -43· 200942233, each -R6 is -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -(CH2)4CH3 > -(CH2)5CH3 > -(CH2)6CH3^-(CH2)7CH3 and -(CH2)8CH3. In some embodiments, R6 is -(CH2)4CH3. In some embodiments, only one of R2, R3, and R4 of the formula is not Η. In some embodiments, R2 is not H. In some embodiments, ... is not awkward. In some embodiments 'R4 is not Η. In some embodiments, only two of r2, r3, and r4 are not ίί. In some embodiments, the feet 2 and R3 are not Η. In some embodiments, ... and ruler 4 are not H. In some embodiments, R3 and R4 are not deuterium. In some embodiments, R4 is one of HiR2 and R3 and is not Η. In some embodiments, each of the formulas niR3 & R4 is in some embodiments, R3 and R4 are each deuterium; and R6 is substituted or unsubstituted, selected from the group consisting of _Cl_Ci5 alkyl, _Ci_Ci5 alkenyl, and aryl. section. In some embodiments, R and R are each deuterium; and R6 is substituted or unsubstituted aryl or desubstituted or unsubstituted -C^-Ci5 alkyl. In some embodiments, R3 and R4 are each deuterium; and R6 is an unsubstituted aryl or unsubstituted alkyl group. In some embodiments, ... and ... are each H; and Rule 6 is unsubstituted phenyl or unsubstituted -CrCioalkyl. In some embodiments, each of Han 3 and R 4 is deuterium; and R 6 is an unsubstituted aryl group. In some embodiments, R and R are each Η; and R6 is phenyl. In some embodiments, Han 3 and Han 4 are each Η; and R 6 is an unsubstituted _Ci_Cis alkyl group. In some embodiments, R3 and R4 are each Η; and R6 is unsubstituted _Ci_Ci 〇 alkyl. In some embodiments, R3 and R4 are each H; and r6 is unsubstituted -Cp 134531.doc -44 - 200942233 C10 alkyl. In some embodiments, R3 and R4 are each H; and r is -(CH2)4CH3. In some embodiments, the hydrophobic taxane derivative has a lower #

Wherein R 2 , R 3 and R 4 are independently hydrazine or -C(0)R 6 ; each R 6 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, hetero a substituted or unsubstituted portion of an aryl, aralkyl, and heteroaryl group wherein at least one of R2, R3 and R4 is not H. In some embodiments, when R2, R3, and R5 are each deuterium, R4 is not an ethylidene moiety. In some embodiments, each R6 of formula iv is independently selected from the group consisting of alkyl, -c丨-c15 Substituted or unsubstituted moieties of alkenyl, _Cl-Cl5 alkynyl, _Ci_Ci decyl, 4a cycloalkyl-alkyl, aryl, 5 to 7 membered heteroaryl, aralkyl and heteroarylalkyl In the H embodiment, each of the ground is selected from the group consisting of 〇^15 alkyl, _Ci_c]5 alkenyl and aryl substituted moieties, in each of the implementations, each - R6 is independently taken = not i = generation of fang Substituted or substituted filaments. In this case, each R6 is independently an unsubstituted aryl group or is not taken: instead of a cage m. In the two embodiments, each - R6 is independently an unsubstituted stupid or unsubstituted fluorenyl group. . This site is the unsubstituted argon A force in the examples. In some embodiments, each R6 independently is 134531.doc • 45. 200942233 is an unsubstituted phenyl group. In some embodiments, each R6 is independently unsubstituted -C1-C15 alkyl group. In some embodiments, each R6 is independently unsubstituted -Cl-Cl 〇院基' or -C4_C 10 base. In some embodiments, each R6 is -CH3, _ch2ch3, -(ch2)2ch3, -(CH2)3CH3, -(CH2)4CH3, -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3 And -(CH2)8CH3. In some embodiments, it is -(ch2)4ch3. In some embodiments, only one of R2, R3, and R4 of Formula IV is not ©Η. In some embodiments, R2 is not H. In some embodiments, &3 is not a defect. In some embodiments, R4 is not H. In some embodiments, only two of R R and R are not η. In some embodiments, r2 and r3 are not Η. In some embodiments, the scales 2 and R4 are not Η ^ In some embodiments, R3 and R4 are not Η » In some embodiments, R4 is an acetamidine moiety and only one of R2 and R3 is not Hey. In some embodiments, R4 of Formula IV is an ethylidene moiety and R3 is deuterium. In some embodiments, R4 is an ethylenic moiety; R3 is deuterium; and V is selected as: substituted or unsubstituted moieties of -Ci-C15 alkyl, -C丨-Cl5 alkenyl, and aryl * In the examples, R4 is an ethylenic moiety; and the uldent 6 is a 2-substituted or unsubstituted aryl or substituted filament. In some embodiments, R4 is an ethylenic moiety; R3 is H; m = aryl group A substituted by = 々 A (four). In some embodiments, the ethyl fluorenyl moiety ' R3 is H; and is R6 unsubstituted phenyl or unsubstituted _c4_c, G alkyl. R3 is 未经(10) unsubstituted: Example: R is the ethyl π t aryl group. In some embodiments, 134531.doc -46. 200942233 R4 is an ethylidene moiety; R3 is deuterium; and r6 is phenyl^ in some embodiments 'R is an ethylidene moiety; R3 is H; Unsubstituted alkyl. In some embodiments 'R4 is an ethylidene moiety; R3 is deuterium; and R6 is unsubstituted -CfC1decylalkyl. In some embodiments, R4 is an ethylidene moiety; R3 is deuterium; and R6 is an unsubstituted _C4_Cig alkyl group. In some embodiments 'R4 is an ethylidene moiety; r3 is η; and the ruler 6 is _(CH2)4CH3. In some embodiments, the hydrophobic taxane derivative has the formula:

Wherein R 2 is -C(0)R 6 ; and R 6 is independently selected from the group consisting of alkylalkenynyl, ring-based, ring-based, tert-butyl, aryl, heteroaryl, aryl, and heteroarylalkyl a substituted or unsubstituted moiety; or a pharmaceutically acceptable sulfonium salt, isomer or solvate thereof. In some embodiments, Formula V and Formula V&R6 are substituted or unsubstituted moieties selected from the group consisting of Ci-Ci5 alkyl, alkenyl, and aryl. In some embodiments, R6 is substituted or unsubstituted aryl or substituted or unsubstituted -CVC,5 alkyl. In some embodiments, R6 is unsubstituted aryl or unsubstituted _Cl_Cl5 alkyl. In some embodiments, r6 is unsubstituted phenyl or unsubstituted methyl. In some embodiments, r6 is an unsubstituted aryl group (e.g., phenyl). In some embodiments, the _C丨-Cls alkyl group is replaced by I34531.doc -47- 200942233. In some embodiments, R6 is unsubstituted _Ci_Ci 〇 alkyl (eg, -CH3, -CH2CH3, -(CH2)2CH3, -(<:Η2)3(:Η3, -(CH2)4CH3, - (CH2)5CH3, -(CH2)6CH3, -(ch2)7ch3, -(CH2)8CH3). In some embodiments, the hydrophobic taxane derivative is any of the following compounds:

