MX2008002742A - Compositions and methods for preparation of poorly water soluble drugs with increased stability - Google Patents

Abstract

The present invention provides stable pharmaceutical compositions of poorly water soluble pharmaceutical agents and stabilizing agents which function to increase stability of the compositions. The use of stabilizing agents provide extended stability of nanoparticle suspensions and other formulations of poorly water soluble pharmaceutical agents such as docetaxel under certain conditions, for example upon dilution for administration.

Description

COMPOSITIONS AND METHODS FOR THE PREPARATION OF SMALL SOLUBLE DRUGS IN WATER WITH INCREASED STABILITY Field of the Invention The invention provides compositions and methods of producing stable pharmaceutical formulations of docetaxel. BACKGROUND OF THE INVENTION There is an ever-increasing number of pharmaceutical drugs that are formulated that are sparingly soluble or insoluble in aqueous solutions. Such drugs provide a challenge to their delivery in an injectable form such as by parenteral administration. A well-designed formulation must be capable, at a minimum, of presenting a therapeutically effective amount of the sparingly soluble drug to the desired absorption site, in a form that can be absorbed. In addition, these compositions tend to be unstable, with sedimentation and / or precipitation occurring in the course of less than 24 hours after rehydration or reconstitution. The taxanes, in particular the two currently available taxane drugs, paclitaxel and docetaxel, are potent antitumor agents. Paclitaxel is very sparingly soluble in water (less than 10 μg / ml), and as a result, can not be formulated practically with an aqueous medium for IV administration. Commonly, paclitaxel is Ref .190430 formulated for IV administration to cancer patients in a solution with polyethoxylated castor oil (Polyoxyl 35 or Cremophor®), as the solvent / primary surfactant, with high concentrations of ethanol used as the cosolvent. One of the greatest difficulties in the administration of paclitaxel is the presentation of hypersensitivity reactions. These reactions, which include severe skin rashes, hives, redness, dyspnea, tachycardia and others, can be attributed at least in part to the high concentrations of ethanol and Cremophor used as solvents in the formulation. Docetaxel, as an analogue of paclitaxel, is produced semisynthetically from 10-desacetyl baccatine III, a non-cytotoxic precursor extracted from the needles of Taxus bacca ta and esterified with a chemically synthesized side chain (Cortes and Pazdur, 1995, J Clin Oncol 13 (10): 2643-55). Similar to paclitaxel, docetaxel is very sparingly soluble in water. Currently, the most preferred solvent / surfactant used to dissolve docetaxel is polysorbate 80 (Tween 80) (Bissery et al., 1991 Cancer Res. 51 (18): 4845-52; Tomiak et al., 1992). Similar to Cremophor, Tween frequently causes hypersensitivity reactions in patients. In addition, Tween 80 can not be used with a PVC supply device because of its tendency to leaching of diethylhexyl phthalate, which is highly toxic. The purification of semisynthetic paclitaxel and docetaxel is a challenging problem due to the formation of a number of degradation drugs along the synthetic route. In addition, purified taxanes were found to be degraded, even under controlled storage conditions. Therefore, it becomes desirable to develop stable forms of these molecules that retain the desirable anti-cancer properties. Previous efforts in obtaining the appropriate docetaxel have been focused on the preparation processes of the trihydrated forms of docetaxel, which are believed to have a stability substantially greater than that of the anhydrous product. See, for example, U.S. Nos. 6,022,985; 6,838,569. To achieve the expected therapeutic effects of poorly water soluble pharmaceutical agents such as paclitaxel and docetaxel, it is usually required that a solubilized form or a nanodispersed form of the agent be administered to a patient. Therefore, a number of methods have been developed which are based on the use of: auxiliary solvents; surfactants; soluble forms of the drug, for example, salts and solvates; shapes chemically modified drugs, for example, prodrugs; polymer-drug complexes, soluble; carriers of special drugs such as liposomes; and others. Actually, the use of amphiphilic block copolymer micelles has attracted a great deal of interest as a carrier of a potentially effective drug that is capable of solubilizing a hydrophobic drug in an aqueous environment. Each of the above methods is hampered by one or more particular problems. For example, the method based on the use of the micelles of the surfactant to solubilize the hydrophobic drugs has problems because some of the surfactants are relatively toxic and the precipitation of the hydrophobic drug occurs when they are subjected to dilution. Previously, formulations of phospholipid-based liposomes for paclitaxel, Taxotere and other active taxanes have been developed (Straubinger et al., 1993, J. Na ti. Cancer Inst. Monogr. (15): 69-78; Straubinger et al. 1994, Sharma et al 1993, Cancer Res. 53 (24): 557-81, Sharma and Straubinger 1994, Pharm. Res. 11 (6): 889-96, A. Sharma et al., 1995, J. Pharm. Sci. 84 (12): 1400-4), and the physical properties of these and other taxane formulations have been studied (Sharma and Straubinger 1994, Pharm. Res. 11 (6): 889-96; US Sharma et al. 1995, J. Pharm. Sci. 84 (10): 1223-30; Balasubramanian and Straubinger 1994, Biochemistry 33 (30): 8941-7; Balasubramanian et al. 1994, J. Pharm. Sci. 83 (10): 1470-6). The main utility of these formulations is the elimination of the toxicity related to the excipient of Cremophor EL, and a reduction in the toxicity of the taxane itself, as demonstrated in various animal tumor models (Sharma et al., 1993, Cancer Res. 53 (2): 557-81, A. Sharma et al., 1995, J. Pharm. Sci. 84 (12): 1400-4, Sharma et al., 1996, Cancer Lett. 107 (2): 265-272). . This observation is maintained for several taxanes in addition to paclitaxel (A. Sharma et al., 1995, J. Pharm. Sci. 84 (12): 1400-). In some cases, the antitumor potency of the drug appears to be slightly higher for liposome-based formulations (Sharma et al., 1993, Cancer Res. 53 (24): 557-81). These liposome formulations comprise phospholipids and other additives, in addition to the taxane, and can be stored in a dry state. During the addition of an aqueous phase to the mixture, the particles are formed spontaneously and can take the form of liposomes (Straubinger et al., 1993). Liposomes are closed vesicular structures, which consist of a limiting bilayer membrane surrounding an aqueous core. A preferred formulation composition (Sharma and Straubinger 1994) contains a neutral phospholipid (zwitterionic) such as lecithin (phosphatidylcholine, 80-90% of the molar ratio), in company of a negatively charged phospholipid such as phosphatidylglycerol (10-20%). The latter avoids the aggregation of the particles by means of electrostatic repulsion. The more stable taxane content is in the range of 3-4 mol% (relative to the total phospholipid content); such liposomes can be physically and / or chemically stable for 2 months after hydration. Under most conditions, paclitaxel formulations containing higher concentrations of the drug (e.g., 8 mol%) are highly unstable and can precipitate within minutes of preparation (Sharma and Straubinger, 1994). The greatest interest on these formulations has been the relatively low taxane content of the acceptably stable formulations (3-5 mol%), which necessitates the administration of a large amount of phospholipids (5-10 gm) to the patients to provide the anticipated dose of the drug. Although humans are frequently provided with large amounts of the lipids intravenously for total parenteral nutrition (TPN), a major development objective has been to produce taxane liposomes which have a higher taxane content. Other methods for the formulation of sparingly soluble drugs for oral or parenteral delivery they include, for example, formulations in which the sparingly soluble drug is an oil-in-water emulsion, a microemulsion, or a solution of micelles or other multi-sheet carrier particles. Although such methods may be appropriate for some hydrophobic therapeutic agents, both ionizable and non-ionizable, they fail to take advantage of the unique, acid-based chemical properties and associated solubility properties of the ionizable compounds. Drugs that are insoluble in water can have significant benefits when formulated as a stable suspension of submicron particles. Accurate control of particle size is essential for the safe and effective use of these formulations. The particles must be less than seven microns in diameter to pass safely through the capillaries without causing embolism (Alien et al., 1987, Davis and Taube, 1978, Schroeder et al., 1978, Yokel et al., 1981, Toxicol, Let t.9 (2): 165-70). Another method is described in U.S. Pat. No. 5,118,528 which describes a process for preparing the nanoparticles. The process includes the steps of: (1) preparing a liquid phase of a substance in a solvent or a mixture of solvents to which one or more may be added; more surfactants, (2) prepare a second liquid phase of a non-solvent or a mixture of non-solvent substances, the non-solvent is miscible with the solvent or the solvent mixture for the substance, (3) add the solutions together of (1) and (2) with agitation and (4) removing the unwanted solvents to produce a colloidal suspension of the nanoparticles. The '528 patent discloses that it produces particles of the substance smaller than 500 nm without the energy supply. In particular, the? 528 patent states that it is undesirable to use high energy consumption equipment such as sonicators and homogenizers. The U.S. patent No. 4,826,689 discloses a method for making particles uniformly sized from drugs insoluble in water or other organic compounds. First, a suitable solid organic compound is dissolved in an organic solvent, and the solution can be diluted with a non-solvent. Then, an aqueous precipitation liquid is infused, precipitating the non-aggregated particles with a substantially uniform average diameter. The particles are then separated from the organic solvent. Depending on the organic compound and the desired particle size, the parameters of the temperature, the ratio of the non-solvent to the organic solvent, the infusion rate, the speed of Agitation, and volume, can be varied according to the patient. The '689 patent discloses that this process forms a drug in a metastable state which is thermodynamically unstable and which is eventually converted to a more stable crystalline state. The '689 patent describes the capture of the drug in a metastable state in which the free energy lies between that of the solution of the starting drug and the stable crystalline form. The '689 patent discloses the use of crystallization inhibitors (eg, polyvinylpyrrolidinone) and surface active agents (eg, poly (oxyethylene-co-oxypropylene)) to make the precipitate sufficiently stable to be isolated by centrifugation, filtration with a membrane or reverse osmosis. Another method for providing insoluble drugs for parenteral delivery is described in U.S. Pat. No. 5,145,684. The '684 patent describes the wet grinding of an insoluble drug in the presence of a surface modifier to provide a drug particle having an effective, average particle size of less than 400 nm. The '684 patent describes the surface modifier which is adsorbed on the surface of the drug particle in an amount sufficient to preserve the agglomeration in the larger particles. The nanoparticles of the insoluble drugs prepared under the High shear forces (eg, sonication, high pressure homogenization, or the like) with biocompatible polymers (e.g., albumin) are described in, for example, U.S. Pat. Nos. 5,916,596, 6,506,405, and 6,537,579 and also in U.S. Patent publication. 2005/0004002 Al. In view of the foregoing, there is a need for pharmaceutical compositions comprising poorly water soluble drugs with increased physical and chemical stability, which eliminates the use of physiologically damaging solvents and excipients, and production methods of the same. It is desirable that such pharmaceutical compositions are not degraded, that they remain stable under storage conditions and that they remain physically and / or chemically stable after rehydration. It may also be desirable to have a pharmaceutical composition comprising an anhydrous form of the sparingly water soluble drug having a greater solubility in conventionally used solvents and excipients, as well as in solvents and excipients that are not physiologically harmful. The present invention provides such pharmaceutical compositions and methods. The description of all publications, patents, patent applications and published patent applications, referred to herein, are hereby incorporated herein by reference. reference in their totalities. Brief Description of the Invention The invention provides compositions and methods of production of stable pharmaceutical formulations of docetaxel. In one embodiment, the invention provides pharmaceutical formulations of docetaxel comprising citrate or derivatives thereof. In a second embodiment, the invention provides pharmaceutical formulations of docetaxel comprising sodium pyrophosphate. In a third embodiment, the invention provides pharmaceutical formulations of docetaxel comprising EDTA or a derivative thereof. In a fourth embodiment, the invention provides pharmaceutical formulations of docetaxel comprising sodium gluconate. In a fifth embodiment, the invention provides pharmaceutical formulations of docetaxel comprising citrate and sodium chloride. In a sixth embodiment, the invention provides a docetaxel formulation comprising a surfactant, wherein the docetaxel used to prepare the formulation is in an anhydrous form prior to being incorporated into the formulation. Accordingly, in one aspect, the invention provides compositions (such as pharmaceutical compositions) comprising a poorly water soluble pharmaceutical agent (such as docetaxel) and a stabilizing agent, wherein the stability of the composition is improved when compared to that of the composition without the stabilizing agent. In some embodiments, the compositions further comprise a biocompatible polymer (such as the carrier proteins described herein). The stabilizing agent includes, for example, chelating agents (such as citrate, maleic acid, edetate, and pentetate) sodium pyrophosphate, and sodium gluconate. In another aspect, various compositions (such as pharmaceutical compositions), comprising docetaxel, are provided, wherein the docetaxel used for the preparation of the composition is in an anhydrous form (for example, docetaxel may be anhydrous prior to being incorporated in the composition). In some embodiments, the composition further comprises a biocompatible polymer (such as a carrier protein described herein). In some embodiments, the composition further comprises a stabilizing agent (such as the stabilizing agents described herein). In some embodiments, the composition comprises both a biocompatible polymer (such as the carrier proteins described herein) and a stabilizing agent. In some embodiments, the invention provides compositions (such as pharmaceutical compositions) comprising docetaxel and a surfactant, wherein the docetaxel used for the preparation of the composition is in an anhydrous form (eg, example, docetaxel can be anhydrous prior to being incorporated into the composition). In some embodiments, the composition further comprises a stabilizing agent (such as the stabilizing agents described herein). Unitary dosage forms of the compositions described herein are also provided, articles of manufacture comprising the compositions of the invention or unit dosage forms in a suitable package, and kits comprising the compositions. The invention also provides methods of making and using such compositions as described herein. It is to be understood that one, some, or all of the properties of the various embodiments described herein, may be combined to form other embodiments of the present invention. Brief Description of the Figures Figure 1 shows the body weight loss of the rats at a docetaxel dose of 5 mg / kg for an albumin formulation of docetaxel nanoparticles (Nab-docetaxel) and Tween 80-docetaxel (Taxotere®) . Dosing occurred on days 0, 4 and 8. Figure 2 shows the comparison of neutropenia in rats at a dose of 5 mg / kg for NaJ-docetaxel and Tween 80-docetaxel (Taxotere®). Dosing occurred on days 0, 4 and 8.