134531.doc -48· 200942233

134531.doc -49- 200942233

134531.doc -50- 200942233

134531.doc -51 · 200942233

134531.doc -52 200942233 Carrier Proteins The nanoparticle compositions described herein may utilize suitable examples of naturally occurring or oral protein-forming oral carrier proteins including proteins commonly found in blood or blood pools, including but not limited to Albumin, immunoglobulin (including g), scorpion protein apolipoprotein α, α-acid glycoprotein, β 2 _ macroglobulin, scorpion globulin, transferrin, fibronectin, vitronectin blood Fibrinogen, Factor, Factor VIII, Factor ΙΧ, Factor ❹X and analogues thereof. In some embodiments, the carrier protein is a non-blood protein, such as a complex protein, alpha-lactalbumin or beta-lactoglobulin. The carrier protein can be prepared from a natural source or synthetically. In some embodiments, a pharmaceutically acceptable carrier comprises albumin&apos; such as human serum albumin (HSA). The ship is a highly soluble globular protein f of 65K and consists of milk amino acid. It is the most abundant protein in plasma and accounts for 70_80% of the osmotic dust of human plasma. The amino acid sequence of HSA contains a total of (7) solid disulfide bridges, a free thiol coffee 34) and mono-tryptophan acid (Trp2i4). Covers other albumin, yak serum albumin. For example, in the case where the compositions are used in non-human mammals (skins including household pets and farm animals), the use may be appropriate. In some implementations :::: ostrich- lysozyme, immunoglobulin, . :: a group of humans and their analogs, and any two or more of them. In the examples, the suitable protein f is selected from the group consisting of albumin, white (including IgA), lipoprotein, apolipoprotein B, = group of thyroglobulin. In some embodiments, the acceptable carrier comprises albumin (e.g., human albumin). Suitable: 134531.doc -53- 200942233 The proteins (including albumin) of the invention may be prepared from natural sources or synthetically. Human serum albumin (HSA) has multiple hydrophobic binding sites (eight fatty acids (endogenous ligands for HSA) binding sites) and binds to a different set of drugs, especially neutral and negatively charged. Compound (Goodman et al, The Pharmacological Basis of Therapeutics, % 9 edition, McGraw-Hill New York (1996)). Two high-affinity binding sites have been proposed for subdomain IIA of HSA and sputum, which have charged ionization acid and fine amine acid residues near the surface serving as a junction for polar ligand characteristics. The highly elongated hydrophobic pocket. (See, for example, Fehske et al, Biochem. Pharmcol., 30, 687-92 (1981), Vorum, Dan. Med. Bull., 46, 379-99 (1999), Kragh-Hansen, Dan. Med. Bull., 1441, 131-40 (1990), Curry# A » Nat. Struct. Biol., 5, 827-35 (1998), Sugiof A » Protein. Eng., 12, 439-46 (1999), He# Λ &gt Nature, 358, 209-15 (1992) &gt; and Carter et al, di/v. Proiez.w. C/zem·, 45, 153-203 (1994)) o O carrier protein in the composition (eg Albumin) generally acts as a carrier for the hydrophobic taxane derivative, i.e., the carrier protein in the composition allows the hydrophobic taxane derivative to be more easily suspended in the composition than the composition not comprising the limulus protein. In an aqueous medium or to help maintain suspension. This avoids the use of toxic solvents to dissolve the hydrophobic taxane derivative, and thereby reduces one or more side effects of administering the derivative to an individual (e.g., a human). In some embodiments, the composition is substantially free (e.g., free of) organic solvents or surfactants. If the amount of organic solvent or surfactant in the composition is insufficient to cause one or more side effects to the individual when the composition is administered to the individual, the composition 134531.doc -54- 200942233 &quot;substantially free of organic solvents&quot; Or &quot;substantially free of surfactants." In some embodiments, the nanoparticles in the composition have a solid core. In the ":" embodiment, the nanoparticles in the composition have a non-aqueous core (also That is, the same as the aqueous core. In some embodiments, the nanoparticle of the composition lacks a polymer matrix. In some embodiments, the nanoparticle of the composition is sterilizable by hydrazine. In some embodiments The nanoparticle in the composition comprises at least one cross-linking carrier protein. In some embodiments, the nanoparticle in the composition comprises at least 1% cross-linking carrier protein. If the hydrophobic taxane derivative remains Suspension in an aqueous medium (eg, no significant precipitation or sedimentation) for a longer period of time (eg, at least about 〇1, 〇2, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 1) 〇, U, 12, 24, 36, 48, It is "stable" in an aqueous suspension for any of 60 or 72 hours. This suspension is usually, but not necessarily, suitable for administration to an individual (e.g., a human). The stability of the suspension is usually (but not necessarily) evaluated at storage temperature, such as at room temperature (eg 2〇-25.〇 or refrigerated conditions (eg 4. underarm φ evaluation. For example, if in suspension) About fifteen minutes after the liquid, it does not exhibit significant flocculation or particle coalescence when viewed under the naked eye or under a 1000x optical microscope. The suspension is stable at storage temperature. Stability can also be evaluated under accelerated test conditions. , such as at a temperature above about 4 (according to rc) In some embodiments, the composition comprises a hydrophobic taxane derivative (eg, any of compounds 1, 2, 3-23, and any formula I) Nanoparticles of π, ΠΙ, IV, V or VI compounds) and carrier proteins (consisting essentially of such materials in various variations). When the derivative is in liquid form, 134531.doc -55- 200942233 Or nanoparticles are also referred to as droplets or nanodroplets. In some embodiments, the hydrophobic taxane derivative is coated with a carrier protein. Particles of poorly water soluble medical agents (such as nanoparticles) have been Revealed in, for example, US patents U.S. Patent Application Publication No. 2005/0004002 A1, and PCT Application Publication No. WO No. 98/14174, No. WO99/00113, No. 5, 916, 596, No. 6, 506, 405, No. 6, No. 96, 331, No. 6, 749, 868, and No. 6, 537, 579. No. WO07/027941 and WO 7/027819. The contents of these documents are hereby incorporated by reference in its entirety herein. The amount of carrier protein in the compositions described herein will depend on the particular hydrophobicity. The taxane derivative, other components of the composition, and/or the intended route of administration vary. In some embodiments, the composition comprises sufficient to provide an aqueous suspension, such as a stable colloidal suspension (eg, nanoparticle) A stable amount of carrier protein in the form of a stable suspension. In some embodiments, the carrier protein is in an amount that reduces the rate of sinking of the hydrophobic taxane derivative in an aqueous medium. In one embodiment, the amount of the carrier protein included in the composition is an amount effective to reduce one or more side effects of the hydrophobic taxane derivative. The amount of the carrier protein can also be regarded as a hydrophobic taxane derivative. Depending on the particle size and density of the granules. In some embodiments, the composition in liquid form comprises from about 01% to about 25% by weight (eg, about 5% by weight, about 5% by weight, about 1% by weight, about 15% by weight, or about 20% by weight, of carrier protein (eg, albumin) In some embodiments, the liquid form of the composition comprises from about Q5 wt% to about 5 wt% of carrier protein (eg, albumin). The material can be dehydrated, for example, by strand drying, 134531.doc -56 - 200942233 spray drying, fluid bed drying, wet granulation, and other suitable methods known in the art. Carrier proteins (eg, albumin) and other excipients, if present, are prepared, for example, by wet granulation, fluid bed drying, and other methods known to those skilled in the art to prepare the compositions in solid form. Applying the active pharmaceutical agent as a solution. In some embodiments, the solution is from about 1% to about 25% by weight (eg, about 5% by weight, about 5% by weight, about 10% by weight, about 15% by weight, or about 20% by weight). Carrier protein (eg albumin). In some embodiments, the composition comprises greater than, equal to, or less than about 5%, about 10%, about 20%, about 25%, about 30%, about 403⁄4, about 45〇/〇, about 50%, about 55%. A carrier protein (eg, albumin) in the form of nanoparticles in the form of about 60%, about 65%, about 750/〇 or about 80%. In some embodiments, the &apos;carrier protein is present in an amount effective to reduce one or more side effects associated with administration of the hydrophobic taxane derivative to a human compared to a composition without the carrier protein. Such side effects include, but are not limited to, myelosuppression, neurotoxicity, allergies, inflammation, venous irritation, phlebitis, pain, skin irritation, neutropenic fever, allergic reactions, hematological toxicity, and brain or neurotoxicity, and combinations thereof. . In some embodiments, methods are provided for reducing an allergic response associated with administration of a hydrophobic taxane derivative, including, for example, severe rash, measles, redness of the face, difficulty breathing, and heartbeat Rapid, pulmonary circulation high blood pressure (such as lymphoma); chest pain; melena, asphalt-like stool; general morbid sensation, shortness of breath; gland swelling; weight loss; skin and eye yellowing, abdominal pain; unexplained anxiety; hematuria or Turbid urine; bone pain; chills; confusion; 136531.doc •57- 200942233 厥 (seizure); cough; decreased desire for urination; rapid, slow or disregarded heartbeat; fever; frequent urination; Increase; eat your pain; lower back or body side pain; mood changes; muscle pain or cramps; nausea or vomiting; paralysis or tingling around the lips, hands or feet; pain or difficulty urinating; rash; sore throat; Sore or leukoplakia in the mouth; swelling of the hands, tendons, feet or calves; swelling of the glands; difficulty breathing; unusual bleeding or bruising; unusual fatigue or weakness; weakness or depression of the legs , skin ulcers or sores, weight gain, acne "more secret; abdominal filling; difficulty in movement; headache; energy loss or weakness; muscle pain or stiffness; pain; tremor or trembling; difficulty sleeping; nosebleeds; and / or face Swollen. However, such side effects are merely exemplary and may reduce combinations of other side effects or side effects associated with hydrophobic taxane derivatives. Side effects may be immediate or delayed (such as days, weeks after the start of treatment) , does not occur for months or years.) Antimicrobial Agents in the Compositions In some embodiments, the compositions of the present invention also include those sufficient to significantly inhibit sputum (eg, delay, decrease, slow, and/or prevent) for use herein. Illustrative therapeutic methods, methods of administration, and amounts of antimicrobial agents in the composition of the dosage regimen (eg, changes in the use of exemplary microbial agents and microbial agents other than hydrophobic taxane derivatives) The form is disclosed in U.S. Patent Application Publication No. 2007/0117744 A1 (such as those described in paragraphs [〇〇36] to [0058], _) The method cited in the full text is incorporated herein by reference. In this example, the antimicrobial agent is a chelating agent such as EDTA, ethylenediaminetetraacetate, salt (tetra) salt, pentamidine acid (Pedate), tromethlic acid. Amine, sorbate, ascorbate, derived therefrom 134531.doc-58-200942233 or mixtures thereof. In some embodiments, the antimicrobial agent is a multidentate chelating agent. In some embodiments, the antimicrobial agent is non- An integrator, such as sulfite, benzoic acid, hexanol, oxybutanol, and a p-benzoic acid brewing. In some embodiments, different from the anti-microbial agent of the yew plant discussed above The agents are not included or used in the methods of administration and dosing regimens described herein. Sugar-Containing Compositions In some embodiments, the compositions of the present invention comprise a sugar for use in the methods of treatment described herein. . In some embodiments, the compositions of the present invention comprise both a sugar and an antimicrobial agent for use in the methods of treatment described herein. A variation of the use of exemplary sugars and sugars is disclosed in U.S. Patent Application Publication No. 2007/0117744 A1 (such as the sugars described in paragraphs [0084] through [〇〇9〇]), The content is incorporated herein by reference in its entirety. In some embodiments the &apos;sugar acts as a rehydration enhancer that dissolves or suspends the lyophilized composition more quickly or in suspension in water and/or aqueous solution than dissolution of the lyophilized composition in the absence of sugar. In some embodiments, the composition is a liquid (e.g., aqueous) composition obtained by rehydrating or resuspending a dry composition. In some embodiments, the concentration of the sugar in the composition is greater than about 50 mg/ml. In some embodiments, the 'saccharide system is effective to increase the hydrophobic taxane derivative in the composition as compared to the sugarless composition. The amount of stability. In some embodiments, the saccharide is an amount effective to improve the filterability of the composition as compared to a sugarless composition. The sugar-containing compositions described herein may additionally comprise one or more antimicrobial agents such as those described herein or in U.S. Patent Application Publication No. 2007/0117744. In addition to one or more of the 134531.doc •59-200942233 other rehydrating enhancers (such as those described in U.S. Patent Application Publication No. 2005/0152979, the disclosure of which is incorporated herein in its entirety by reference. ) can also be added to the composition. In some embodiments, the sugar is not included or used in the methods of treatment, methods of administration, and dosing regimens described herein. Stabilizers in the Compositions In some embodiments, the compositions of the present invention also include stabilizers for use in the methods of treatment, methods of administration, and dosing regimens described herein. In some embodiments, the compositions of the present invention include An antimicrobial agent and/or a sugar and/or a stabilizing agent for use in the methods of treatment, methods of administration, and dosing regimens described herein. Variations in the use of exemplary instable stabilizers and stabilizers are disclosed in MUs 2007/0082838 (such as those described in paragraphs [〇〇38] to [〇〇83] and pp. pp. [0114]]. stabilizer). The present invention provides, in another variation, a hydrophobic violet that retains a desired therapeutic effect upon exposure to certain conditions, such as long-term storage, high temperature or dilution for parenteral administration, and maintains physical and/or chemical stability. A composition of a cedar derivative and a preparation method thereof. Stabilizers include, for example, chelating agents (e.g., citrate, malic acid, ethylenediaminetetraacetate, or pentarate), sodium pyrophosphate, and sodium gluconate. In some embodiments, the invention provides a pharmaceutical formulation comprising a hydrated taxane derivative of citrate, sodium pyrophosphate, EDTA, sodium gluconate, citrate, and sodium hydride. In another variation, the invention provides a composition of a hydrophobic yew-fired organism, wherein the derivative used to prepare the formulation is in anhydrous form prior to incorporation into the composition. In some embodiments, the &apos;stabilizers are not included or used in the methods of treatment, administration methods, and dosing regimens described herein for treatment 134531.doc-60-200942233. Pharmaceutical Compositions and Formulations The compositions described herein can be used to pharmaceutically acceptable carriers by using the described nanoparticle compositions, as described in the methods of treatment, administration methods, and dosing regimens described herein, Formulations, such as pharmaceutical compositions or formulations, are prepared by excipients, stabilizers, and/or other agents known in the art. 0 To increase the stability by increasing the negative zeta potential of the nanoparticles, a certain negatively charged component can be added. Such negatively charged components include, but are not limited to, bile wind bile acid, glycocholic acid, cholic acid, chenodeoxycholic acid, taurocholic acid, erodeoxycholic acid, bovine oxydeoxycholic acid, stone gallstone Acid, ursodeoxycholic acid, dehydrocholic acid and other n include fats based on egg (four) (yolk yolk), including the following fats and fats: soft fat 醯 base oil basal fat choline, soft lipid base Oil-based base dish fat choline, stearin linoleic acid phosphatase 醯 验 验 验 验 验 验 曰醯 曰醯 曰醯 油 油 油 油 、 、 、 、 、 、 硬 硬 硬 硬 硬 硬 硬 硬 硬 硬 硬 硬 硬 硬 硬 硬 硬 硬 硬 硬Two soft fat brewing base rouge 醯 验 test. Other breaks include U-digestive phosphatidylcholine (DMpc), diterpenoid phospholipid choline (DOPC), distearyl phospholipid choline (1) spc, and hydrogenated soybean phospholipids ( HSPC) and other related compounds. Negatively charged surfactants or emulsifiers are also suitable as additives, such as sodium cholesteryl sulfate and the like. The nanoparticle compositions described herein can be stabilized using a pharmaceutically acceptable surfactant. The terminology used in this article, surfactants, is two! The surface active group of the knife. The surfactant can be anionic, 134531.doc 200942233 cationic, nonionic and zwitterionic. Any suitable surfactant can be included in the pharmaceutical compositions of the present invention. Suitable surfactants include nonionic surfactants such as phospholipids, polyoxyethylene sorbitan esters, and tocopherol polyethylene glycol succinates. In some embodiments, the surfactant is lecithin, Tween 80 or vitamin 匕丨d_ac_tocopherol polyethylene glycol _ 1000 succinate (TPGS) » suitable pharmaceutical carriers include sterile water; physiological saline; Dextrose; dextrose in water or barium physiological saline; condensation product of cannabis oil and ethylene oxide, about 30 to about 35 moles of ethylene oxide per mole of castor oil; liquid acid; lower alkanol; Emulsifiers (such as monoglycerides or diglycerides of fatty acids, or phospholipids such as lecithin and analogs thereof) are present together with oils (such as corn oil, peanut oil, sesame oil and the like); ethylene glycol; polyalkanes a leavening agent (eg, sodium carboxymethylcellulose, sodium alginate, poly(vinylpyrrole), alone or in combination with a suitable partitioning agent such as lecithin, polyoxyethylene stearate, and the like. An aqueous medium in the presence of ketone ketone) and its analogs. The carrier may also contain adjuvants such as preservative stabilizers, wet lake agents, emulsifiers and the like, as well as penetration enhancers. The final form can be sterile and may also easily pass through an injection device, such as a hollow needle. The proper viscosity can be achieved and maintained by appropriate selection of solvents or excipients. In addition, the use of molecules such as lecithin or the use of a particulate coating, the appropriate choice of particle size in the dispersion, or the use of materials having surfactant properties can be utilized. The nanoparticulate compositions described herein may include other agents, excipients or stabilizers which modify the properties of the composition. Examples of suitable excipients and diluents include, but are not limited to, lactose, dextrose, inexpensive sugar, sorbitol, mannose 134531.doc -62- 200942233 sugar alcohol, starch, gum arabic, calcium phosphate, alginate , tragacanth, koji acid, microcrystalline cellulose, polyethylene piroxicam, cellulose, water, physiological saline solution, syrup, methyl cellulose, hydroxy benzoate and hydroxybenzoic acid Propyl ester, talc, magnesium stearate and mineral oil. Formulations may additionally include lubricants, wetting agents, emulsifying and suspending agents, preservatives, sweeteners or flavoring agents. Examples of the emulsifier include tocopherol esters (such as tocopherol polyglycol butyl citrate and the like), plur〇niC (g), an emulsifier based on polyoxyalkylene ethyl compound, Span 80 (Span 80) And related compounds and other emulsifiers known in the art and approved for use in animal or human dosage forms. The composition can be formulated by the use of procedures well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a patient. In some embodiments, the composition is formulated to have a pH in the range of from about 4.5 to about 9.0, including, for example, from about 5 Torr to about 8 Torr, from about 65 to about 75, and from about 6.5 to about 7.0. The pH range of either. In some embodiments, the pH of the composition is formulated to be no less than about 6, including, for example, not less than about ◎ 6_5, 7 or 8 (eg, about 8) » also by adding, for example, glycerol A suitable tonicity adjusting agent is used to make the composition is isotonic with blood. In some embodiments, the composition is suitable for administration to a human. There are a number of suitable formulations of the present invention, and are disclosed in U.S. Patent Nos. 5,916,596 and 6, <RTIgt; The following formulations and methods are merely illustrative and are in no way limiting. Formulations suitable for oral administration may comprise (a) a liquid solution, such as an effective amount of a compound dissolved in a diluent such as water, physiological saline or orange juice, capsules, sachets or lozenges each containing a predetermined amount of activity Ingredients, solid 134531.doc •63· 200942233 in bulk or granular form, electric a) suitable liquid suspension, (4) suitable emulsion, m dosage form may include lactose, mannitol, corn house powder, starch, micro Crystalline cellulose, gum arabic, gelatin, colloidal dioxide cross-linked m-methylcellulose sodium, talc, magnesium stearate, stearic acid, and other excipients, label &amp; ash, thinner, buffer One or more of humectants, preservatives, flavoring agents, and pharmacologically compatible excipients. The mouth-containing form of the sword may be included in the active ingredients of the flavoring agent (usually sucrose and arabin or scutellaria) and the active ingredients contained in an inert matrix such as gelatin and glycerin or glaucous or gum arabic. Tablets, in addition to the active ingredient, contain emulsions, gels and the like of the excipients known in the art. The nanoparticle of the present invention may be encapsulated in a hard or soft capsule, may be compressed into a suspect&apos; or may be combined with a beverage or food or otherwise incorporated into a snack. The capsules can be formulated by mixing the nanoparticles with an inert pharmaceutical diluent and inserting the mixture into a hard capsule of appropriate particle size. If a soft capsule is desired, the nanoparticle can be encapsulated in a capsule with an acceptable slurry of vegetable oil, light petroleum or other inert oil. Formulations suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injectable solutions which contain antioxidants, buffers, bacteriostatic agents, and solutes which are compatible with the intended recipient's blood, • An aqueous and non-aqueous sterile suspension which may include suspending agents, solubilizing agents, thickening agents, stabilizers and preservatives. Formulations may be presented in single or multiple dose sealed containers (such as ampoules and vials) and may be stored under lyophilized (lyophilized) conditions, with the exception of the use of sterile liquid excipients for injection (ie, Water) for use in the methods of administration described herein as the method of administration and dosing regimen. I34531.doc 200942233 Ready-to-use injection solutions and suspensions can be prepared from sterile powders, granules and lozenges of the type previously described. Injectable formulations are preferred. The invention also includes a hydrophobic taxane derivative suitable for administration by inhalation for use in the method of the invention (e.g., in compounds 1, 2, 3-23)