Figure 3A, Figure 3B, Figure 3C, and Figure 3D, show the pharmacokinetic comparison of Na? -docetaxel and Taxotere. Figures 3A-3C show the plasma concentration of Nab-docetaxel and Taxotere® at the doses of 10 mg / kg, 20 mg / kg, and 30 mg / kg, respectively. Figure 3D shows the linear relationship between AUC (Area Under the Curve) and the dose for Nah-docetaxel and the non-linear relationship between AUC and the dose for Taxotere. Nab-docetaxel exhibited a linear relationship adjusted by the equation AUC = 218 * dose; Taxotere exhibited an exponential curve adjusted by the equation AUC = 722 * exp (0.10 * dose). Figure 4 shows the inhibition of the agglutination of the drug to albumin in the presence of the surfactant Tween 80 and Cremophor EL® / EtOH. Figure 5A and Figure 5B show the antitumor activity (5A) and the body weight loss (5B) with the Nab-docetaxel in a mouse with a xenograft of the H29 colon tumor. The mice were dosed with ab-docetaxel at 15 mg / kg, q4dx3. Figure 6A and Figure 6B show the antitumor activity (6A) and the body weight loss (6B) in a mouse with colon tumor xenograft HCT116 dosed with a saline solution, Na £ > -cetataxel (22 mg / kg) and Taxotere (15 mg / kg). Figure 7A and Figure 7B show the loss of body weight (7A) and antitumor activity (7B) in a mouse with a PC3 prostate tumor xenograft dosed with a saline solution, Nab-docetaxel (10, 15, 20, 30 mg / kg), and Tween 80- docetaxel (10 mg / kg). Detailed Description of the Invention The present invention in one of its embodiments provides compositions and methods for the preparation of docetaxel and other pharmaceutical agents or drugs sparingly soluble in water which retain the desirable therapeutic effects and remain physically and / or chemically stable during exposure to certain conditions such as prolonged storage, elevated temperature, or dilution for parenteral administration. A stable composition is, for example, one that remains physically and / or chemically stable and therefore shows no evidence of precipitation or sedimentation for at least about 8 hours, including for example at least about any of 24 hours, 48 hours, or until approximately 96 hours after reconstitution or rehydration. For example, the compositions may remain stable for at least 24 hours after reconstitution or rehydration. The stability of the suspension is generally (but not necessarily) evaluated to the usual conditions of expected transport and storage during product distribution (such as room temperature (such as 20-25 ° C) or refrigerated conditions (such as 4 ° C)). For example, a suspension is stable at a storage temperature if it does not exhibit flocculation or agglomeration of visible particles with the naked eye or when observed under the optical microscope at a 1000-fold amplification (or other suitable particle characterization techniques), approximately fifteen minutes after the preparation of the suspension. The stability can also be evaluated under exaggerated conditions of temperature, humidity, light and / or others, to test the stability of the compositions in an accelerated test. For example, the stability can be evaluated at a temperature that is higher than about 40 ° C. The stability of the composition can also be evaluated, for example, by the ability of the composition to remain suspended without showing evidence of sedimentation or the formation of a cream, or by the ability of the composition to remain unchanged (i.e. no visible difference) in terms of color or consistency. The stability of a dry composition (such as lyophilized) can be evaluated based on the behavior of the liquid suspension resulting from the reconstitution or rehydration of the dry composition.

It is an object of the invention to provide pharmaceutical compositions capable of maintaining physically and / or chemically stabilized, therapeutically effective amounts of pharmaceutical agents sparingly soluble in water. It is another object of the invention to provide pharmaceutical compositions capable of maintaining chemically and / or chemically stabilized pharmaceutical agents sparingly soluble in water during dilution for administration to a patient. It is a further object of the invention to provide pharmaceutical compositions capable of maintaining physically and / or chemically stabilized, therapeutically effective amounts of poorly water soluble pharmaceutical agents with reduced toxicities. It is a further object of the invention to provide stable pharmaceutical formulations using anhydrous docetaxel, as well as compositions resulting from the use of anhydrous docetaxel. It is a further object of the invention to provide improved methods for preparing pharmaceutical compositions capable of maintaining physically and / or chemically stabilized, therapeutically effective amounts of poorly water soluble pharmaceutical agents. It is a further object of the invention to provide improved methods of preparing pharmaceutical compositions capable of maintaining chemically and / or chemically stabilized pharmaceutical agents sparingly soluble in water during the dilution for administration to a patient. It is a further object of the invention to provide improved methods of preparing the pharmaceutical compositions capable of maintaining chemically and / or chemically stabilized, therapeutically effective amounts of poorly water soluble pharmaceutical agents with reduced toxicities. In one embodiment, the invention provides a sterile pharmaceutical composition for parenteral administration comprised of a pharmaceutical agent poorly soluble in water, which is physically and / or chemically stabilized by the addition of excipients to the composition. Prior to the present invention, the relative stability of certain sparingly soluble pharmaceutical agents has limited use in parenteral pharmaceutical compositions due to degradation, due to storage conditions and / or precipitation during dilution. Many different pharmaceutical agents could be prepared unsatisfactorily as parenteral substances due to the absence of a stable composition. The present invention involves the surprising discovery that common excipients such as citrate are capable of stabilizing sparingly water-soluble pharmaceutical agents such as docetaxel. Therefore it is a primary object of the invention to provide compositions comprising docetaxel (and other pharmaceutical agents sparingly soluble in water) and excipients to obtain stable, parenteral pharmaceutical compositions. Therefore, in one embodiment, the invention provides a pharmaceutical composition comprising docetaxel and citrate. In another embodiment, the invention provides a pharmaceutical composition comprising docetaxel, citrate and sodium chloride. Various Modes of the Invention The invention provides compositions (such as pharmaceutical compositions) comprising a poorly water soluble pharmaceutical agent and a stabilizing agent, wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. . For example, the composition may comprise docetaxel and a stabilizing agent, wherein the stability of the composition is improved when compared to that of the composition without the stabilizing agent. In some embodiments, the compositions further comprise a biocompatible polymer. In some embodiments, the biocompatible polymer is a carrier protein (such as an albumin, e.g., such as human serum albumin (HSA)). In some embodiments, the stability of the composition is at least 1.5 times (including for example at least about any of 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, lOx, 15x, 20x, 25x, 30x, or greater) larger when compared to that of a composition without the stabilizing agent. In some embodiments, the pharmaceutical agent poorly soluble in water is unstable in a composition that does not comprise the stabilizing agent. In some embodiments, a composition comprising a poorly water soluble pharmaceutical agent and a stabilizing agent is provided, wherein the stabilizing agent is a chelating agent, and wherein the stability of the composition is improved when compared to that of a composition. without the stabilizing agent. In some embodiments, a composition comprising docetaxel and a stabilizing agent is provided, wherein the stabilizing agent is a chelating agent, and wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. In some embodiments, the composition further comprises a biocompatible polymer. In some embodiments, the biocompatible polymer is a carrier protein (such as albumin, e.g., HSA). In some embodiments, the stabilizing agent is a polydentate chelating agent. In some embodiments, the stabilizing agent comprises one or more carboxylic acid groups. In some modalities, the chelating agent is not deferoxamine (ie, it is different of deferoxamine). In some embodiments, the chelating agent is any of (and in some embodiments selected from the group consisting of) edetate, citrate, malic acid, pentetate, tromethamine, derivatives thereof, and mixtures thereof. In some embodiments, the stabilizing agent is a citrate or a derivative thereof (such as sodium citrate and in some embodiments citric acid). In some embodiments, the composition comprises sodium citrate and sodium chloride. In some embodiments, the composition comprises approximately 200 mM citrate and approximately 300 mM sodium chloride. In some embodiments, the stabilizing agent is an edetate or a derivative thereof (such as EDTA). In some embodiments, a composition comprising a poorly water soluble pharmaceutical agent and a stabilizing agent is provided, wherein the stabilizing agent is sodium gluconate, and wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. In some embodiments, a composition comprising docetaxel and a stabilizing agent is provided, wherein the stabilizing agent is sodium gluconate, and wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. In some embodiments, the composition further comprises a biocompatible polymer In some embodiments, the biocompatible polymer is a carrier protein (such as albumin, e.g., HSA). In some embodiments, a composition comprising a poorly water soluble pharmaceutical agent and a stabilizing agent is provided, wherein the stabilizing agent is sodium pyrophosphate, and wherein the stability of the composition is improved when compared to that of a composition. without the stabilizing agent. In some embodiments, a composition comprising docetaxel and a stabilizing agent is provided, wherein the stabilizing agent is sodium pyrophosphate, and wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. In some embodiments, the composition further comprises a biocompatible polymer. In some embodiments, the biocompatible polymer is a carrier protein (such as albumin, e.g., HSA). In some embodiments, the composition comprises a poorly water soluble pharmaceutical agent, an albumin, and a stabilizing agent, wherein the weight ratio of the albumin to the poorly water soluble pharmaceutical agent in the composition is about 0.01: 1. to about 100: 1, and wherein the stability of the composition is improved when compare with that of a composition without the stabilizing agent. In some embodiments, the composition comprises a poorly water soluble pharmaceutical agent, an albumin, and a stabilizing agent, wherein the weight ratio of the albumin to the poorly water soluble pharmaceutical agent in the composition is approximately 18: 1. or smaller (including for example any of from about 1: 1 to about 18: 1, about 2: 1 to about 15: 1, about 3: 1 to about 12: 1, about 4: 1 to about 10: 1, and about 9: 1), and wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. In some embodiments, the composition comprises docetaxel, an albumin, and a stabilizing agent, wherein the weight ratio of the albumin to docetaxel in the composition is about 18: 1 or less (including for example any of about 1: 1 to about 18: 1, about 2: 1 to about 15: 1, about 3: 1 to about 12: 1, about 4: 1 to about 10: 1, and about 9: 1), and wherein Xa stability of the composition is improved when compared to that of a composition without the stabilizing agent.