A formulation of a nanoparticle composition of any and any of the formulae, π, m, IV, V or VI compounds) and a carrier. Formulations suitable for aerosol administration comprise a composition of the invention comprising an aqueous and non-aqueous isotonic sterile solution which may contain antioxidants, buffers, bacteriostats and solutes; and aqueous and non-aqueous sterile Suspensions 'which may include suspending agents, solubilizers, stabilizers, and preservatives, alone or in combination with other suitable ingredients which may be formulated as an aerosol formulation to be administered by inhalation. Such aerosol formulations can be placed in pressurized acceptable propellants such as di-dioxane, propane, nitrogen and the like. It can also be formulated into pharmaceutical preparations for use in non-pressurized formulations, such as in a spray or atomizer. The invention also includes formulations of nanoparticles for administration as a suppository for rectal administration. Such formulations may be prepared by mixing the agent with a suitable (tetra) excimer which is liquid at room temperature but liquid at the rectal temperature and which will therefore melt in the rectum to release the drug. These (4) include fat, beeswax and polyethylene glycol. It also includes the formulation of the nanoparticle composition for topical administration, in particular, the therapeutic target includes each of the diseases which can be easily accessed by topical application, the skin of the intestines, and the intestinal tract. A suitable topical formulation is prepared. Topical application to the lower intestinal tract can be accomplished in the form of a rectal suppository formulation (see above) 134531.doc-65-200942233 or a suitable enema formulation. Local transdermal patches can also be used. Unit dosage forms comprising the compositions and formulations described herein are also provided. These unit dosage forms can be stored in a suitable package in single or multiple unit dosages and can be further sterilized and sealed. For example, a pharmaceutical composition (eg, a dosage form or unit dosage form of a pharmaceutical composition) can include (1) a hydrophobic taxane derivative (eg, any of compounds 1, 2, 3-23, and any formula I, II, III) , IV, ¥ or ¥1 compound) and carrier protein nanoparticle and (H) pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions also include one or more other compounds (or pharmaceutically acceptable salts thereof) useful for treating cancer. In various variations, the amount of hydrophobic taxane derivative in the composition is included in any of the following ranges: from about 5 to about 50 mg, from about 20 to about 50 mg, from about 50 to about 1 Torr. 〇mg, from about 1 〇〇 to about 125 mg, from about 125 to about 150 mg, from about 150 to about 175 mg, from about 175 to about 200 mg, from about 200 to about 225 mg, from about 225 to about 250 mg, from about 250 to About 300 mg, from about 300 to about 350 mg, from about 350 to about 4 mg, from about 400 to about 450 mg, or from about 450 to about 500 mg. In some embodiments, the composition (eg, dosage form or unit dosage form) The amount of hydrophobic taxane derivative in the range of from about 5 mg to about 500 mg, such as from about 3 mg to about 300 mg or from about 50 mg to about 200 mg of the derivative. In some embodiments, the carrier is suitable for parenteral administration (e.g., intravenous administration). In some embodiments, the hydrophobic taxane derivative is the sole pharmaceutically active agent for treating cancer contained in the composition. In some embodiments, the invention provides a dosage form (e.g., a unit dosage form) for treating cancer, the dosage form comprising (1) a carrier protein and a hydrophobic derivative of yam 134531.doc-66-200942233 (e.g., compound i, 2) a nanoparticle of any one of 3 to 23 and any of the formulas of diterpenoids, oxime, oxime, compound, wherein the amount of the derivative in a unit dose is in the range of from about 5 mg to about 500 mg and is pharmaceutically acceptable Carrier. In some embodiments, the amount of hydrophobic taxane derivative in a unit dosage form comprises from about 30 mg to about 3 mg. Also provided are articles, compositions, and unit dosages described herein that are included in a suitable package for use in the methods of treatment, administration methods, and dosing regimens described herein. Suitable packages of the compositions described herein are known in the art and include, for example, vials (such as sealed vials), containers (such as sealed containers), ampoules, bottles, jars, flexible packages (eg, sealed) Mylar or plastic bags and the like. Such articles may be further sterilized and/or sealed. Kits The present invention also provides kits of the present invention comprising the compositions, formulations, unit doses, and articles described herein for use in the methods of treatment, methods of administration, and dosage regimens described herein. The kit includes one or more containers comprising a nanoparticle composition (formulation or unit dosage form and/or preparation) comprising a hydrophobic taxane derivative, and in some embodiments further comprising a method of treatment according to the description herein Instructions for use of either. In some embodiments, the kit comprises i) comprising a hydrophobic taxane derivative (eg, any of compounds 1, 2, 3-23, and any compound of formula I, n, m, iv, oxime or VI) And a composition of nanoparticles of a carrier protein (such as albumin) and ii) instructions for the simultaneous and/or sequential administration of such nanoparticles and chemotherapeutic agents for the treatment of cancer. The amount of hydrophobic purple 134531.doc-67·200942233 cedar derivative in the 'set of the various variations is included in any of the following ranges: from about 5 to about 20 mg, from about 20 to about 50 mg From about 50 to about 100 mg, from about 100 to about 125 mg, from about 125 to about 150 mg, from about 150 to about 175 mg, from about 175 to about 200 mg, from about 200 to about 225 mg, from about 225 to about 250 mg, From about 250 to about 300 mg, from about 300 to about 350 mg, from about 350 to about 400 mg, from about 400 to about 450 mg, or from about 450 to about 500 mg. In some embodiments, the amount of hydrophobic taxane derivative in the kit ranges from about 5 mg to about 5 mg, such as from about 30 mg to about 300 mg or from about 50 mg to about 200 mg. In some embodiments the &quot;set includes one or more other compounds useful in cancer (i.e., one or more compounds other than hydrophobic taxane derivatives). The instructions provided in the kit of the present invention are generally instructions written on a label or package insert (such as a sheet of paper included in a kit), but the machine readable instructions (eg, on a storage disk or a disc) Instructions) are also acceptable. Instructions for the use of the nanoparticulate composition generally include information regarding the dosage of the intended treatment, the time course of administration, and the route of administration. The kit may further include a description of the individual selected for treatment or treatment. The invention also provides kits comprising the compositions (or unit dosage forms and/or articles) described herein and which may further comprise instructions for the use of such compositions, such as those described further herein. In some embodiments, the kit of the present invention comprises the above package. In other variations, the kit of the present invention comprises the above package and a second package comprising a buffer. Other steps may include other materials that are desirable from a commercial and user standpoint, including other buffers 'diluents, filters, needles, syringes, and package inserts for instructions for performing any of the methods described herein. 134531.doc -68- 200942233 十; Combination therapy of the present invention, the kit may contain instructions for simultaneous and/or sequential administration of the first--therapy for effective treatment of cancer. The first and beta therapies may be present in separate containers or in a single container. It is to be understood that the kit may be composed of three unique compositions or one or two or more of the compositions constituting the first and the second composition.

G ❹ 々 may also provide a sufficient dose of the hydrophobic yew as disclosed herein to provide the individual with a longer period of time (such as week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, A set of effective treatments for any of 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, or longer. The kit may also include a plurality of unit doses of the hydrophobic taxane derivative compositions, pharmaceutical compositions and formulations described herein and instructions for use and storage and use in a pharmacy such as a hospital pharmacy and a pharmaceutical office. f to package. In some embodiments, the kit comprises reconstitutable, resuspended or rehydrated to generally form a navel comprising hydrophobic yew (iv) organisms and albumin (eg, albumin coated hydrophobic yew yard derivatives) A dry (e.g., lyophilized) composition of a stable aqueous suspension of rice granules. The kit of the present invention is in a suitable package. Suitable packages include, but are not limited to, small bottles, bottles, jars, flexible packages (e.g., sealed Myra or plastic bags), and the like. The kit may provide additional components, such as buffers and descriptive information, as appropriate. &amp; $ Method of Making Nanoparticle Compositions Manufacturing methods containing carrier proteins and poor water solubility are known in the art. For example, the formula of the composition of the agent and the carrier protein (such as albumin) 3 have poor water solubility of the medical water-free particles can be in the high shear force of the strip 134531.doc • 69- 200942233 (for example, ultrasonic Prepared under treatment, high pressure homogenization, etc.). Such methods are disclosed, for example, in U.S. Patent Nos. 5,916,596, 6, 6, 96, ???, 6, 749, 868, and 6, 537, 579, and PCT Application Publication No. 98/14174, No. WO99/00113, No. W007/ 027941 and W007/027819. Briefly, a hydrophobic taxane derivative (e.g., a hydrophobic European paclitaxel derivative) is dissolved in an organic solvent. Suitable organic solvents include, for example, ketones, esters, ethers, gasification solvents, and other solvents known in the art. For example, the 'organic solvent can be dioxane, gas/ethanol or gasoline/butanol (for example, having about 1:9, 1:8, 1:7, 1:6, 1:5, 1) Ratio of any of: 4, 1, 2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or 9:1 'Or have any of about 3:7, 5:7, 4:6, 5:5, 6:5, 8.5, 9.5, 9.5.5, 5.3, 7:3, 6:4 or 9.5:0.5 Ratio). The solution is added to a carrier protein (eg, human serum albumin). High pressure homogenization of the mixture (eg using Avestin, APV Gaulin,

MicrofluidizerTM, such as from Microfluidics, Stansted

MicrofluidizeiTM Processor M-110EH or Ultra Turrax Homogenizer) 0 allows the emulsion to circulate through the high pressure homogenizer for from about 2 to about 100 cycles, such as from about 5 to about 50 cycles or from about 8 to about 20 Loop (eg, any of about 8, 10, 12, 14, 16, 18, or 20 cycles). The organic solvent can then be removed by utilizing suitable equipment known for this purpose, including but not limited to rotary evaporators, falling film evaporators, scraping that can be operated in batch mode or continuous operation Membrane evaporators, spray dryers and the like. The solvent can be under reduced pressure (such as about 25 mm Hg, 30 mm Hg, 40 134531.doc -70. 200942233 mm Hg, 50 mm Hg, 100 mm Hg, 200 mm Hg or 300 mm

Remove any of Hg). The length of time for removing the solvent under reduced pressure can be adjusted based on the volume of the formulation. For example, a formulation made on a 3 〇〇 mL scale can have a solvent of from about 1 to about 3 mm Hg (eg, about 5-100 mm Hg, 10-50 mm Hg, 20-40 mm Hg, or 25). Any of mm Hg) lasts from about 5 to about 60 minutes (eg, about 7, 8, 9, i, u, 12, 13, 14, 15, 16, 18, 20, 25, or 30 minutes) )) to remove. The obtained dispersion can be further lyophilized. If desired, a human albumin solution can be added to the dispersion to adjust the ratio of human serum albumin to hydrophobic taxane derivative or to adjust the concentration of the hydrophobic taxane derivative in the dispersion. For example, a human serum albumin solution (eg, 25% w/v) can be added to modulate human serum albumin with a hydrophobic taxane derivative (eg, any of Compounds 1, 2, 3-23, and any The ratio of the compound of formula I, Η, III, IV, V or VI) to about ι 8:1, 15:1 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8 :1, 7.5:1, 7:1, 6:1, 5:1, 4:1 or 3:1. For example, a human serum albumin solution (eg 25% w/v) or another solution is added to adjust the concentration of the hydrophobic taxane derivative in the dispersion to about 〇.5 mg/mi, 1.3 mg/ml , 1.5 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml , 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 40 mg/ml or mg/mL. The dispersion can be continuously passed through a plurality of filters such as a combination of 1.2 μm and 0.8/0.2 μη filters, 1, 2 μm, 〇8 μηη, 0.45 μηη, and 0.22 μιη filters, or is known in the art. 134531.doc -71 - 200942233 = Any other combination of instruments. The obtained dispersion can be manufactured into a nanoparticle composition by a knife method or a continuous process (e.g., mass production of the composition). . If desired, the composition may also include a second therapy (e.g., one or more compounds; / alpha therapeutic cancer compound), an antimicrobial agent, a sugar, and/or a stabilizer. The additional agent may be mixed with the hydrophobic taxane derivative and/or the carrier protein during the preparation of the hydrophobic taxane derivative/carrier protein composition, or may be used to prepare a hydrophobic taxane derivative/carrier protein composition. Thereafter added: In some embodiments, the agent is mixed with the hydrophobic yew-element derivative/carrier protein composition prior to stem drying. In some embodiments, the agent is added to the lyophilized hydrophobic taxane derivative/carrier protein composition. In the second embodiment, when the addition of the agent changes the pH of the composition, it is not (but not necessarily Adjusting the pH of the composition to the desired pH" The exemplary pH of the sigma includes, for example, from about 5 to about 85. In some embodiments, the pH of the composition is adjusted to not less than about 6 〇 includes, for example, any of not less than about 6.5, 7 or 8 (e.g., about 8). Hydrophobic taxane derivatives (e.g., compound 1, 2 are provided in some embodiments of the month of the month). An emulsion of any of 3_23 and any of the compounds n, m, ιν, v or νι), the emulsion comprising: (a) comprising an organic solvent soluble in a hydrophobic taxane derivative and a hydrophobic yew a first phase of a nanodroplet of at least a portion of the hydrophobic taxane derivative, and (b) a second phase comprising water and a biocompatible polymer, wherein the emulsion is substantially absent Containing a surfactant. Method for producing a hydrophobic yew derivative 134531.doc -72- 200942233 The hydrophobic taxane derivatives of the present invention are synthesized by a suitable combination of generally known synthetic methods. Techniques for synthesizing the compounds of the present invention are apparent to those skilled in the art and are readily available, particularly in this context. The teachings of the description provide the following discussion to illustrate some of the various methods that can be used to assemble the compounds of the present invention. However, this discussion is not intended to define the scope of the reaction or reaction sequence used to prepare the compounds of the present invention, nor is it intended to The scope of the compounds themselves is defined. The synthesis of some of the compounds used in the present invention is disclosed in WO 2006/089207, which is hereby incorporated by reference in its entirety in its entirety in its entirety in its entirety in Some of the hydrophobic taxane derivatives can be synthesized by altering the 2,-hydroxyl group of the taxane as shown in Scheme 1. About one equivalent of reactive hydrophobic group in the presence of a base such as triethylamine or pyridine Treatment of the taxane (e.g., taxol), such as a benzylic tooth, such as benzamidine, provides the desired hydrophobic taxane derivative. Alternatively, about one equivalent of a reactive hydrophobic group (e.g., benzene) in the presence of a coupling agent (e.g., dicyclohexylcarbodiimide) Q and optionally a catalytic amount of pyrrolidinium pyridine or 4-dimethylaminopyridine. Treatment of the taxane with formic acid provides the desired hydrophobic taxane derivative (for example, 2·_benzimidyl taxol) shown in Scheme i.

134531.doc 73· 200942233 Some of the hydrophobic taxane derivatives used in the present invention can be synthesized by changing the position of the taxane 7 as shown in Scheme 2, and are novel functional groups which introduce a hydrophobic group at the 7 position. The protective group can block the reactivity of the 2,_hydroxyl group of the taxane. A selective protecting group such as triethylsulfanyl can be used because it is easily removed from the 2'-hydroxyl group by treatment with an acid such as hydrochloric acid in decyl alcohol or hydrofluoric acid in 0 pyridine. Therefore, as shown in Scheme 2, after about one equivalent of triethyl decane (TESCl^S yew 6 (for example, European paclitaxel) in the presence of a base such as triethylamine (TEA) or pyridine, it can be produced well. The rate provides 2'. protected hydroxy taxane (eg 2,-triethyldecyl-pacific paclitaxel). Alternatively, other protecting groups such as 2,2,2-trisethyl-oxycarbonyl derivatives may also be used. And then removing the protecting groups by treatment with zinc and an acid such as acetic acid. The taxane containing the 2'-protected hydroxyl group can then be contacted with a reactive hydrophobic group as described herein (eg, in a bicyclic ring a hexylcarbodiimide and a catalytic amount of 4_pyrrolidinium pyridine or benzoic acid in the presence of 4-dimethylaminopyridine to produce a hydrophobic taxane derivative in which the oxime is changed at the 7 position. The protecting hydroxyl group (e.g., 2-diethyldecyl) can be readily released by removal of a protecting group (e.g., under moderately acidic conditions) to yield the desired product.

134531.doc -74· 200942233

Some of the hydrophobic taxane derivatives used in the present invention can be synthesized by changing the position of the taxane 10 as shown in Scheme 3. To introduce a novel functional group of a hydrophobic group at the 10 position, the protecting group can block the reactivity of the 21-hydroxyl group and the 7-hydroxyl group of the taxane. The taxane is treated with about two equivalents of a suitable protecting group (e.g., chlorotriethyl decane (TESC1)) in the presence of a base such as pyridine (e.g., Europe)

After paclitaxel), a double-protected taxane (e.g., 2',7-bis(triethyldecyl)pacific paclitaxel) can be produced. The protected taxane is contacted with a reactive hydrophobic group as described herein (eg, benzoquinone/pyridine in the presence of dicyclohexylcarbodiimide and a catalytic amount of 4-dimethylaminopyridine or In the case of benzoic acid), the desired 10-deuterated product (e.g., 10-deuterated) is obtained, and two protecting groups can be readily removed from the product (e.g., under moderately acidic conditions). Process 3:

By the availability of 2'-protected taxanes and 7-protected taxanes, different functional groups can be used (eg esters, carbonates, amine phthalates and their classes 134531.doc -75· 200942233) A further change in the thiol-functional group at the 10 position is accomplished by attachment of a hydrophobic group and a taxane. According to one embodiment of the invention, a hydrophobic group such as a phenylhydrazine group can be combined with virtually any pharmaceutical compound or diagnostic agent formulated and used in accordance with the methods of the present invention. Pharmaceutical agents include the following categories and specific examples. It is not desirable for a category to be limited by a specific instance. Those skilled in the art will recognize many other compounds that are within the classes and that can be used in accordance with the present invention in light of the teachings provided herein. The invention also includes products made by the methods described herein. Method for Measuring Anticancer Activity The anticancer activity of a hydrophobic taxane derivative or a nanoparticle composition containing a hydrophobic taxane derivative can be, for example, by cultivating a cancer cell culture together with a derivative, The cell growth inhibition in the culture was then assessed for in vitro testing. Suitable cells for this test include murine P388 leukemia cells, B16 melanoma cells and Lewis lung cancer cells, as well as human breast MCF7, Indian OVCAR_3, A549 lung cancer cells, Μχι (human breast tumor cells), HT29 (colon cancer cell lines). ), HepG2 (hepatoma cell line) and HCT116 (colon cancer cell line). Alternatively, a hydrophobic taxane derivative (or a composition comprising a hydrophobic taxane derivative) can be tested in vivo for anticancer activity, for example, by first establishing a tumor in a suitable test animal (eg, a nude mouse). . Cells suitable for establishing tumors include those described above for in vitro testing and other cells commonly accepted in the art for establishing tumors. Subsequently, the taxane derivative is administered to the animal; then the ee &gt; 5g value, i.e., the amount of derivative (or 134531.doc -76 - 200942233 composition) required to achieve 50% inhibition of tumor growth in the animal, is determined. Also determining the survival rate β is generally familiar to those skilled in the art in view of the teachings described herein, and is fully capable of being based on, for example, Eh. And the factor of the survival value selects a specific hydrophobic taxane derivative (or a composition containing a hydrophobic taxane derivative) for use against certain cancers. Therapeutic Methods The nanoparticle compositions of the present invention are useful for treating diseases associated with cell proliferation or hyperproliferation, such as cancer. In some embodiments, a method of treating a proliferative disease (eg, cancer) in an individual comprising administering to the individual an effective amount of a composition comprising nanoparticle, wherein the nanoparticle comprises a hydrophobic taxane derivative (eg, a compound) Any of 丨, 2, 3_23 and any of the compounds of Formulas I, II, III, IV, V*VI) and a carrier protein (eg, albumin). Examples of cancers that can be treated by the methods of the invention include, but are not limited to, multiple myeloma, renal cell carcinoma, prostate cancer, lung cancer, melanoma, colon cancer, colorectal cancer, ovarian cancer, liver cancer, kidney cancer, gastric cancer And breast cancer. An individual undergoing treatment for a proliferative disease in - some variations has been identified as having one or more of the conditions described herein. The identification of a condition as described herein by a skilled physician is routine in the art (eg, via blood tests, X-rays, CT scans, endoscopy, biopsy, etc.) and may also be inferred by an individual or other person. For example, due to tumor growth, bleeding, ulcers, pain, enlarged lymph nodes, cough, jaundice, swelling, weight loss, cachexia, sweating, anemia, paraneoplastic phenomenon, thrombosis, and the like. In some embodiments, the individual has been determined to be susceptible to one or more of the conditions as described herein. The individual's susceptibility may be based on any one or more of a number of risk factors and/or diagnostic methods known to those skilled in the art, including, but not limited to, genetic profiles, family history, medical records. (eg the occurrence of related conditions), lifestyle or habits. In some embodiments, the methods and/or compositions are alleviated as compared to corresponding symptoms of the same individual prior to treatment or compared to corresponding symptoms of other individuals not receiving the methods and/or compositions used herein. The severity of one or more symptoms associated with a proliferative disease (eg, cancer) is at least about (four), 20%, 3G%, 4G%, 5G%, 嶋, 7 ()%, 8 ()%, 9%, V 95% or 100% either. Combination Therapy In some embodiments, the present invention provides a method of treating cancer in an individual by administering a combination of an effective amount of the individual, the combination having a) a first therapy comprising a composition comprising nanoparticle, the nano The particles comprise rapamycin or a derivative thereof and a carrier protein (such as albumin), and ... can be used in the treatment of cancer as a second therapy. In some embodiments, the second therapy package includes surgery, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormone therapy, targeted therapy, cryotherapy, ultrasound therapy, photodynamic therapy, and/or chemistry Therapy (eg one or more compounds that can be used to treat cancer). It is to be understood that the methods of treating cancer as mentioned and described below are exemplary, and the description is equally applicable to methods of treating cancer using combination therapies and methods of treating cancer using combination therapies. Administration and Administration Methods The amount of the compositions of the present invention administered to an individual, such as a human, can vary depending on the particular composition, method of administration, and the particular type of recurrent cancer being treated. The amount of 134531.doc -78- 200942233 should be sufficient to produce the desired beneficial effect. For example, in some embodiments, the amount of the composition is effective to produce an objective response (such as a partial reaction or a complete reaction). In some embodiments, the hydrophobic taxane derivative nanoparticle composition is in an amount sufficient to produce a complete response in the individual. In some embodiments, the amount of the composition is sufficient to cause a partial response to the individual. In some embodiments, the amount of the composition administered alone is sufficient to produce a total response rate of greater than about 40%, 50%, 60%, or 64% in the population of individuals receiving the composition. The response of an individual to the treatment of the methods described herein can be determined, for example, by a rating of RECIST or CA-125. For example, when CA-125 is used, a complete response can be defined as returning from a pre-treatment value to a normal range value for at least 28 days. Local reactions can be defined as a continuous reduction of more than 50% from pre-treatment values. In some embodiments, the amount of hydrophobic taxane derivative nanoparticle composition is sufficient to prolong disease-free survival of the individual (e.g., to measure changes in RECIST or CA-125). In some embodiments, the amount of the composition is sufficient to prolong the overall survival of the individual. In some embodiments, the amount of the composition is sufficient to be

G The clinical benefit of producing more than about 50%, 60%, 70%, or 77°/〇 in a population of individuals treated with the composition. In some embodiments, the amount of hydrophobic taxane derivative in the composition is lower than the level that causes the toxicological effect (ie, above the clinically acceptable level of toxicity) or is in the composition of the individual The potential side effects can be controlled or tolerated. In some embodiments, the amount of the composition is approximately the maximum tolerated dose (MTD) of the composition following the same dosage regimen. In some embodiments, the amount of the composition is greater than about 80%, 90%, 134531.doc • 79-200942233 95% or 98% of the MTD. In some embodiments, the amount of the composition is compared to the corresponding tumor 'size, number of cancer cells, or tumor growth rate of the same subject prior to treatment or to the corresponding activity of other subjects not receiving treatment, Sufficient to reduce tumor size, reduce the number of cancer cells or reduce the rate of tumor growth by at least about i 〇 0 /. 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%/〇 The amount of any one of 100〇/〇. Standard methods can be used to measure the magnitude of this effect, such as in vitro assays using purified enzymes, cell-based assays,

A ^ animal model or human test. In some embodiments, the amount of hydrophobic taxane derivative in the composition is included in any of the following ranges: from about 0.5 to about 5 mg, from about 5 to about 10 mg, from about 10 to about 15 mg. , from about 15 to about 20 mg, from about 20 to about 25 mg, from about 20 to about 50 mg, from about 25 to about 50 mg, from about 50 to about 75 mg, from about 50 to about 100 mg, from about 75 to about 100 mg, From about 1 to about 125 mg, from about 125 to about 150 mg, from about 150 to about 175 mg, from about 175 to about 200 q mg, from about 200 to about 225 mg, from about 225 to about 250 mg, from about 250 to about 300 Mg, from about 300 to about 350 mg, from about 350 to about 400 mg, from about 400 to about 450 mg, or from about 450 to about 500 mg. In some embodiments, the amount of hydrophobic taxane derivative in an effective amount of the composition (eg, unit dosage form) is in the range of from about 5 mg to about 500 mg, such as from about 3 mg to about 300 mg or about 50 mg to about 200 mg. In some embodiments, the concentration of the hydrophobic taxane derivative in the composition is relatively dilute (about 1 mg/ml) or more concentrated (about 1 〇〇 mg/ml) 'including, for example, about 〇丨 to About 5 mg/ml, about 0.1 to about 20 mg/ml, about 1 to about 1 mg/nU, about 2 mg/ml to about 8 mg/ml, about 134531.doc • 80-200942233 4 to Any of about 6 mg/ml and about 5 mg/ml. In some embodiments, the concentration of the hydrophobic taxane derivative is at least about 〇5 mg/mi, u mg/ml, 1.5 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 Mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, l〇mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, Any of 4 〇 mg/ml or 50 mg/ml. Exemplary effective amounts of hydrophobic taxane derivatives in the nanoparticulate composition include, but are not limited to, about 25 mg/m2, 30 mg/m2, 50 mg/m2, 60 mg/m, 75 mg/m , 80 mg/m2, 90 mg/m2, 100 mg/m2, 120 mg/m2, 160 mg/m2, 175 mg/m2, 180 mg/m2, 200 mg/m2, 210 mg/m2, 220 mg/m2 250 mg/m2, 260 mg/m2, 300 mg/m2, 350 mg/m2, 400 mg/m2, 500 mg/m2, 540 mg/m2, 750 mg/m2, 1000 mg/m2 or 1080 mg/m2 A hydrophobic taxane derivative of either of them. In various variations, the composition includes less than about 350 mg/m2, 300 mg/m2, 250 ❿ mg/m2, 200 mg/m2, 150 mg/m2, 120 mg/m2, 1 〇〇mg/m2, 90. A hydrophobic taxane derivative of any of mg/m2, 50 mg/m2 or 30 mg/m2. In some embodiments, the amount of hydrophobic taxane derivative administered per time is less than about 25 mg/m2, 22 mg/m2, 20 mg/m2, 18 mg/m2, 15 mg/m2, 14 mg/ M2, 13 mg/m2, 12 mg/m2, 11 mg/m2, 10 mg/m2, 9 mg/m2, 8 mg/in2, 7 mg/m2 &gt; 6 mg/m2 '5 mg/m2 ' 4 mg /m2 ' 3 mg/m2 'either 2 mg/m2 or 1 mg/m2. In some embodiments, the effective amount of the hydrophobic taxane derivative in the composition is included in any of the following ranges: 134531.doc -81 - 200942233

❹ Medium: from about 1 to about 5 mg/m2, from about 5 to about 10 mg/m2, from about 10 to about 25 mg/m2, from about 25 to about 50 mg/m2, from about 50 to about 75 mg/m2, about 75 Up to about 100 mg/m2, from about 100 to about 125 mg/m2, from about 125 to about 15 mg/m2, from about 150 to about 175 mg/m2, from about 175 to about 200 mg/m2, from about 200 to about 225 mg /m2, from about 225 to about 250 mg/m2, from about 250 to about 300 mg/m2, from about 300 to about 350 mg/m2, or from about 350 to about 400 mg/m2. Preferably, the effective amount of the hydrophobic taxane derivative in the composition is from about 5 to about 300 mg/m2, such as from about 1 to about 150 mg/m2, about 120 mg/m2, about 130 mg/ M2, or about 140 mg/m2. In some embodiments of any of the above aspects, the effective amount of the hydrophobic yew-burning organism in the composition comprises at least about 1 mg/kg, 2.5 mg/kg, 3.5 mg/kg, 5 mg/kg, 6.5 mg. /kg,.. 7.5 mg/kg, 10 mg/kg, 15 mg/kg or 20 mg/kg. The effective amount of the hydrophobic taxane derivative in the composition in various variations. Includes less than about 35 mg/kg, 300 mg/kg, 250 mg/kg, 200 mg/kg, 150 mg/kg, 100 mg/kg, 50 mg/kg, 25 mg/kg, 20 mg/kg, 10 A hydrophobic taxane derivative of any of mg/kg, 7.5 mg/kg, 6.5 mg/kg, 5 mg/kg, 3.5 mg/kg, 2.5 mg/kg or 1 mg/kg. Exemplary dosing frequencies include, but are not limited to, uninterrupted once a week, four weeks in a week, once every three weeks, once every two weeks, two weeks in two weeks, or one of two weeks in a week . In some embodiments, the composition is applied approximately every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks, or every 8 weeks, in some embodiments, the composition is at least about once a week, 2 - person, 3-, 4, 5, 6 or 7 (ie once a day) 134531.doc -82- 200942233 vote. In some embodiments, the interval between 6 months, 3 months, _: human and is less than about 8 days, 7 days, 6 days, 5 days, 4 days, 12 days, 1 day (&gt; day, 9 Day, in some embodiments, any of 2 or 1 day of the month. Month, 2 months, 3 months: The time interval between doses is greater than about any of the months! January 5 months, 6 months, 8 months or 12 ❹

G In some embodiments, each "column" is uninterrupted during the administration schedule. Weeks. Each: the time interval between human administrations does not exceed about one. For example, about one month of straight years. In some embodiments, up to about seven, the composition is at least about 2, 7 , 8 , 9 , 1 , U , ^ 4 5 ' 6 ' 2 , 18 , 24 , 30 , In any of the 36, 48, 6 〇 84 months, 庐 72 or slave. In some embodiments, the alkane derivative is at least about one week apart and at least one week apart, and t] . . . _ and wherein each of the hydrophobic taxane derivatives administered is from about 〜m2 to about 75 mg/m2, such as from about 25 mg/m to about 25 mg/m2 or from about 25 mg/m2 to about 5 mg. /m2. In one embodiment, the dose of the hydrophobic taxane derivative in the nanoparticulate composition can be in the range of 5 to 4 in the range of 5 to 4 in the course of 3 weeks' or The weekly-secondary time administration can be exemplified in the range of 5 rhyme 2. The amount of the hydrophobic taxane derivative is from about 60 to about 300 mg/m2 (for example, about 260 mg/m2). Combined with nanoparticle Other exemplary time courses for administration (eg, hydrophobic taxane derivative/albumin nanoparticle composition) include, but are not limited to, 100 mg/m2 once a week, 3 weeks per week for 3 weeks. Weekly 75 134531.doc -83- 200942233 mg/m2, once every week for 3 weeks in 4 weeks, 1〇〇mg/m2, 3 weeks in 4 weeks, once a week U5 mg/m2, 3 weeks, 2 weeks, once a week 125 mg/m2, uninterrupted 130 mg/m2 per week, 175 mg/m2 every 2 weeks, 260 mg/m2 every 2 weeks, 260 mg/m2 every 3 weeks, 180-300 every 3 weeks Mg/m2, without interruption, 6〇-丨75 mg/m2 twice a week, 20-150 mg/m2 twice a week, and 150-250 mg/m2 twice a week. The frequency of the drug can be adjusted during the course of treatment based on the judgment of the administering physician.