In some embodiments, the stabilizing agent is a chelating agent, such as any of (and in some embodiments selected from the group consisting of) edetate, citrate, malic acid, pentetate, tromethamine, derivatives thereof, and mixtures thereof. In some embodiments, the stabilizing agent is a citrate or a derivative thereof (such as sodium citrate). In some embodiments, the composition comprises sodium citrate and sodium chloride. In some embodiments, the stabilizing agent is an edetate or a derivative thereof (such as EDTA). In some embodiments, the stabilizing agent is sodium gluconate. In some embodiments, the stabilizing agent is sodium pyrophosphate. In some embodiments, the pharmaceutical agent / protein is in particulate form (s), which in various embodiments may be of the average diameters as described herein. In some embodiments, the composition comprises a sparingly water-soluble pharmaceutical agent associated with a protein and a stabilizing agent, wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. In some embodiments, the composition comprises a docetaxel associated with the protein and a stabilizing agent, wherein the stability of the composition is improved when compared with that of a composition without the stabilizing agent. In some embodiments, the stabilizing agent is a chelating agent, such as any of (and in some embodiments selected from the group consisting of) edetate, citrate, malic acid, pentetate, tromethamine, derivatives thereof, and mixtures thereof. In some embodiments, the stabilizing agent is a citrate or a derivative thereof (such as sodium citrate). In some embodiments, the composition comprises sodium citrate and sodium chloride. In some embodiments, the stabilizing agent is an edetate or a derivative thereof (such as EDTA). In some embodiments, the stabilizing agent is sodium gluconate. In some embodiments, the stabilizing agent is sodium pyrophosphate. In some embodiments, the composition comprises (1) particles (such as nanoparticles) comprising (in various embodiments consisting of or consisting essentially of) a poorly water soluble pharmaceutical agent and the biocompatible polymer (such as a carrier protein, which it can be an albumin such as HSA); and (2) a stabilizing agent, wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. In some embodiments, the composition comprises particles (such as nanoparticles) comprising (in various embodiments that consist of or consisting essentially of) (1) docetaxel and a biocompatible polymer (such as a carrier protein, which may be albumin such as HSA); and (2) a stabilizing agent, wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. In some embodiments, docetaxel is coated with the biocompatible polymer (such as the carrier protein). In some embodiments, the stabilizing agent is a chelating agent, such as any of (and in some embodiments selected from the group of) edetate, citrate, malic acid, pentetate, tromethamine, derivatives thereof, and mixtures thereof. In some embodiments, the stabilizing agent is a citrate or a derivative thereof (such as sodium citrate). In some embodiments, the composition comprises sodium citrate and sodium chloride. In some embodiments, the stabilizing agent is an edetate or a derivative thereof (such as EDTA). In some embodiments, the stabilizing agent is a malic acid. In some embodiments, the stabilizing agent is sodium gluconate. In some embodiments, the stabilizing agent is sodium pyrophosphate. In some embodiments, the composition comprises (1) particles (such as nanoparticles) comprising (in various embodiments consisting of or consisting essentially of) a sparingly soluble pharmaceutical agent in water and albumin; and (2) a stabilizing agent, wherein the weight ratio of the albumin to the poorly water soluble pharmaceutical agent in the composition is from about 0.01: 1 to about 100: 1, and wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. In some embodiments, the pharmaceutical agent poorly soluble in water is coated with albumin. In some embodiments, the composition comprises (1) particles (such as nanoparticles) comprising (in various embodiments consisting of or consisting essentially of) a pharmaceutical agent poorly soluble in water and albumin; and (2) a stabilizing agent, wherein the weight ratio of the albumin to the sparingly water soluble pharmaceutical agent in the composition is about 18: 1 or less (including for example any of about 1: 1 to 18: 1, about 2: 1 to about 15: 1, about 3: 1 to about 12: 1, about 4: 1 to about 10: 1, and about 9: 1), and wherein the stability of the composition is improved when it is compared to that of a composition without the stabilizing agent. In some embodiments, the pharmaceutical agent poorly soluble in water is coated with albumin. In some embodiments, the composition comprises (1) particles (such as nanoparticles) comprising (in various embodiments consisting of or consisting essentially of) docetaxel and albumin; and (2) a stabilizing agent, wherein the weight ratio of albumin and docetaxel in the composition is from about 0.01: 1 to about 100: 1, and wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. In some embodiments, the composition comprises (1) particles (such as nanoparticles) comprising (in various embodiments consisting of or consisting essentially of) docetaxel and albumin; and (2) a stabilizing agent, wherein the weight ratio of albumin and docetaxel in the composition is about 18: 1 or less (including, for example, anything from about 1: 1 to about 18: 1, about 2: 1 to about 15: 1, about 3: 1 to about 12: 1, about 4: 1 to about 10: 1, and about 9: 1), and wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. In some modalities, docetaxel is coated with albumin. In some embodiments, the composition is substantially free (such as free) of the surfactant. In some modalities, the composition it comprises a stable aqueous suspension of particles (such as nanoparticles) comprising docetaxel and albumin (such as albumin coated particles of docetaxel), wherein the composition further comprises a stabilizing agent, wherein the weight ratio of albumin and docetaxel in the composition is about 18: 1 or less (including for example any of from about 1: 1 to about 18: 1, about 2: 1 to about 15: 1, about 3: 1 to about 12: 1, about 4: 1 to about 10: 1, and about 9: 1), and wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. In some