The compositions described herein can infuse the composition into an individual within an infusion time of less than about 24 hours. For example, in some embodiments the composition is in any of less than about 24 hours, 12 hours, 8 hours, 5 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 2 minutes, or 1 minute. Invested in the period of the loss of the village. In some embodiments, the composition is administered during an infusion period of about 3 minutes. In some embodiments, the invention provides a nanoparticle comprising a hydrophobic taxane derivative and a carrier protein (eg, albumin, such as human serum albumin) in an amount effective by parenteral administration to an individual (eg, a human) A method of treating a cancer of an individual with a composition of particles. The present invention also provides an effective amount of a carrier protein containing a hydrophobic taxane derivative by intramuscular, intramuscular, subcutaneous, inhalation, oral, intraperitoneal, nasal or intratracheal administration to an individual (for example, a human). A method of treating a cancer of an individual by a nanoparticle H of (for example, albumin, such as human serum albumin). In some embodiments, the route of administration is intraperitoneal. In some embodiments, the route of administration is intravenous, intraarterial, intramuscular, or subcutaneous. In various variations, about 5 to about (four) per dose is called 'such as from about 3 〇 mg to about 3 〇〇 mg or from about 50 to about 134531. doc - 84 - 200942233. In some embodiments, hydrophobic The only pharmaceutical active 500 mg hydrophobic taxane derivative for the treatment of cancer. The taxane derivative is a sexual agent included in the composition. Any of the compositions described herein may include, for example, intravenous, intraarterial, intraperitoneal, intrapulmonary, inhalation, intravesicular, intramuscular, intratracheal, subcutaneous, ocular. Involvement of individuals (such as humans) in various ways, including internal, sheath, inward, transmucosal, and transdermal. In one embodiment 4. ^ ^ ^ - in the examples, the composition can be used

Continuous continuous release of the formulation. In a variation of the invention, the nanoparticles of the compounds of the invention (such as albumin nanoparticles) may be accepted by any means including, but not limited to, orally, intramuscularly, transdermally, intravenously. The route is administered via an inhaler or other empty sputum delivery system and its analogues. 0. Nanoparticles containing hydrophobic yew-burning derivatives and 笫-# people t first treatment together Cast. The frequency of administration of the group and the compound can be adjusted based on the judgment of the administration doctor during the treatment. In some embodiments, the first and second therapies are concurrently administered in parallel. When administered separately, the composition containing the hydrophobic yew/dimethoate and the second compound can be administered at different administration rates J time intervals. For example, the composition can be administered once a week, while the first compound can be administered at a frequency of .... In some embodiments, the nanoparticles and/or the ligands and devices of the hydrophobic yew-staining derivative are known in the art as a combination of configurations. Using the drug described in this article 134531.doc -85- 200942233

The invention also provides a beat-type treatment regimen for any of the methods of treatment and methods of administration described herein. A variation of the use of the exemplary beat regimen and the beat regimen is discussed below and is disclosed in US Pat. Such schemes as described in paragraphs [0138] through [〇157], which are incorporated herein by reference in their entirety. In some embodiments, the nanoparticulate composition is administered for at least one month, wherein the time interval between each administration is no more than about one week, and wherein the dose of the hydrophobic taxane derivative administered each time is administered It is about 25% to about 25% of the maximum tolerated dose for conventional dosing regimens. In some embodiments, the nanoparticle composition is administered over at least two months, wherein the time interval between each administration is no more than about one week, and wherein the dose of the hydrophobic taxane derivative administered each time is administered For example, from about 1% to about 20% of the maximum tolerated dose of a conventional dosing regimen. In some embodiments, the dose of the hydrophobic taxane derivative administered each time is less than about 25% of the maximum tolerated dose. , 24%, Μ%, 12%, ιι〇/0, 1〇0/〇, 22%, 20%, 18%, 15%, 14%, 130/〇9%, 8〇/〇, 7〇/ 〇, 6〇/〇, 5〇/〇, 4〇/〇, 3〇/〇, 2% or 1%. In some embodiments, any nanoparticle composition is administered at least about one week, two times, three times, four times, five times, six times, or seven times (i.e., once daily). In some embodiments, the time interval between each administration is less than about 6 months, 3 months, 1 month, 20 days, μ

丄J mouth, 丄2曰, 1Q 曰, 9曰, 8曰, 7曰, 6 days, any of them. In some embodiments, on the 5th '4th' 3曰, 2曰 or 1曰, the time interval between each administration is 134531.doc -86 - 200942233 in about 1 month, 2 months, 3 , 6 months, 8 compositions in at least 18, 24, 30, months, 4 months, 5 weeks, or 12 months. Month, in some embodiments, about 2, 3, 4, 5, 6, 7, 8〇1 8 , 9 , 10 , 11 , 12 , 36 , 48 , 60 , 72 , or 84 instances in the middle of the month Responsibility

It is an effort to exemplify the invention and thus to describe and detail the examples of the invention discussed above to make an effort to ensure that the numbers used (eg, =, but should be considered - some experimental errors and deviations). Unless: 2) the exact fraction is part by weight, the molecular weight is the weight average molecular weight, = not 'otherwise' and the force is atmospheric or near atmospheric. Celsius Example 1: Instrument 2, - Benzoyl-European paclitaxel (1)

(1) mmol) in dioxane·3〇 mmol), and mix the mixture at room temperature. Add triethylamine to the solution of European paclitaxel (2〇1 mg, 〇25 topography (6 mL) by adding saturated 〇 °C (42 ,, after adding benzoquinone gas (29 this, 〇 · 25 mm 〇 1). After stirring for 2 hours, followed by TLC to indicate the disappearance of the starting material and sodium bicarbonate solution to quench the reaction, the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The product was purified by flash column chromatography (hexane: DCM '1:1) to afford product as a white foam (181 mg, 80%). NMR (CDC13, 500 MHz): δ 8.10 (d, J = 7.5 Hz, 2H), 7.98 (d, J = 7.6 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.50 (t, J=7.9 Hz, 2H), 7.45 (t, J=7.8 Hz, 2H), 7.41-7.36 (m, 4H), 7.29-7.26 (m, 1H), 6.25 (t, J=8.6 Hz, 1H), 5.67 (d, J=7.0 Hz, 1H), 5.58-5.45 (m, 3H), 5.22 (s, 1H), 4.94 (dd, J=9.6, 1.9 Hz, 1H), 4.31 (d, J=8.5 Hz , 1H), 4.27 (dd, J=10.9, 6.6 Hz, 1H), 4.19 (s, 1H), 4.18 (d, J=8.5 Hz, 1H), 3.93 (d, J=6.9 Hz, 1H), 2.60 -2.58 (m, 1H), 2.43 (s, 3H), 2.32-2.25 (m, 1H), 2.17 (s, 3H), 2.15-2.05 (m, 1H), 1.98 (s, 3H), 1.88-1.80 (m, 1H), 1.75 (s , 3H), 1.34 (s, 9H), 1.22 (s, 3H), 1.11 (s, 3H)· ESI-MS: C50H57NO Calculated value of 5Na (M+Na)+: 934, Experimental value: 934. 2: Preparation of 2'-hexyl hydrazine paclitaxel (2)

Add triethylamine (〇95 claws 6 8〇mm〇1) to a solution of European paclitaxel (2.20 g, 2.72 mmol) in di-methane (220 mL) at 0 ° C, followed by the addition of hexose (0.38 mL, 2.72 mmol). The mixture was stirred at (TC for 1.5 hours) followed by TLC to indicate the disappearance of the starting material. After the reaction was quenched by the addition of saturated 134531.doc •88·200942233 sodium bicarbonate solution, the mixture was extracted with dioxane. Washed with brine, dried over anhydrous EtOAc EtOAc EtOAc. Product (2. 〇〇g, 81%) NMR (CDC13, 500 ΜΗζ): δ 8.10 (d, J = 7.3 Hz,

2H), 7.61 (t, J=7.4 Hz, 1H), 7.50 (t, J=7.9 Hz, 2H), 7.38 (t, J=7.4 Hz, 2H), 7.30 (m, 3H), 6.25 (t, J=8.6 Hz, 1H), 5.69 (d, J=7.1 Hz, 1H), 5.46-5.37 (m, 3H), 5.21 (s, 1H), 4.96 (dd, J=7.7, 2.0 Hz, 1H), 4.32 (d, J=8.5 Hz, 1H), 4.27 (dd, J=10.9, 6.6 Hz, 1H), 4.19 (d, J=8.5 Hz, 2H), 3.93 (d, J=7.2 Hz, 1H), 2.60-2.58 (m, 1H), 2.44 (s, 3H), 2.39-2.30 (m, 3H), 2.29-2.20 (m, 1H), 2.07 (s, 3H), 1.96-1.85 (m, 1H), 1.75 (s, 3H), 1.57-1.53 (m, 4H), 1.33 (s, 9H), 1.23 (s, 3H), 1.26-1.17 (m, 4H), \.\2 (s, 3H), 0.85 (t, J = 7.1 Hz, 3H). ESI-MS: calc. Example 3: Preparation of 2'-mercapto-European Taxus (3)

Add triethylamine (134 pL, 0.96 mmol) to a solution of docetaxel (144 mg, 0.18 mmol) in dioxin (10 mL) at 〇 ° C, 134531.doc -89 - 200942233 followed by Helium (37 pL, 0.18 mm〇i). The mixture was allowed to stir for 4.5 hours at 〇〇c. Then TLC indicated the disappearance of the starting material. After the reaction was stopped by adding a saturated sodium hydrogencarbonate solution, the mixture was extracted with dioxane. The organic layer was washed with brine, dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) δ 8.10 (d, J=7.3 Hz, 2H), 7.61 (t, J=7.4 Hz, 1H), 7.50 (t, J=7.9 Hz, 2H), 7.38 (t, J=7.4 Hz, 2H), 7.30 (m, 3H), 6.25 (t, J=8.6 Hz, 1H), 5.69 (d, J=7.1 Hz, 1H), 5.46-5.37 (m, 3H), 5.21 (s, 1H), 4.96 (d, J=7.7 Hz, 1H), 4.32 (d, J=8.5 Hz, 1H), 4.27 (m, 1H), 4.19 (m, 2H), 3.93 (d, J=7.2 Hz, 1H), 2.60-2.58 ( m, 1H), 2.44 (s, 3H), 2.39-2.30 (m, 3H), 2.29-2.20 (m, 1H), 2.07 (s, 3H), 1.96-1.85 (m, 1H), 1.75 (s, 3H), 1.57- 1.45 (m, 4H), 1.33 (s, 9H), 1.23 (s, 3H), 1.26-1.21 (m, 12H), 1.12 (s, 3H), 0.85 (t, J = 7.1 Hz , 3H). Example 4: Preparation of 2'-pentamethylene-European paclitaxel (4)

Add triethylamine (100 pL, 0.72 mmol) to a solution of docetaxel (144 mg, 0.98 mmol) in dioxin (10 mL) at 0. 0 with 134531.doc -90- After 200942233, pentamidine (44 μί ' 0.18 mmol) was added. The mixture was incubated for 5.5 hours at 〇 ° C, followed by TLC indicating the disappearance of the starting material. After the reaction was terminated by adding a saturated sodium hydrogencarbonate solution, the mixture was extracted with a two-gas methane. The organic layer was washed with brine~ dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography eluting with EtOAc EtOAc EtOAc H NMR (CDC13, 500 MHz): δ 8.10 (d, J = 7.3 Hz, ©2H), 7.61 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.9 Hz, 2H), 7.38 (t , J=7.4 Hz, 2H), 7.30 (m, 3H), 6.25 (t, J=8.6 Hz, 1H), 5.69 (d, J=7.1 Hz, 1H), 5.46-5.37 (m, 3H), 5.21 (s, 1H), 4.96 (d, J=7.7 Hz, 1H), 4.32 (d, J=8.5 Hz, 1H), 4.27 (m, 1H), 4.19 (m, 2H), 3.93 (d, J= 7.2 Hz, 1H), 2.60-2.58 (m, 1H), 2.44 (s, 3H), 2.39-2.30 (m, 3H), 2.29-2.20 (m, 1H), 2.04 (s, 3H), 1.96-1.85 (m, 1H), 1.75 (s, 3H), 1.57-1.45 (m, 4H), 1.33 (s, 9H), 1.23 (s, 3H), 1.26-1.21 (m, 2H), 1.12 (s, 3H) ), 0.85 (t, J = 7.1 Hz, 3H). Example 5: Preparation of 2'-propenyl-European paclitaxel (5)

Add triethylamine (1〇〇 from, 0.72 mmol) to a solution of docetaxel (195 mg, 0.24 mmol) in dioxane (10 mL) at 0 C, 134531.doc •91 - 200942233 Propylene gas (20.8 pL, 0·24 mm〇1) was added. The mixture was stirred at 0 °c for 5 hours, then TLC indicated the starting material disappeared. After the reaction was stopped by adding a saturated sodium hydrogen carbonate solution, the mixture was extracted with dioxane. The organic layer was washed with brine, dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc (EtOAc) MHz): δ 8.10 (d, J=7.3 Hz> 2H)&gt; 7.61 (t, J=7.4 Hz, 1H), 7.50 (t, J=7.9 Hz, 2H), 7.38 (t, J=7.4 Hz, 2H), 7.30 (m, 3H), 6.25 (t, J=8.6 Hz, 1H), 5.69 (d, J=7.i Hz, 1H), 5.46-5.37 (m, 3H), 5.21 (s, 1H ), 4.96 (d, J=7.7 Hz, 1H), 4.32 (d, J=8.5 Hz, 1H), 4.27 (m, 1H), 4.19 (m, 2H), 3.93 (d, J=7.2 Hz, 1H ), 2.60-2.58 (m, 1H), 2.44 (s, 3H), 2.39-2.30 (m, 3H), 2.29-2.20 (m, 1H), 2.04 (s, 3H), 1.96-1.85 (m, 1H) ), 1.75 (s, 3H), 1.57- 1.45 (m, 2H), 1.33 (s, 9H), 1.23 (s, 3H), 1.12 (s, 3H), 1.10 (t, J=7.1 Hz, 3H) 〇o Example 6: Preparation of 2,-benzoinyl-pacific paclitaxel (6)

Add triethylamine (104 pL '0.74 mmol) to a solution of docetaxel (5〇2 mg, 〇.62 mmol) in dioxane 134531.doc -92- 200942233 (5 mL) at 〇C. Then benzamidine gas (72 ML, 0.62 mmol) was added. The mixture was stirred at room temperature for 2 hours and the tlc was indicated to indicate the disappearance of the starting material. After the reaction was stopped by adding a saturated sodium hydrogencarbonate solution, the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The residue was purified by EtOAc EtOAc EtOAc (EtOAc) *H NMR (CDC13, 500 MHz): δ 8.10 (d, J = 7.6 Hz, 2H), 7.99 o (d, J = 7.5 Hz, 2H), 7.76 (d, /=7.1 Hz, 2H), 7.62- 7.56 (m, 2H), 7.55-7.39 (m, 13H), 7.32 (d, /=7.1 Hz, 1H), 7.05 (d, /=9.0 Hz, 1H), 6.30 (s, 1H), 6.25 (t , /=8.6 Hz, 1H), 6.04 (dd, J=8.9, 3.8 Hz, 1H)} 5.68 (d, J=3.8 Hz, 1H), 5.67 (d, /=7.6 Hz, 1H), 4.94 (dd , /=9.7, 1.8 Hz, 1H), 4.46 (dd, 7=10.9, 6.6 Hz, 1H), 4.30 (d, J=8.4 Hz, 1H), 4.19 (d, J=8.5 Hz, 1H), 3.81 (d, J=7.1 Hz, 1H), 2.56-2.48 (m, 1H), 2.43 (s, 3H), 2.36-2.31 (m, 1H), 2.23 (s, 3H), 2.17-2.12 (m, 1H) ), 1.96 (d, J=0.S Hz, 3H), 1.91-1.85 (m, 1H), 1.67 (s, 3H), 1.24 (s, 3H), 1.13 (s, 3H). ESI-MS: Calcd for C54H55N015Na (M+Na): 980, found: 980. Example 7: Preparation of 7-benzimidyl-European Taxus (7)

(7) 134531.doc • 93· 200942233 A solution of taxol in dioxane was mixed with imidazole and triethylsulfonium alkyl chloride under argon at room temperature. The reaction mixture was stirred at room temperature, diluted with methylene chloride, washed with water, sat. Flash chromatography of the residue gave 2,3-triethyldecylamine paclitaxel. A solution of 2, triethyl sulphate, paclitaxel in methylene chloride under argon was mixed with pyridine and styrene at ambient temperature. The reaction mixture was stirred at room temperature, diluted with diethyl ether and evaporated. Flash chromatography of the residue was performed to give the intermediate 2'-triethylmethanol- 7-benzhydryl-based paclitaxel. A solution of the intermediate 2,-triethyldecyl 7-benzylidene-based paclitaxel in methanol was mixed with Ηα aqueous solution under argon under argon and the reaction mixture was stirred at the same temperature. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The crude product was purified by flash column chromatography to give 7-benzylidene-based paclitaxel. Q Example 8: Preparation of 10-benzylidene-based taxol (8)

(8) The cold liquid of the European paclitaxel in the two gas and the bite was mixed with diethylhydrazine alkyl valine under argon at room temperature. The reaction mixture was stirred at room temperature, diluted with di-methane, washed with water and saturated aqueous sodium chloride 134531.doc. Flash chromatography of the residue gave 2,7-bis(triethyldecyl)-Europe paclitaxel. First, a solution of 2,7-bis(triethyldecyl)-catechol in m was mixed with sodium chloride under argon at room temperature, and then benzamidine was added. The reaction mixture was stirred at room temperature, diluted with ethyl ether and evaporated. Flash chromatography of the residue was carried out to give the intermediate 2,7-bis(diethyl sulphate) _ 〇 〇 benzylidene thiol. A solution of the intermediate 2,7-bis(triethyldecyl) 1 〇 benzylidene-based taxol in decyl alcohol was mixed with the aqueous HCl solution under argon at 〇 °c and at /JBL After the reaction mixture was stirred with EtOAc (EtOAc) EtOAc. The crude product was purified by flash chromatography on a flash column to give 10-bens-yl-hydrazin. Example 9: In vitro growth inhibition of ΜΧ-1 (human breast cancer) cells The Promega CellTiter Blue Cell viability assay was used to quantify cytotoxicity assays. Briefly, cells (5 cells/well) were plated onto 96-well microtiter plates in RPMI 1640 medium supplemented with 10% FBS and humidified at 37 ° C C2 at 37 °C. Cultivate. After 24 hours, the cells were exposed to hydrophobic taxane derivatives at various concentrations in DMSO and incubated for an additional 72 hours. 100 μM medium was removed and 2 μ μl pr〇mega CellTiter Blue reagent was added to each well and shaken to mix. After incubating for 4 hours in a humidified 5% C 2 atmosphere at 3 &lt; rc, the titration plate was read at 544 ex/62 〇em. The resulting fluorescence is proportional to the number of living cells. After plotting the generated fluorescence relative to the drug concentration, the IC50 is calculated as the resulting half-life of the nonlinearity back to 134531.doc -95 - 200942233. The data is provided in Table 1. Table 1: Cytotoxicity of hydrophobic European paclitaxel derivatives \1 OH 〇y. Wei H〇Bz0 α&lt;λ^0 ID R IC50(MX-1) (μΜ) 2 -CO(CH2)4CH3 103 3 -CO(CH2)8CH3 8.8 4 -co(ch2)3ch3 211 5 -COCH2CH3 209 1 - COPh 38.4 Example 10: Conversion of Hydrophobic European Taxus Yeast Derivatives to European Paclitaxel Samples in Human Liver Microsomes Preparation and Incubation of Pharmaceutical Stock Solution The drug stock solution was prepared in DMSO at 5 mg/mL and used in the same sputum. For the control solution containing no microsomes, the drug stock solution was incorporated into the following incubation mixture: 83 mM K2HP〇4 buffer (pH 7_4), 13.3 mM MgCl2, 1.3 mM NADP+, 3.3 mM glucose-6-phosphate, 0.4 U/mL glucose-6-phosphate dehydrogenase and 0.05 mM sodium citrate NADPH regeneration system (NRS) together with 1% DMSO gave a final drug concentration of 50 gg/mL. For control solutions that do not contain the NADPH regeneration system, the drug stock solution is incorporated into the following incubation mixture: 84 mM K2HP〇4 buffer (pH 7.4), 10 mM MgCl2, 12·5 mM sucrose, and 1 mg/mL human 134531. Doc -96- 200942233 Liver microsomes (HLM) together with 1% DMSO give a final drug concentration of 50 gg/mL. For the active solution, the drug stock solution was incorporated into the following incubation mixture: 78 mM K2HP〇4 buffer (pH 7.4), 13.3 mM MgCl2, 1.3 mM NADP+, 3.3 mM glucose-6-phosphate, 0.4 U/mL glucose- The NADPH regeneration system (NRS) of 6-phosphate dehydrogenase, 0.05 mM sodium citrate, 12.5 mM sucrose, and 1 mg/mL HLM, along with 1% DMSO, gave a final drug concentration of 50 pg/mL. The enzymatic reaction was initiated by the addition of HLM. The control solution and the active solution were incubated in a Thermomixer for about 5 minutes prior to incorporation of HLM to initiate the reaction. The total sample volume is between 1 and 2.5 mL. Aliquots of the control solution and the active solution were taken at different time points for HPLC analysis. The sample was briefly vortexed by tapping the vial to improve the homogeneity of the solution prior to skimming. After the sample was taken, the reaction aliquot was immediately diluted with acetonitrile (ACN) 1:2 to precipitate the protein and stop the enzymatic reaction. The sample was vortexed and centrifuged at 14,000 rpm for 8 minutes. The supernatant was transferred to a 1 mL autosampler vial and injected into the HPLC. HPLC conditions HPLC separation using a Synergi Fusion-RP column (Phenomenex, 15 〇 x 4.6 mm, 80 A, 4 μm) and below mobile phase gradient: mobile phase A: water; mobile phase B: acetonitrile; from 0 min to 10 minutes start with A/B (50:50); A/B (10:90) from 10 minutes to 30 minutes; A/B (10:90) from 30 minutes to 40 minutes; 40 minutes in the 40th minute Resume to A/B (50:50); terminate operation at 50 minutes. The flow rate was 1 134531.doc -97- 200942233 mL/min. Detection at 228 nm. The oven temperature was maintained at 35 °C. The sample injection volume is 20 pL. The HPLC retention times for various hydrophobic taxane derivatives are summarized in Table 2. Table 2: HPLC residence time of hydrophobic taxane derivatives 〇 C HC OH 槪. Bz0 AcO ID R HPLC Retention time (minutes) Relative residence time (relative to European paclitaxel) Lipid water partition coefficient (Log P) 2 CO(CH2)4CH3 23.0 2.77 6.44 3 CO(CH2)8CH3 29.3 3.53 8.64 4 CO(CH2) 3CH3 21.2 2.55 6.37 5 -COCH2CH3 16.9 2.04 5.31 1 -COPh 20.4 2.46 6.67 European yew yam 8.3 1 4.20 The result is the taxol produced by in vitro metabolism of hydrophobic taxane derivatives in human liver microsomes. The yield was determined by the relative peak area percentage of European paclitaxel detected in the HPLC chromatogram. In Fig. 1, the paclitaxel produced by each of the hydrophobic taxane derivatives was plotted against the incubation time. A comparison of the graphs indicates that the yield of taxol in Europe depends on the structure of the taxane derivative 134531.doc -98- 200942233. European paclitaxel is not produced in the hydrophobic taxane derivative (compound-1) having a benzylidene group substituted on the side chain of paclitaxel in Europe. However, a large amount of European paclitaxel is produced in the hydrophobic taxane derivative having an alkyl group on the side chain of taxol in Europe. The length of the alkyl side chain is not related to the percentage of the produced paclitaxel. In fact, after 2 hours of incubation in human liver: granules, a European paclitaxel yield is most significant in compound-2 with a side bond (about 16%). ), followed by compound-4 (C5) and compound-3 (C9) having a very similar conversion rate (about 11%). Compound-5 with a shorter (C3) side chain produced less European paclitaxel. Surprisingly, Compound 2 is metabolized and produces the most European paclitaxel. This situation cannot be predicted based on side chain substitution. The dependence of the taxol production in Europe on the structure of the hydrophobic taxane derivative may be related to the ability of the R side chain to fit in the active site of the enzyme responsible for the hydrolysis reaction. Without being bound by theory, among the five European paclitaxel hydrophobic taxane derivatives, the compound containing C6 alkyl group can be optimally complexed to the hydrophobic capsule at the active site of the enzyme in stereochemistry Q. In the bag. The rigid nature of the phenylhydrazine group prevents it from reaching the hydrophobic pocket completely, or the different reactivity of the aromatic vinegar prevents the enzymatic hydrolysis reaction from occurring. Example 11. Preparation of 2,-benzylidene-based taxol and albumin nanoparticles by high pressure homogenization 48.5 mg of 2,-benzitol-based taxol (prepared in Example 1) was dissolved in 〇·56 mL In a gas-like butanol mixture (1〇.2:1). The solution was added to 10.0 mL of human serum albumin solution (5%, w/v). The mixture was pre-homogenized at 10.000 rpm for 5 minutes (VirTi^, Tempest j Q type) 134531.doc •99· 200942233

To form a coarse emulsion ' and then transferred to a high pressure homogenizer (Avestin). The tip of the rotor/stator assembly of the pre-homogenizer and the container of the emulsion were rinsed with 3.0 mL of water and the wash solution was transferred to a high pressure homogenizer (Avestin). Emulsification was performed at i8, 〇〇〇 20,000 psi while the emulsion was recycled 3-12 times. The resulting system was transferred to a rotary evaporator and the chloroform and the third butanol were quickly removed at 4 Torr (&gt;c under reduced pressure (4 〇mm Hg) for 1 。 minute. The resulting dispersion was translucent. 'The typical diameter of the obtained nanoparticle is 1217 soil 14 nm (Z average ' Malvern Zetasizer). The dispersion can be directly filtered through a 0.22 μϊ syringe transition (Costar, μ star, 8110). In the case of a cryoprotectant or a lyoprotectant, the dispersion is further lyophilized for 48 hours. The obtained cake can be easily reconstituted as an original dispersion by adding an anhydrous water or a physiological saline solution. The diameter is the same as before the drying. Example 12: Preparation of 2,-〇·hexyl chelerythroside and albumin nanoparticle by high pressure homogenization 64.9 mg 2'-0-hexyl thioglycolate was dissolved in 〇.56 ^ [formaldehyde-tert-butanol (10.2:1, v/v). Then add the solution to 15 mL of 5% (w/v) HSA solution. Mix the mixture at 1 Torr, 〇〇〇 rpm Pre-homogenization for 5 minutes (Vitris homogenizer, Tempest IQ type) to form a coarse emulsion 'and then transferred to high pressure homogenization (Avestin) The tip of the rotor/stator assembly of the pre-homogenizer and the container of the emulsion were washed with 3.0 mL of a 5% (w/v) HSA solution and the wash liquor was transferred to a high pressure homogenizer (Avestin). The emulsification was performed at 18,000-20,000 psi while the emulsion was recycled 3-12 times. The resulting system was transferred to a rotary evaporator and rapidly moved at 40 ° C under reduced pressure (40 mm Hg) 134531.doc -! 00- 200942233 Degassing and third butanol for 10 minutes. The resulting suspension was made into 20 mL using WFI and subsequently subjected to microscopic characterization and particle size measurement. The particle size of the suspension under the microscope was too small to be observed. The suspension can be filtered through 0.8 μηι and the particle size of the filtered composition is 95 nm. Example 13.1: Preparation of a pharmaceutical formulation comprising 2,-0-hexyl thioglycol and albumin will be as described in Example 12. Approximately 100 mL of 0. 8 μηι composition, manufactured in 4 separate batches, was filtered through a 0.45 μηη 1000 mL particle size Steri-cup®. The entire composition was filtered through one of the above filters. The filtered composition was transferred. Up to 20 mL of serum with a 5 mL fill volume And lyophilized according to a scheme of performing basic drying at 245 ° C for 840 minutes and secondary drying at 3 ° C for 480 minutes. This gives a good white to off-white cake. The material can be rehydrated from a 0.9% (w/v) physiological saline solution to a light blue translucent solution in less than 2 minutes. The particle size is 107 nm. This rehydration composition maintained its integrity for 24 hours at 4 °C. After storage at 4 ° C for 24 hours, the particle size was 1 〇 8 nm and there was no significant change in particle size distribution. Example 13.2: Preparation of a pharmaceutical formulation comprising 2,-〇-hexylcarbazone and albumin The additives in this test were selected from injectable excipients, i.e., tonicity modifiers, NaCl, and d-mannitol. Approximately 20 mL of 0.8 μη composition prepared by the method as described in Example 12 was filtered through a 0.45 μηη syringe filter. The composition filtered through 〇_45 μη was divided into two separate portions of 2 mL each. To a portion, d·mannitol was added to a concentration of 5% (w/v) and NaCl was added to another portion of 134531.doc -101 to 200942233 to have a concentration of 150 mM. The composition containing mannitol and sodium hydride was transferred to a 2 mL serum vial with a 5 mL fill volume and followed by a primary drying at 25 ° C for 84 〇 minutes and at 3 ° C. The 48-minute dry solution was lyophilized. This produces a good cake from white to off-white. The lyophilized cake can be rehydrated to a light blue translucent solution in less than 2 minutes using WFI. The rehydration composition maintained its integrity for 24 hours under ye. There was no significant change in particle size and particle size distribution before and after bed drying and storage. Example 13.3: Preparation of a pharmaceutical formulation comprising 2,-indole-hexyl-based taxol and albumin This example shows the preparation of a pharmaceutical formulation comprising 2,-indole-hexyl-based taxol and albumin The diameter is less than 100 nm and the filterability and recovery rate are better. Eight batches of the composition were prepared with the following parameters and their characteristics were summarized in tabulated form (the particle size distribution is shown in, for example, Figure 8. ❹ 1^8 concentration = 5% (comment ~), gas pattern: Tributyl alcohol = 1 〇. 2:1; organic solvent 0 / 〇 = 3 · 6; batch size = 22.5 mL; HSA: drug = 9-10 Table 3: Batch preparation of 2'-〇-hexyl thiol taxol / Albumin composition batch name drug amount, mg filtration (0·45 μη^Ζ^ϋπΟ 1 127.6 70.8 2 122.9 67.4 3 121.3 67.6 4 121.4 68.0 5 123.7 66.9 6 121.5 73.7 7 122.6 74.4 8 121.7 71.8 134531.doc 200942233 All of the 0.45 μη filtered compositions in Table 3 were mixed together. The total volume of the mixed composition was about 150 mL and was filtered through a 250 mL size Steri-cup (0.22 μηι pore size). The composition was placed in 34 20 mL serum vials with a 4 mL fill volume. The composition was lyophilized and rehydrated without significant changes in particle size. Example 14: Nanoparticle stability at 2-8 ° C, The stability of the lyophilized 2'-0-hexyl Europain/albumin composition was assessed after RT and storage at 40 ° C to determine storage. Temperature/storage period and identification of possible degradation products under accelerated conditions to determine disposal and transportation options. Rehydration stability at 2-8 ° C and RT is also performed to determine the shelf life during use. Measure visual observations, rehydration Time, pH, RP-HPLC (% for potency and degradation), particle size (by Malvern Nanosizer) to determine the integrity and stability of albumin-containing formulations. The formulation was found to be cake-like, rehydratable. The particle size and particle size distribution were stable for 3 months. The results of this test are shown in Table 4. Table 4: 2'-0-hexyl thiol/albumin composition storage characteristics time point temperature cake Detail details reconstituted aqueous solution rehydration (mL) rehydration time (min) pH value zav (nm) Vision microscopy 0 RT grayish white good cake 0.9% (w/v) NaCl 2.0 3.1 6.60 68.7 No obvious grain particles too Small can not be observed for 1 month -20. As above, above 2.0 2.8 6.62 67.2 No obvious particles are too small to be observed 134531.doc -103- 200942233 2-8〇C as above 2.0 2.6 6.63 68.8 No obvious particles are too small Can not Observed 25〇C as above 2.0 3.2 6.64 68.6 No obvious particles are too small to observe 40°C as above 2.0 3.8 6.61 82.6 No obvious particles ------- The particles are too small to observe Example 15: by Preparation of 2,_benzylidene-based Pacific paclitaxel by high pressure homogenization