embodiments, the composition comprises a dry (such as lyophilized) composition that can be reconstituted, resuspended, or rehydrated to form a generally stable aqueous suspension of particles (such as nanoparticles) comprising docetaxel and albumin (such as docetaxel coated with albumin. ), wherein the composition further comprises a stabilizing agent, wherein the weight ratio of albumin and docetaxel in the composition is about 18: 1 or less (including, for example, anything from about 1: 1 to about 18: 1). , approximately 2: 1 to approximately 15: 1, approximately 3: 1 to about 12: 1, about 4: 1 to about 10: 1, and about 9: 1), and wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. In some embodiments, the stabilizing agent is a chelating agent, such as any of (and in some embodiments selected from the group consisting of) edetate, citrate, malic acid, pentetate, tromethamine, derivatives thereof, and mixtures thereof. In some embodiments, the stabilizing agent is a citrate or a derivative thereof (such as sodium citrate). In some embodiments, the composition comprises sodium citrate and sodium chloride. In some embodiments, the stabilizing agent is an edetate or a derivative thereof (such as EDTA). In some embodiments, the stabilizing agent is sodium gluconate. In some embodiments, the stabilizing agent is sodium pyrophosphate. In some embodiments, the particles (such as nanoparticles) in the composition have a mean or average diameter no greater than about any of 1000, 900, 800, 700, 600, 500, 400, 300, 200, and 100 nm. In some embodiments, the mean or average diameter of the particles is between about 20 to about 400 nm. In some embodiments the mean or average diameter of the particles is between approximately 40 to approximately 200 nm. In some embodiments, the particles or droplets are filterable in sterile conditions. The compositions described herein may be a stable aqueous suspension of the sparingly water soluble pharmaceutical agent, such as a stable aqueous solution of the poorly water soluble pharmaceutical agent at a concentration of anywhere from about 0.1 to about 100 mg / ml, including for example about 0.1 to about 50 mg / ml, about 0.1 to about 20 mg / ml, about 1 to about 15 mg / ml, about 1 to about 10 mg / ml, about 2 to about 8 mg / ml, about 4 to about 6 mg / ml, and approximately 5 mg / ml. In some embodiments, the concentration of the sparingly soluble pharmaceutical agent in water is at least about 1 mg / ml, 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, and 50 mg / ml. In some embodiments, the composition is a dry composition (such as lyophilized) that can be reconstituted, resuspended, or rehydrated to generally form a stable aqueous suspension of the poorly water soluble pharmaceutical agent. In some embodiments the composition is a liquid (such as aqueous) composition obtained by the reconstitution or resuspension of a dry composition. In some embodiments, the composition is an intermediate liquid composition (such as aqueous) that can be dried (such as lyophilized). In some embodiments, the composition is suitable for parenteral administration (such as intravenous). In some embodiments, the composition is suitable for multiple dose administration. In some embodiments, the composition is filterable in sterile conditions. In some embodiments, the composition does not cause significant side effects in an individual (such as a human) when administered to an individual. In some embodiments, the compositions described herein are substantially free (such as free) of the surfactants. The stabilizing agent containing the compositions described herein may further comprise a sugar (including, for example, sucrose, mannitol, fructose, lactose, maltose, and trehalose) or other adjuvants of lyophilization or reconstitution. In some embodiments, the amount of the stabilizing agent in the composition is below a level that induces a toxicological effect (i.e., above a clinically acceptable level of toxicity) or is at a level where a potential side effect may be controlled or tolerated when the composition is administered to an individual. In another aspect, compositions (such as a pharmaceutical composition) comprising docetaxel are provided, wherein the docetaxel used for the preparation of the composition is in an anhydrous form (for example docetaxel can be anhydrous prior to being incorporated into the composition ). In some embodiments, the composition further comprises a stabilizing agent (such as the stabilizing agents described herein). Compositions that include the use of anhydrous docetaxel are further described in a later section. In some embodiments, the composition comprises docetaxel and a biocompatible polymer (such as a carrier protein, e.g., albumin), wherein the docetaxel used for the preparation of the composition is in an anhydrous form. In some embodiments, the composition comprises particles (such as nanoparticles) comprising docetaxel and a biocompatible polymer (such as a carrier protein e.g. albumin), wherein the docetaxel used for the preparation of the composition is in an anhydrous form. In some embodiments, the composition comprises nanoparticles comprising docetaxel and albumin, wherein the docetaxel used for the preparation of the composition It is in the anhydrous form. In some embodiments, the weight ratio of albumin and docetaxel in the composition is less than 18: 1, including for example any of from about 1: 1 to about 18: 1, about 2: 1 to about 15: 1, about 3: 1 to about 12: 1, about 4: 1 to about 10: 1, and about 9: 1. In some modalities, docetaxel is coated with albumin. In some embodiments, the nanoparticles in the composition have a mean or average size no greater than about 200 nm. In some embodiments, the particles in the composition are filterable in sterile conditions. In some embodiments, the nanoparticles in the compositions have two or more of these properties. In some embodiments, the composition comprises docetaxel and a surfactant, wherein the docetaxel used for the preparation of the composition is in an anhydrous form. In some embodiments, the surfactant used in the preparation of the composition is anhydrous. In some embodiments, the surfactant is a polysorbate (such as Tween 80). In some embodiments, the surfactant is Cremophor. In some embodiments, the composition further comprises a stabilizing agent (such as the stabilizing agents described herein).