5 57.6 mg of 2,-benzimidylpaclitaxel was dissolved in 6 mL of a gas-ethanol mixture (9:1, v/v). The solution was added to a 12 〇 mL human serum albumin solution (3%, w/illusion. The mixture was pre-homogenized at 1 rpm for 5 minutes (VirTis homogenizer, Tempest q type) to form a crude emulsion And then transferred to a high pressure homogenizer (Avestin). Emulsification was performed at 18, 〇〇〇2〇〇〇〇pd while the emulsion was recycled 3_1 。. The homogenized emulsion was transferred to a 500 mL flask of a rotary evaporator. The gas and ethanol were quickly removed under reduced pressure (4 〇 mm H (2) at 4 ° C for 2 G minutes. The resulting dispersion was a light blue translucent solution. The diameter of the obtained benzamidine Pacific paclitaxel was found. 86.7 ± 3.1 nm (Z average, Malvern Zetasizer). The dispersion can be directly passed through a 0.22 (four) syringe filter (c〇star, μ_, 8 ιι〇) and the particle size of the nanoparticles is 61.1 ± 0.2 nme without adding In the case of any cryoprotectant or lyoprotectant, the dispersion is further lyophilized. The obtained cake can be easily reconstituted as a raw liquid by adding sterile water or physiological saline. The particle size after rehydration The same before lyophilization. The sickle instance contains 2'_〇_ Sleeping base European taxol and albumin medicine 134531.doc -104- 200942233 Maximum tolerated dose (MTD) of the compound In the first, fifth and fifth weeks, the mice were intravenously administered 15,30 60, 90, 120, and 150 mg/kg (q4dx3) of physiological saline (control) or nab-2 (2·-brown-based taxol nanoparticles prepared in Example 12). The mortality vs. dose relationship was shown and shown in Figure 7. According to the q4dx3 time course, the Nab-2 formulation was well-fed with LDn) = 61 mg/kg and LD50 = 113 mg/kg. Example 17: nab -2 (Prepared 2 in Example 12, -Hexylpyrazine yew granules) anti-cancer activity against breast cancer xenografts 10 million MDA-MBs were implanted subcutaneously in the right abdomen of female nude mice -23 1 cells. After eleven days, they will be divided into ten groups of tumor-bearing mice (mean tumor size = 126 mm3) to be administered intravenously or different doses according to the q4dx3 time course (60, 90). And 120 mg/kg of Nab-2 (prepared in Example 12) or 15 mg/kg of Taxotere®. Tumor measurements and animal body weight were recorded twice a week. In MDA-MB-23 1 In the breast cancer model, the tumors of the treated control animals grew well to the estimated size in nine of the ten mice, and the median time to the tumor was 12.2 days (Fig. 2A; the mean value SEM) The maximum average body weight was observed to be reduced by 1 _3% (Fig. 2B is the mean soil SEM). Treatment with Nab-2 effectively delayed the growth of MDA-MB-231 human breast tumors, with T_c values of 83.1, 80.7 and &gt; 84.8 分别 at doses of 120, 90 and 60 mg/kg/injection, respectively, and with vehicle The control was compared to tumor growth inhibition &gt; 96% (P &lt; 〇〇〇〇 1, aN 〇 va statistic compared to physiological saline control). Nab-2 was intolerant at the highest test dose of 120 mg/kg/injection and had a 50% mortality rate from 134531.doc-105-200942233, despite significant inhibition of tumor growth. Nab-2 was well tolerated at doses of 90 and 60 mg/kg/injection, with a maximum mean weight loss of 5% and 3%, respectively. In the MDA-MB-231 model, a dose of 15 mg/kg/injection of Ding & 〇 16 generation @可财, the maximum average weight loss was 3.3%. Taxotere® delayed the growth of MDA-MB-231 breast tumors (T-C value 49.5 曰) and reduced tumor growth by 88% (compared to physiological saline control P &lt; 0.0001). There was no significant difference in tumor growth inhibition between Taxotere® and Nab-2 treated animals, whereas at equivalent toxic dose levels, ® Nab-2 achieved superior antitumor efficacy with 30-40% tumor regression (see table) 5). Table 5: Anti-tumor activity model of Nab-2 compared to Taxotere® in a subcutaneous human breast cancer xenograft model in nude mice η dose (0, 龛 4, day 8, mg/kg) TGI (%)a BWL maximum (%) 3⁄4 death? Tumor regression part c Complete d MDA-MB-231 (breast) 10 Physiological saline 0 _ 0/10 0/10 Test number ABS-15 10 Nab-2e 120 96 5/10 3/10 0/10 10 Nab-2 90 96 -5.00 2/10 1/10 10 Nab-2 60 97 -3.30 4/10 2/10 10 Taxotere® 15 88 -3.30 4/10 0/10 aTGI, tumor growth inhibition; bB WL max, max. The percentage is alleviated; after the treatment, the tumor becomes &50% of its size or becomes untouchable, but then relapses. d Tumor becomes invisible; eNab, a combination of albumin nanoparticles. Example 18: nab-2 (2'-hexyl thioglycolate 134531.doc-106-200942233 granules prepared in Example 12) Anticancer activity against lung cancer xenografts To determine the efficacy of Nab-2 against lung cancer One million H358 cells were implanted subcutaneously near the right abdomen of male nude mice. After eleven days, they will be divided into seven or nine groups of tumor-bearing mice (mean tumor size = 422 mm3) to be administered intravenously or 60 mg/kg intravenously according to q4d&gt;&lt;3 time course Nab-2 or 10 mg/kg Taxotere® treatment. Tumor measurements and animal body weight were recorded twice a week. In the H3 58 human non-small cell lung cancer model, 60 mg/kg Nab-2 was well tolerated, with a maximum mean weight loss of 9.1% and a reduction in tumor growth of 53% (P<0.001 compared with physiological saline); Figure 3 (values mean SEM) and Table 6) Nab-2 at 90 mg/kg causes 100% mortality, while Taxotere® at 10 mg/kg reduces tumor growth by 93% (compared to saline control) P &lt; 0.001), but it caused 57% mortality. Unlike Taxotere®, Nab-2 at a dose of 60 mg/kg caused some tumor regression in six of the nine animals with minimal toxicity. ^ Table 6: Nab-2 and Taxotere® phase contrast in a nude mouse xenograft model of nude mice. Antitumor activity model η dose (0, 窠 4, 8th, mg/kg) TGI (% a BWL maximum (%) 3⁄4 death r tumor regression part c complete d H358 (NSCLC) f 7 physiological saline 0 - 0/7 0/7 test number CA-AB-24 7 Nab-2 90 N/A 7 /7 — — 9 Nab-2 60 53 -9.10 6/9 0/9 7 Taxotere® 10 93 4/7 1/7 1/7 aTGI, tumor growth inhibition; bB WL maximum, maximum weight loss 134531. Doc -107- 200942233 ratio; after treatment, the tumor becomes <50% of its size or becomes untouchable, but then relapses; d tumor becomes untouched; eNab, bound to albumin nanoparticles, fNSCLC, Non-small cell lung cancer. Example 19: nab-2 (2,-bis-decyl-based paclitaxel nanoparticles prepared in Example 12) was tested in two independent experiments against the anti-cancer activity of the xenon-resistant cancer xenografts to determine Nab-2 against colon The efficacy of rectal cancer. In trial number CA-AB-6, 1 million HT29s were implanted in the right and left abdominal epithelium ® of male nude mice. Fifteen days later, the mice were divided into three groups (tumor tumor size = 143 mm3) to be administered intravenously or 90 mg/kg Nab-2 intravenously according to q4d&gt;&lt;3 time course. Or 22 mg/kg Nab-European paclitaxel. Tumor measurements and animal body weight were recorded 3 times a week. In the test No. ABS-18, 1 million HT29 cells were implanted subcutaneously near the right abdomen of male nude mice. After eleven days, they will be divided into a group of tumor-bearing mice (mean tumor size = 186 mm3) to be administered intravenously or 60 and 90 mg/kg intravenously according to q4d&gt;&lt;3 time course q Nab-2 or 15 mg/kg Taxotere® treatment. Tumor measurements and animal body weights were recorded twice a week. In HT29 colon tumor xenografts (test numbers abs_丨8 and ca-AB-6), Nab-2 caused significant tumor growth inhibition (95-99%) and tumor growth at doses of 60 and 90 mg/kg. Delay (P &lt; 0.0001 compared to physiological saline control, Figure 4-6 (values mean SEM) and Table 7). Ninety of the ten tumor-bearing mice treated with 9〇 or 6〇 mg/kg Nab-2 showed partial tumor regression, with a maximum mean weight loss of u 6% (abs_i8). At 9 〇 134531.doc -108 - 200942233 mg/kg, one animal died and one was euthanized. Under the same experimental conditions, '15 mg/kg2Tax〇tere® caused 94〇/〇TGI and 19% weight loss. Table 5. Nab_2 and Nab·European paclitaxel and TaX〇tere in a subcutaneous human colon cancer xenograft model in nude mice ® Anti-tumor activity Chess η dose (0nd, 4th, 8th, mg/kg) TGI (%)* BWL maximum (%) or death) b 膣瘸 Regression * Complete d HT29 (colon) Test No. CA-AB-6 12 Physiological saline - 0 0/12 0/12 3 Nab-2 90 95.1 -19.00 1/3 0/3 3 Nab-2 30 -53.5 -7.20 0/3 0/3 3 Nab-2 15 -5.1 -9.60 0/3 0/3 3 Nab-European paclitaxel---.. 22 91.2 -27.10 0/3 0/3 3 Taxotere® 15 86.1 -27.30 0/3 0/ 3 HT29 (colon) Test No. ABS-18 10 Physiological saline----, 0 - - 0/10 0/10 10 Nab-2 —--—, 90 99 3/10 9/10 1/10 10 Nab-2 — — 60 98 -11.60 9/10 0/10 10 Taxotere® 15 94.3 -19.10 3/10 0/10 aTGI, tumor growth inhibition; bBWL·maximum, percentage of maximum weight loss; The size of &lt;5〇% becomes unknowable, but then relapses; d tumor becomes untouchable eNab, a combination of albumin nanoparticles. The comparative efficacy test of Nab-2, Nab-European paclitaxel and Taxotere® in the HT29 colon tumor model (test number CA-AB-6) revealed dose-limiting toxicity of Nab-catechol and Taxotere® with an average weight loss of 134,531. Doc -109- 200942233 27/. , although the TGI was 86 to 91% (P<0.01 compared to physiological saline). In contrast, Nab 2 at a dose of 9 〇 mg/kg caused a complete tumor regression with a maximum weight loss of 丨9% (compared to physiological saline control P &lt; 0.0001). Therefore, in the HT29 colon tumor model, unlike Nab-2, Taxerter® &amp; Nab_g paclitaxel did not cause partial or complete tumor regression in its MTDt, resulting in significant weight loss. Example 20: Pharmacokinetics and Safety of Nab-2 in Monkeys Materials and Methods The first dose administration date was designated as the day after the test, and the subsequent days were numbered sequentially. In the case where the final adaptation date is referred to as the first day, the first dose is administered to the previous test day in order. Three non-native, male cynomolgus crabs confirmed to have not been previously exposed to albumin were assigned to the dose group specified in Table 6 as shown below. At the start of the experiment, the animals weighed 5.4-6.7 kg and were aged 4 to 7 years. Table 6_Pharmacokinetic test design group material route dose level administration 曰 male animal number 3 Nab-2 IV 5 mg/kg 1 , 8 , 15 1 4 Nab-2 IV 10 mg/kg 1 5 Nab-2 IV 20 mg/kg 1 1 10 mg/kg 8 ' 15 All animals were dosed once a week on days 1, 8 and 15 . Animals in groups 3 and 4 were administered 5 and 10 mg/kg Nab-2 (batch number: ABI139-2-83) via intravenous infusion over 30 minutes, and administered to group 5 animals 20 , 10 and 1〇mg/kg (in categories 1, 8 and 15 respectively) 134531.doc .110- 200942233

Nab-2. Clinical observations were performed twice daily throughout the trial and body weights were recorded once a week. On Days 1 and 15, animals in Group 1 were collected at 8 time points and in Groups 3, 4, and 5 at 9 time points for continuous pharmacokinetic analysis for pharmacokinetic analysis. Results and conclusions No treatment-related effects were found in the body weight or clinical observation of Group 3 and Group 4 animals. In general, nab-2 test articles are well tolerated following repeated oral and intravenous doses. Nab-2 test articles were well tolerated by intravenous administration at 5 and 1 mg/kg. In contrast, administration of Nab-2 (Group 5) at a single IV dose of 2 〇 mg/kg resulted in adverse clinical signs and weight loss. For these reasons, the dose level for this animal was reduced to 10 mg/kg for administration on days 8 and 15. Unfavorable clinical observations in Group 5 animals included vomiting of fecal faeces, soft feces and liquid feces, and loss of appetite. On the 7th day, it was observed that the fifth group of animals lay down and the 17th day showed a hunched posture. Appetite 〇 及 及 and overall condition decreased and its weight loss was about 7 by the 7th day. /. (Compared to the measured dose of the precursor) and about 15% of the weight loss before dosing on the 15th day. Analyte and PK analysis are shown in Tables 7 and 8, respectively. Nab2 exhibits a final half-life of 3.0-3.7 hours and a knife solution in the blood at the earliest collection time of τ83 彳. Nab_2 and its metabolite (European paclitaxel) showed an increase in the ratio of Μη and whip to dose. Compound 2 exhibited a larger distribution volume with a VZ of 7. g. The metabolite conversion rate (European paclitaxel age ^ compound 2 whip ratio) was 4859%. 134531.doc • 111 - 200942233 These data clearly show that Nab_2 can be safely administered at a dose proportional to the dose of 10 mg/kg or 120 pawns. Compound 2 showed the production of European paclitaxel at a conversion of 4.8-5.9%. Table 7. Analyte data from Nab-2 IV administration Time (hours) Concentration (ng/raL) Dose (mg/kg) - Analyte 0 0 5 - Compound 2 0.083 1074.29 5-Compound 2 0.25 939.925 5 - Compound 2 0.5 774.415 5 _Compound 2 1 534.3 19 5-Compound 2 2 421.84 5-Compound 2 8 136.199 5 -Compound 2 0 0 5-European paclitaxel 0.083 36.706 5-European paclitaxel 0.25 40.729 5-European paclitaxel 0.5 35.458 5-European paclitaxel 1 32.11 5-European paclitaxel 2 34.063 5-European paclitaxel 8 1.154 5-European paclitaxel 0 0 10-compound 2 0.083 1547.177 10-compound 2 0.25 1300.995 10-compound 2 0.5 935.651 10-compound 2 1 733.656 10-compound 2 2 657.257 10. Compound 2 8 202.185 10 - Compound 2 0 0 10-European paclitaxel 134531.doc 112- 200942233 0.083 99.44 10-European paclitaxel 0.25 70.117 10-European paclitaxel 0.5 63.362 10-European paclitaxel 1 47.475 10-European paclitaxel 2 44.227 10- European Paclitaxel 8 0 10-European Paclitaxel 0 0 20-Compound 2 0.083 2387.681 20-Compound 2 0.25 2617.855 20-Compound 2 0.5 1819.776 20-Compound 2 1 1365 .583 20-Compound 2 2 958.369 20-Compound 2 8 264.147 20-Compound 2 0 0 20-European paclitaxel 0.083 381.848 20-European paclitaxel 0.25 231.964 20-European paclitaxel 0.5 157.466 20-European paclitaxel 1 90.505 20-European paclitaxel 2 69.21 20-European paclitaxel 8 0 20-European paclitaxel Table 8. Pharmacokinetic analysis dose from Nab-2 IV administration (mg/kg) / analyte HL λ z (small-hour one) Tmax (hour) Cmax ( Ng/mL) Cmax/D (kg*ng/mL/mg) AUCINF (hr*ng/mL) 10-Compound 2 3.7 0.0830 1547 155 5346 10-European paclitaxel 3.2 0.0830 99 10 314 20-Compound 2 3.0 0.2500 2618 131 7857 134531.doc -113- 200942233 20-European paclitaxel 1.4 0.0830 382 19 394 5-compound 2 3.6 0.0830 1074 215 3613 5-European paclitaxel 1.4 0.2500 41 8 175 Dose (mg/kg) / Analyte AUCINF/D (hr* Kg*ng/mL/mg) Vz (mL/kg) Cl (mL/hr/kg) Vss (mL/kg) Ratio: European paclitaxel/compound 2 10-compound 2 535 9927 1871 8120 5.9% 10-European paclitaxel 31 20-Compound 2 393 11176 2545 8740 5.0% 20-European paclitaxel 20 5-compound 2 723 7176 1384 5837 4.8% 5-European paclitaxel 35 Example 21 ·· Nab-2 and Nab-European Taxus yeast dissolution profiles were performed in Nab-2 and Nab-European paclitaxel dissolution experiments (see Table 9 for Nab-2 ginseng) / Figure 9, see Table 10 / Figure 10 for Nab-European paclitaxel. The particles of Nab-2 remained intact (5 pg/mL) at the lowest tested concentration. In contrast, nab-European paclitaxel rapidly decomposes into an albumin-drug complex at 100 pg/mL, and no detectable nanoparticles (20-fold difference in stability). Correspondingly, the EC50 of nab-2 (half of the dissolution pattern) was 103 pg/mL and the EC50 of nab-European paclitaxel was 230 pg/ml (Fig. 11) -2 fold difference. The EC90 (90 ° / 〇 dissolution) of nab-2 was 16 pg / ml and the EC90 of nab - European paclitaxel was 121 pg / ml - 7.6 times difference. Normalized dissolution of Nab-2 and Nab-European paclitaxel 134531.doc -114- 200942233 The curve is shown in Figure 11. Table 9: Dissolution data for Nab-2 Drug concentration particle size (rnn) Standard deviation (pg/mL) (earth nm) 0 23.9 3.5 5% over 0.2 μιη (w/v) HSA solution 0 23.9 3.2 5 24.4 4.3 10 27.6 5.1 25 28 3.7 50 35.9 4.5 75 41.5 3.5 5% (w/v) HSA solution over 0.1 μm 100 100 45.6 3.6 150 52.1 4.7 200 56.3 3.4 300 61.3 3.5 400 64.3 2.8 Table 10: Nab-European paclitaxel Dissolution data drug concentration bg/mL) particle size (nm) standard deviation (±nm) 0 8.1 1.5 10 7.6 1.7 25 8.2 1.6 50 8.1 1.5 75 8.7 2.3 100 10.1 3.9 150 35.7 13.2 200 77.8 12.7 300 135.4 12 500 183.3 7.2 134531.doc -115- 200942233 [Simplified Schematic] Figure 1 shows the relationship between the amount of European paclitaxel produced by hydrophobic yew and its incubation time. Figure 2A shows the effect of increasing concentrations of hydrophobic pecan derivatives and albumin-containing nanoparticles on tumor growth in a breast cancer xenograft model compared to Taxotere®. Figure 2B shows the effect of increasing concentrations of nanoparticle containing hydrophobic taxane derivatives and albumin on the change in body weight in a breast cancer xenograft model compared to Taxotere®. Figure 3A shows the effect of nanoparticle containing hydrophobic taxane derivatives and albumin on tumor volume changes in the H3 58 lung cancer xenograft model compared to Taxotere®. Figure 3B shows the effect of nanoparticle containing hydrophobic taxane derivatives and albumin on body weight changes in the H358 lung cancer xenograft model compared to Taxotere®. Figure 4A shows the effect of nanoparticle containing a hydrophobic taxane derivative and albumin on tumor growth in the HT29 colon cancer xenograft model compared to Nab-CH. paclitaxel (test number CA_AB_6). Effect of Nab-Paclitaxel Containing Hydrophobic Taxane Derivative and Albumin Nanoparticles on Body Weight Changes in HT29 Colon Carcinoma Xenograft Model (Test No. CA_AB_6). Figure 5A shows the effect of nanoparticle containing a hydrophobic taxane derivative and albumin on tumor growth in a colon cancer HT29 xenograft model compared to TaXotere® (test number CA_AB_6). 134531.doc -116- 200942233 Figure 5B shows the effect of nanoparticle containing hydrophobic taxane derivative and albumin on body weight change in colon cancer HT29 xenograft model compared to Taxotere® (test number CA-AB) -6). Figure 6A shows the effect of increasing concentrations of nanoparticle containing hydrophobic taxane derivatives and albumin on tumor growth in a colon cancer HT29 xenograft model compared to Taxotere® (test number ABS-18). Figure 6B shows the effect of increasing concentrations of nanoparticle containing hydrophobic taxane derivatives and albumin on body weight changes in colon cancer HT29 xenograft 0%^ model compared to Taxotere® (test number ABS-18) ). Figure 7 shows the repeated dose toxicity of a nanoparticle containing a hydrophobic taxane derivative and albumin. Fig. 8 shows the particle distribution and average particle diameter of a nanoparticle containing a hydrophobic taxane derivative and albumin. Figure 9 shows the particle dissolution pattern of the nanoparticle composition Nab-2. Figure 10 shows the particle dissolution pattern of the nanoparticle composition Nab-European paclitaxel. Figure 11 shows the normalized dissolution pattern of the nanoparticle composition Nab-2 and Nab-European paclitaxel. 134531.doc 117-

Claims (1)

200942233 X. Application for Patent Park: 1. A composition containing nano particles. Aqueous yew and _ protein. 4 Nai (4) granules contain sparse 2. As requested by the composition 'where the hydrophobic cedar prodrug. The organism is purple 3. The composition of the claim ... wherein the carrier protein is albumin. 4. The composition of claim 3, wherein the albumin is human serum albumin. A composition according to any one of the preceding claims, wherein the composition comprises a carrier egg in the form of 'd particles and in the form of non-nano particles, and about 25% of the carrier eggs are self-assembled into nano particles. form. 6. The composition of any one of the preceding claims, wherein the average particle diameter of the composition of the composition is less than about (4). The composition of any one of the preceding claims wherein the average particle diameter of the rice particles in the composition is less than about 100 nm. The composition of any one of the above, wherein the composition has a diameter of less than about 100 nm. 9. The composition of any of the above-mentioned SB Α 靖 ” 以上 如 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖 靖A composition according to any one of the following, wherein the hydrophobic yew derivative has the formula: 134531.doc 200942233 wherein R is phenyl or -OtBu; R, R, R4 and R5 are independently a ^ or a hydrophobic group; and wherein at least one of R2, r3, R4 and R5 is not H; The condition is that when R1 is a phenyl group and R2, R3 and R5 are each H, R4 is not an ethylidene moiety; or a pharmaceutically acceptable salt, isomer or solvate thereof. The composition of any one of the claims, wherein the hydrophobic taxane derivative has the formula: Wherein R is phenyl or -OtBu; ❹ 12. R, R3, R4 and R5 are independently 11 or _(:(〇)116; each -R6 independent material is selected from the group consisting of silk, county, alkynyl, ring-form, a substituted or unsubstituted moiety of a cycloalkyl-homo, aryl, heteroaryl, aryl, and heteroaryl; and wherein at least one of R2, R3, R4, and R5 is not H The restriction condition is that when Ri is a phenyl group and each of r^r5 is H, R4 is not an ethylidene moiety; or a pharmaceutically acceptable salt, isomer or solvate thereof. The composition of claim 11, wherein Ri is a phenyl group. I34531.doc 200942233. The composition of claim 1, wherein Ri is _〇tBu. 14. The composition of any one of claims 11-13, Each of R6 is independently selected from the group consisting of _ci-c15 alkyl, -cvCm alkenyl, -q-Ch alkynyl, _Cl_Cl5 ring, -CVC1S cycloalkyl-alkyl, aryl, 5 to 7 member The aryl group, the aromatic group: a substituted or unsubstituted partial group of the heteroarylalkyl group. The composition of any one of the items 1-1, wherein each R6 is independently selected From -CVc〗 5 alkyl, -Ci-C! 5;) ^ base and aryl Substituted or unsubstituted partial groups. The composition of any one of the preceding claims, wherein each r0 is independently a substituted or unsubstituted aryl group or a substituted or unsubstituted _CiCi5 alkyl group. The composition of any one of claims 11-13, wherein each R6 is independently an unsubstituted aryl group or an unsubstituted c15 alkyl group. 18. The composition of any of clauses wherein the one of the compositions is a non-substituted phenyl or unsubstituted methyl group. The composition of any one of the items 1113, wherein each of the compositions is an unsubstituted aryl group. 20. The composition of any one of the preceding claims, wherein each of the stupid bases β R6 is independently wherein each R6 is independently wherein each R6 is independently wherein each R6 is - CH3. β, Group 4 of any one of items 11-13, unsubstituted Ci_Ci5 alkyl. 22. If the claim is any one of 3, the unsubstituted _Cl_Ci. alkyl group. The composition of any one of claims 11-13, wherein each R6 is -CH2CH3. 25. Any one of claims 11-13 The composition of any one of claims 11-13, wherein each R6 is -(CH2)3CH3. 27. as claimed in claim U_13 A composition of the composition wherein each R6 is _(CH2)4CH3. 28. The composition of any one of claims ιι.ι3 wherein each R6 is _(CH2)5CH3. The composition of any one of the preceding claims, wherein each R6 is -(CH2)6CH3. The composition of any one of clauses 11-13, wherein each R6 is -(CH2)7CH3. The composition of any one of the items n_13 Each of R6 is -(CH2)8CH3. The composition of any one of clauses 11 to 3, wherein only one of R2, R3, R4 and R5 is not Η. 33 such as a request (1)" A composition according to any one of the preceding claims, wherein the composition of any of clauses 11-33, wherein r3 is not H.: the composition of any of items 11-34, wherein R4 is not a composition of any one of the above-mentioned items 11-35, wherein r5 is not a composition of any one of the above-mentioned jgn), wherein R4 is an ethylidene moiety and only one of them Not a H. 134531.doc 200942233 38. The composition derivative according to any one of claims 1 to 10 having the formula: Wherein the hydrophobic taxane wherein R2 is -C(0)R6; and R6 is independently selected from alkyl-alkyl, aryl, heteroaryl, unsubstituted moiety; alkenyl, Substituted alkynyl, cycloalkyl, cycloalkylarylalkyl and heteroarylalkyl or a pharmaceutically acceptable salt, isomer or solvate thereof. 39. The composition of claim 38, wherein r6 is a substituted or unsubstituted moiety selected from the group consisting of a thiol group and an aryl group. The composition of claim 38, wherein r6 is a substituted or unsubstituted aryl group or a substituted or unsubstituted alkyl group. 41': The composition of claim 38, wherein r6 is an unsubstituted aryl group or an unsubstituted -CrC15 alkyl group. 42. The composition of claim (4) wherein r6 is unsubstituted phenyl or unsubstituted methyl. The composition of claim 38, wherein r6 is an unsubstituted aryl group. The composition of claim 3, wherein R6 is an unsubstituted phenyl group. 5. The composition of claim 38, wherein R6 is an unsubstituted CiC丨$ alkyl group. I34531.doc 200942233 46. The composition of claim 38, wherein R6 is an unsubstituted -cvc^ group. 47. The composition of claim 38, wherein the composition of claim 38, wherein r6 is _(CH2)4CH3. 49. The composition of claim 38, wherein R6 is -(ch2)5ch3. 50. The composition of any one of clauses, wherein the hydrophobic taxane derivative has the formula: Or a pharmaceutically acceptable salt, isomer or solvate thereof. The composition of any one of clauses 1 to 50, wherein, according to HPLC, in a dissolution test in 5% HSA at 37 ° C, at 1 〇pg/m^, the nanoparticles have a larger than A particle size of about 20 nm. The composition of any one of claims 1 to 50, wherein the nanoparticles have a particle size greater than about 30 at 50 gg/mi according to HPLC in a dissolution test at 5% HSA at 37 °C. The granularity of nm. The composition of any one of claims 1 to 50, wherein the nanoparticle exhibits one or more of the following dissolution patterns when measured by HPLC at 5% HS A at 37 °C : a) 'greater than about 5〇nin at 2〇〇pg/mi; b) greater than about 40 nm at 100 μ§/Γη1; and c) greater than about 20 nm at 10 pg/ml 54. The composition of any of claims 1-50, wherein at 37. 5% of hsa 134531.doc 200942233 When measured by HPLC, the nanoparticles exhibit one or more of the following dissolution patterns. a) at 400 pg/ml, greater than about 60 nm; b) at 200 Hg/ml is greater than about 50 nm; c) is greater than about 40 at 1 〇〇 jxg/ml; d) is greater than about 2 〇 nm at 10 pg/mi; e) at 5 pg/ml, More than about 2〇nme 55. The composition of any one of the items of claim 50, wherein the EC5〇 of the dissolution pattern is less than the unmodified taxane in the same nanoparticle formulation when measured in the lower 5% hsa About 25% of the EC 50. The composition of any one of the preceding claims, wherein, in the administration of the primate, the nanoparticle composition is reached in the blood between about 5 hours and about 3 hours after administration. Cmax. The composition of any one of the preceding claims, wherein the nanoparticle composition is decomposed in the blood for a final half-life of from about 1 hour to about 5 hours upon administration of the primate. 58. A method of treating a proliferative disorder in an individual, comprising administering to the individual an effective amount of a composition according to any one of the preceding claims. The method of claim 58, wherein the proliferative disease is cancer. The method of claim 59, wherein the cancer is a solid tumor. 61. The method of claim 59, wherein the cancer is selected from the group consisting of polyoma, renal cell carcinoma, prostate cancer, lung cancer, melanoma, ovarian cancer, and breast cancer. 62. The method of claim 59, wherein the cancer is breast cancer. 63. The method of claim 59, wherein the cancer is a cancer cell. 64. The method of claim 59, wherein the cancer is colon cancer. The method of any one of claims 58-64, wherein the composition is administered parenterally. 66. The method of claim 65, wherein the composition is administered intravenously. 67. An emulsion of a hydrophobic potato derivative of the invention, the emulsion comprising: (4) at least a portion of the alcohol solvent of the lyophilized derivative of the hydrophobic taxane derivative of the hydrophobic taxane derivative Hydrophobic violet = the first phase of the nanodroplet of the organism, and (9) the second phase comprising the water and the biopolymer of the biophase. The emulsion is substantially free of interfacial activity. Agent 0 ❹ 134531. Doc