Compositions prepared with anhydrous docetaxel may be dry compositions (such as lyophilized). In some embodiments, the composition is a liquid (such as aqueous) composition obtained by the reconstitution or resuspension of a dry composition. In some embodiments, the composition is an intermediate liquid composition (such as aqueous) that can be dried (such as lyophilized). Unitary dosage forms of the compositions described herein are also provided, articles of manufacture comprising the inventive compositions or unit dosage forms in the appropriate package (such as vials or containers (including vials or sealed containers and vials or sterile sealed containers). ), and the kits comprising the compositions. The invention also provides methods of making the compositions as described herein. Methods of stabilizing a sparingly water soluble pharmaceutical agent in a composition are also provided. In some embodiments, a method of stabilizing a sparingly water soluble pharmaceutical agent in a composition (such as a nanoparticle composition) is provided, which comprises combining the composition (such as a nanoparticle composition) comprising a sparingly soluble pharmaceutical agent in water with an agent of stabilization, wherein the resulting composition is stable under the same condition under which the composition is unstable prior to the addition of the stabilizing agent. In some embodiments, the method further comprises identifying and selecting a composition that is unstable under one or more conditions. In some embodiments, the composition for screening comprises a pharmaceutical agent sparingly soluble in water and a carrier protein (such as albumin). The methods of use of the compositions described herein are also provided. For example, in some embodiments, a method of treating cancer in an individual (such as a human) is provided, which comprises administering to the individual an effective amount of a composition comprising an antineoplastic agent sparingly soluble in water, a carrier protein (such as albumin), and a stabilizing agent, wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. In some embodiments, there is provided a method of treating cancer in an individual (such as a human), which comprises administering to the individual an effective amount of a composition comprising docetaxel, a carrier protein (such as albumin), and an agent stabilizer, where the stability of the composition is improved when compare with that of a composition without the stabilizing agent. In some embodiments, the composition comprises particles (such as nanoparticles) comprising docetaxel and a carrier protein. In some embodiments, the composition comprises particles (such as nanoparticles) comprising docetaxel and albumin (such as nanoparticle formulations comprising docetaxel or Nab-docetaxel albumin). In some embodiments, the composition comprises Nab-docetaxel and citrate. In some embodiments, the composition comprises NaJb-docetaxel, citrate, and sodium chloride (such as approximately 200 mM sodium chloride and approximately 300 mM sodium citrate). In some modalities, the cancer is either: prostate cancer, colon cancer, head and neck cancer, breast cancer, pancreatic cancer, lung cancer, and cancer of the ovaries. In some modalities, cancer is a solid tumor. In some embodiments, the composition is administered at least approximately any one time every three weeks, once every two weeks, once a week, twice a week, three times a week, four times a week, five times times a week, six times a week or daily. In some embodiments, the composition is administered (with or without interruptions) for at least about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more month (s) . In some modalities, the composition it is administered by intravenous, intra-arterial, oral, topical or inhalation routes. The general reference to "the compositions" or "compositions" include and are applicable to the compositions of the invention. The invention also provides pharmaceutical compositions comprising the components described herein. The reference to docetaxel applies here to docetaxel or its derivatives (or analogs) and accordingly the invention contemplates and includes both of these modalities. The reference to "docetaxel" is to simplify the description and is exemplary. Derivatives or analogues of docetaxel include, but are not limited to, compounds that are structurally similar to d? Cetaxel or are in the same general chemical class as docetaxel, e.g., taxanes. In some embodiments, the docetaxel derivative or analog retains a similar biological, pharmacological, chemical and / or physical property (including, for example, functionality) of docetaxel. Examples of the docetaxel derivatives or analogs include paclitaxel and ortataxel. This same principle of description applies to other agents provided herein such as those which include, for example, stabilizing agents and poorly water soluble pharmaceutical agents (such as taxane (including paclitaxel, ortataxel, or other taxanes), geldanamycin, 17-ally Not me geldanamycin, thiocolchicine and its dimers, rapamycin, cyclosporine, epothilone, radicicol, and combrestatin). It is understood that the aspects and embodiments of the invention described herein include "consisting" and / or "consisting essentially of" the aspects and modalities. Stabilizing agents Various compositions described herein comprise a stabilizing agent. "Stabilizing agent" as used herein, refers to an agent that improves the stability of the composition when compared to a composition without the addition of the stabilizing agent. In some embodiments, the stability of the composition containing the stabilizing agent is at least about 1.5x (including for example at least about any of 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, lOx, 15x, 20x, 25x, 30x, or more) larger when compared to that of a composition without the stabilizing agent. As described above, the stability of a composition can be evaluated by the ability of the poorly water soluble pharmaceutical agent to remain unprecipitated or non-sedimented (for example based on a visual observation and / or microscopy observation) in a liquid suspension during a certain period of time. The stability of a dry composition (such as a lyophilized) can be evaluated based on the behavior of the liquid suspension resulting from the reconstitution or rehydration of the dry composition. In some embodiments, the stabilizing agent retards or prevents precipitation or settling of the poorly water soluble pharmaceutical agent in a liquid suspension. In some embodiments, the stabilizing agent retards or prevents crystallization of the poorly water soluble pharmaceutical agent in the composition. In some embodiments when the composition comprises particles of sparingly water-soluble agents, the stabilizing agent can prevent or retard changes in particle sizes in the composition. Stabilizing agents are particularly useful for compositions that might otherwise exhibit significant instability. For example, in some embodiments, the composition prior to the addition of the stabilizing agent is stable for less than about 24 hours (including for example less than about any of 12, 10, 8, 6, 4, or 2 hours). In the same embodiments, the pharmaceutical agent poorly soluble in water in a liquid suspension prior to the addition of the stabilizer is precipitated or settled in less than about 24 hours (including for example less than about any of 12, 10, 8, 6, 4 or 2 hours). In some modalities, the composition prior to the addition of stabilizing agent is precipitated or settled in less than about 24 hours when the concentration of the sparingly soluble pharmaceutical agent in water is greater than about 0.1 mg / ml (including for example greater than about any 0.5 mg / ml, 1 mg / ml, 1.3 mg / ml, 1.5 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, or 10 mg / ml). In some embodiments, the composition prior to the addition of the stabilizing agent is precipitated or sedimented during the dilution of the composition for parenteral administration. The addition of the stabilizing agent to these compositions allows the composition to remain stable (eg, without precipitating or settling) under similar conditions. Accordingly, in some embodiments, a composition comprising a poorly water soluble pharmaceutical agent and a stabilizing agent is provided, wherein the composition (such as a nanoparticle composition) is stable under the same condition under which the composition without the Stabilizing agent is unstable. In some embodiments, the stabilizing agent retards or prevents the precipitation or settling of the sparingly water-soluble pharmaceutical agent in a liquid suspension of a composition under a condition wherein the poorly water soluble pharmaceutical agent could be precipitated or otherwise pelleted. Suitable stabilizing agents include but are not limited to sodium citrate (all forms, 0.01-0.20% w / v), sodium pyrophosphate (0.1-10% w / v), EDTA (all forms, 0.01-20%), pentetate (all forms, 0.01-20%), sodium gluconate (0.1-10% w / v) and suitable combinations thereof. The percentage by weight (w / v) refers to the percentage of the stabilizing agent in a liquid composition, or, in the case of a solid composition, the percentage by weight (w / v) of the stabilizing agent during reconstitution or rehydration. The stabilizing agent must be used in an amount sufficient to increase the stability of the formulation. Preferably, the amount of the stabilizing agent used will provide a stable composition that shows no evidence of precipitation or settling for at least about 8 hours, more preferably at least 24 hours after reconstitution or rehydration, more preferably for at least about 48 hours, yet more preferably for at least about 72 hours. In some embodiments, the stabilizing agent is a chelating agent. These chelating agents are either specific for a particular metal ion (such as calcium, zinc, magnesium, etc.), or show a broad spectrum of metal ion specificity. In some embodiments, the chelating agent is a polydentate. In some modalities, the The chelating agent comprises one or more carboxylic acid groups. In some embodiments, the chelating agent is not deferoxamine. Suitable chelating agents include, but are not limited to edetate, citrate, malic acid, pentetate, tromethamine, and derivatives thereof. A stabilizing agent contemplated herein is an edetate, ie, ethylenediaminetetraacetic acid (EDTA) and derivatives thereof. Suitable edetates include disodium edetate, trisodium edetate, tetrasodium edetate, and disodium calcium edetate. In some embodiments, the edetate is present in the compositions in a concentration of about 0.01 mg / ml to about 200 mg / ml, including for example about 0.05 mg / ml to about 150 mg / ml, about 0.1 mg / ml to about 100. mg / ml, about 0.2 to about 50 mg / ml, about 0.5 mg / ml to about 20 mg / ml, about 1 mg / ml to about 10 mg / ml, and about 1 mg / ml to about 5 mg / ml. In some embodiments, the weight ratio of the edetate and the sparingly water soluble pharmaceutical agent (such as docetaxel) in the composition is about 0.002: 1 to about 40: 1, including for example about 0.01: 1 to about 30: 1. , approximately 0.02: 1 to approximately 20: 1, approximately 0.04: 1 to about 10: 1, about 0.1: 1 to about 4: 1, about 0.2: 1 to about 2: 1, about 0.2: 1 to about 1: 1. Another stabilizing agent contemplated herein is citrate or a derivative thereof (ie, citric acid or derivatives thereof) such as sodium citrate. Suitable concentrations of citrate include, for example, about 0.1 mg / ml to about 200 mg / ml, including for example, any of from about 0.2 mg / ml to about 100 mg / ml, about 0.3 mg / ml to about 50 mg / ml , about 0.5 to about 10 mg / ml, and about 1 mg / ml to about 5 mg / ml. In some embodiments, the concentration of sodium citrate is less than about 200 mg / ml, such as less than about any of 100, 50, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, or 0.2 mg / ml. In some embodiments, the weight ratio of the citrate and the sparingly water soluble pharmaceutical agent (such as citrate) in the composition is from about 0.02: 1 to about 40: 1, including for example any of from about 0.04: 1 to about 20: 1, approximately 0.06: 1 to approximately 10: 1, approximately 0.1: 1 to approximately 2: 1, and about 0.2: 1 to about 1: 1. In some embodiments, the weight ratio of the citrate and the sparingly water soluble pharmaceutical agent in the composition is less than about any of 20: 1, 10: 1, 8: 1, 5: 1, 2: 1, 1: 1 , 0.8: 1, 0.5: 1, 0.2: 1, and 0.1: 1. Any form of citrate is acceptable for use in the present invention, and includes, for example, citric acid and sodium citrate. Sodium citrate is particularly preferred. When sodium citrate is used, suitable concentrations include about 1 to 600 mM. When citrate and sodium chloride are used, suitable concentrations include about 1 to 600 mM and 1 to 1000 mM, respectively. In some embodiments, the concentrations of citrate and sodium chloride are from about 50 to about 200 mM and about 300 to about 500 mM, respectively. In some embodiments, the composition comprises approximately 50 mM citrate (such as sodium citrate) and approximately 500 mM sodium chloride. In some embodiments, the composition comprises approximately 200 mM citrate (such as sodium citrate) and approximately 300 mM sodium chloride. In some embodiments, the composition is a dry composition (such as lyophilized), wherein the weight ratio of citrate to docetaxel in the composition is about 17: 1 and, when sodium chloride is present, the weight ratio of sodium chloride to docetaxel is about 3.5: 1. In other embodiments, the stabilizing agent is not a citrate (ie, different from citrate). The stabilizing agent can also be a pentetate (including trisodium calcium penterate). In some embodiments, the amount of pentetate is in a concentration of about 0.01 mg / ml to about 200 mg / ml, including, for example, anything from about 0.05 mg / ml to about 150 mg / ml, about 0.1 mg / ml to about 100. mg / ml, about 0.2 to about 50 mg / ml, about 0.5 mg / ml to about 20 mg / ml, about 1 mg / ml to about 10 mg / ml, and about 1 mg / ml to about 5 mg / ml. In some embodiments, the weight ratio of the pentetate and the sparingly water soluble pharmaceutical agent (such as docetaxel) in the composition is from about 0.002: 1 to about 40: 1, including for example any of from about 0.01: 1 to about 30: 1, about 0.02: 1 to about 20: 1, about 0.04: 1 to about 10: 1, about 0.1: 1 to about 4: 1, about 0.2: 1 to about 2: 1, about 0.2: 1 to about 1: 1. Another stabilizing agent contemplated here is tromethamine. The tromethamine as used herein, refers to 2-amino-2-hydroxymethyl-l, 3-propanediol, also known as TRIS. In some embodiments, the tromethamine is in a concentration of about 0.1 mg / ml to about 100 mg / ml, including for example about 0.5 mg / ml to about 50 mg / ml, about 1 mg / ml to about 10 mg / ml, and about 2 mg / ml to about 5 mg / ml. In some embodiments, the weight ratio of the tromethamine and the sparingly water soluble pharmaceutical agent in the composition is from about 0.02: 1 to about 20: 1, including for example 0.1: 1 to about 10: 1, about 0.2: 1. to about 2: 1, and about 0.4: 1 to about 1: 1. Other suitable metal stabilizing, chelating agents, and their exemplary amount include, but are not limited to, potassium sorbate (0.5 mg / ml), sodium ascorbate (1 mg / ml), sodium formaldehyde sulfoxylate (0.1 mg) / ml), and monothioglycerol (5 mg / ml). In some embodiments, the stabilizing agent is sodium pyrophosphate. The appropriate concentration of sodium pyrophosphate includes any of about 0. 1 to about 10% (w / v), about 0.5 to about 5%, and about 1 to about 2%. In some embodiments, the weight ratio of sodium pyrophosphate and the sparingly water soluble pharmaceutical agent in the composition is any of from about 0.2: 1 to about 20: 1, about 1: 1 to about 10: 1, about 2: 1. up to about 4: 1. In some embodiments, the stabilizing agent is sodium gluconate. The appropriate concentration of sodium gluconate includes any of from about 0.1 to about 10% (w / v), about 0.5 to about 5%, and about 1 to about 2%. In some embodiments, the weight ratio of the sodium gluconate and the sparingly water soluble pharmaceutical agent in the composition is any of from about 0.2: 1 to about 20: 1, about 1: 1 to about 10: 1, about 2: 1. up to about 4: 1. In some embodiments, the compositions described herein comprise at least two (including for example at least any of 2, 3, 4, 5, 6, 7, 8, 9, or 10) different stabilizing agents (such as the stabilizing agents described herein) ). Pharmaceutical agents sparingly soluble in water The compositions described herein comprise pharmaceutical agents sparingly soluble in water. For example, the solubility in water of the sparingly soluble agent in water at about 20-25 ° C may be less than about 10 mg / ml, including for example less than about any of 5, 2, 1, 0.5, 0.2, 0.1 , 0.05, 0.02, and 0.01 mg / ml. Pharmaceutical agents sparingly soluble in water for use in the practice of the present invention include pharmaceutically poorly water soluble active agents, diagnostic agents, nutritional value agents and the like. Pharmaceutical agents sparingly soluble in water may be, for example, analgesics / antipyretics, anesthetics, antiasthmatics, antibiotics, antidepressants, antidiabetics, antifungals, antihypertensive agents, antiinflammatories, antineoplastics, anti-anxiety agents, immunosuppressive agents, antimige agents, sedatives, antianginal agents, antipsychotic agents, antimalarial agents, antiarrhythmics, antiarthritic agents, anti-rat agents, anticoagulants, thrombolytic agents, antifibrinolytic agents, haemorheological agents, antiplatelet agents, anticonvulsants, antiparkinson agents, antihistamines / antipruritics, useful agents for the regulation of calcium, antibacterial agents, agents antivirals, antimicrobials, antiinfectives, bronchodilators, hormones, hypoglycemic agents, hypolipidemic agents, antiulcer / anti-reflux agents, anti-nausea / anti-vomit agents, and oil-soluble vitamins (for example, vitamins A, D, E, K, and the like). In some embodiments, the poorly water soluble pharmaceutical agent is an antineoplastic agent. In some embodiments, the pharmaceutical agent poorly soluble in water is a chemotherapeutic agent. Suitable water-sparing pharmaceutical agents include, but are not limited to, taxanes (such as paclitaxel, docetaxel and other taxanes), epothilones, campothothecins, colchicines, geladanamicins, amiodarones, thyroid hormones, amphotericin, corticosteroids, propofol. , melatonin, cyclosporine, rapamycin (sirolimus) and derivatives, tracrolimus, mycophenolic acids, ifosfamide, vinorrelbine, vancomycin, gemcitabine, SU5416, thiotepa, bleomycin, diagnostic radiocontrast agents, and derivatives thereof. Other poorly water soluble pharmaceutical agents that are useful in the compositions of the invention are described in, for example, U.S. Pat. Nos. 5,916,596, 6,096,331, 6,749,868, and 6,537,539. Additional examples of poorly water soluble pharmaceutical agents include those compounds that are sparingly soluble in water and which are listed in the "Therapeutic Category and Biological Activity Index" of The Merck Index (12th edition, 1996). In some embodiments, the poorly water soluble pharmaceutical agent is any of (and in some embodiments is selected from the group consisting of) paclitaxel, docetaxel, ortataxel or other taxane or taxane analog, 17-allyl amino geldanamycin (17-AAG) , 18-derived geldanamycin, camptothecin ", propofol, amiodarione, cyclosporine, epothilone, radicicol, combrestatin, rapamycin amphotericin, liothyronine, epothilone, colchicine, thiocolchicine and its dimers, thyroid hormones, vasoactive intestinal peptide, corticosteroids, melatonin, tracrolimus, mycophenolic acids, epothilones, radicicols, combrestatins, and analogs or derivatives thereof In some embodiments, the sparingly water soluble pharmaceutical agent is any of (and in some embodiments is selected from the group consisting of) paclitaxel, docetaxel, ortataxel, or other taxanes, geldanamycin, 17-allyl amino geldanamycin, thiocolchicine and its dimers, rapamycin, cyclosporine, epothilone, radicicol, and combrestatin. In some embodiments, the sparingly soluble pharmaceutical agent in water is rapamycin. In some embodiments, the poorly water soluble pharmaceutical agent is 17-AAG. In some embodiments, the pharmaceutical agent poorly soluble in water is a dimer of thiocolchicin (such as IDN5404). In some embodiments, the sparingly water soluble pharmaceutical agent is a taxane or derivative thereof, which includes, but is not limited to paclitaxel, docetaxel and IDN5109 (ortataxel), or a derivative thereof. In some embodiments, the composition comprises a non-crystalline and / or amorphous taxane (such as paclitaxel or a derivative thereof). In some embodiments, the composition is prepared using an anhydrous taxane (such as anhydrous docetaxel or a derivative thereof). In some embodiments, the poorly water soluble pharmaceutical agent is docetaxel or a derivative thereof. In some embodiments, docetaxel in the composition is nanocrystalline or amorphous. In some embodiments, docetaxel is in any of one or more of the following forms: the semihydrate, dihydrate, and trihydrate forms. Anhydrous docetaxel has been shown to produce a more stable formulation than that which can be made with a hydrated docetaxel such as the docetaxel trihydrate or hemihydrate, and is particularly useful for the preparation of the docetaxel compositions described herein. Biocompatible Polymers and Carrier Proteins The compositions described herein may also comprise biocompatible polymers, such as the carrier proteins described further herein.

As used herein, the term "biocompatible" describes a substance that does not alter or appreciably affect in any adverse way, the biological system within which it is introduced. The biocompatible polymer includes synthetic and naturally occurring biocompatible materials such as proteins, polynucleotides, polysaccharides (eg, starch, cellulose, dextrans, alginates, chitosan, pectin, hyaluronic acid, and the like), and lipids. Suitable biocompatible polymers include, for example, synthetic or naturally occurring proteins such as albumin, insulin, hemoglobin, lysozyme, immunoglobulins, α-2-macroglobulin, fibronectin, vitronectin, fibrinogen, casein and the like, as well as combinations of any two or more thereof. Synthetic polymers include, for example, polyalkylene glycols (eg, straight or branched chain), polyvinyl alcohol, polyacrylates, polyhydroxyethyl methacrylate, polyacrylic acid, polyethyloxazoline, polyacrylamides, polyisopropyl acrylamides, polyvinylpyrrolidone, polylactide / glycolide and the like, and combinations thereof. The term "proteins" refers to polypeptides or polymers of amino acids of any length (including fragments or full length), which may be linear or branched, comprised of modified amino acids, and / or they will be interrupted by substances other than amino acids. The term also encompasses an amino acid polymer that has been modified naturally or by intervention; for example, the formation of disulfide bonds, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification. Also included within this term are, for example, polypeptides that contain one or more analogues of an amino acid (including, for example, non-natural amino acids etc.), as well as other modifications known in the art.

The proteins described herein may be those that are naturally present, ie, obtained or derived from a natural agent (such as blood), or synthesized (such as those synthesized chemically or synthesized by recombinant DNA techniques). Examples of suitable proteins include proteins normally found in plasma or blood, including, but not limited to, albumin, immunoglobulins including IgA, lipoproteins, apolipoproteins B, α-acid glycoprotein, β-2-macroglobulin, thyroglobulin , transferrin, fibronectin, factor VII, factor VIII, factor IX, factor X, and the like. In some embodiments, the carrier protein is a different protein from blood, such as casein, α-lactalbumin, and β-lactoglobulin. The proteins can be either of origin natural or can be prepared synthetically. In some embodiments, the pharmaceutically acceptable carrier comprises albumin, such as HSA. HSA is a highly soluble globular protein of Mr 65K and consists of 585 amino acids. The HSA is the most abundant protein in the plasma and is quantified in 70-80% of the colloidal osmotic pressure of human plasma. The amino acid sequence of HSA contains a total of 17 disulfide bridges, a free thiol (Cys 34) and a single tryptophan (Trp 214). Intravenous use of the HSA solution has been indicated for the prevention and treatment of hypovolume shock (see, for example, Tullis, JAMA, 237, 355-360, 460-463, (1977)) and Houser et al., Surgery. , Gynecology and Obstetrics, 150, 811-816, (1980)) and in conjunction with exchange transfusion in the treatment of neonatal hyperbilirubinemia (see, eg, Finlayson, Seminars in Thrombosis and Hemostasis, 6, 85-120, (1980)). Other albumins are contemplated, such as bovine serum albumin. The use of such non-human albumins could be appropriate, for example, in the context of the use of these compositions in non-human mammals, such as veterinary animals (including domestic pets and farm animals). Human serum albumin (HSA) has multiple hydrophobic agglutination sites (a total of eight for fatty acids, an endogenous ligand of HSA) and agglutinates a a diverse set of drugs, especially neutral and negatively charged hydrophobic compounds (Goodman et al., The Pharma cological Basic of Therapeutics cs, 9 / a, ed., McGraw-Hill New York (1996)). Two high-affinity agglutination sites have been proposed in HSA subdomains IIA and IIIA, which are highly elongated hydrophobic cavities with charged lysine and near-surface affinin residues that function as binding sites for the characteristics of the polar ligand. (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 et al., Na t. Struct. Biol., 5, 827-35 (1998), Sugio et al., Protein Eng. 12, 439-46 (1999). ), He et al., Na ture, 358, 209-15 (1992), and Carter et al., Adv. Protein, Chem., 45, 153-203 (1994)). Paclitaxel and propofol have been shown to bind to HSA (see, for example, Paal et al., Eur, J. Biochem., 268 (7), 2187-91 (2001), Purcell et al., Biochim. Biophys., Acta, 1478 (1), 61-8 (2000), Altmayer et al., Arzneimi ttelforschung, 45, 1053-6 (1995), and Garrido et al., Rev. Esp. Anestestiol. Reanim, A l, 308-12 (1994)). In addition, docetaxel has been shown to bind to proteins in human plasma (see, for example, Urien et al., Invest, New Drugs, 14 (2), 147-51 (1996)). To provide an example, proteins carriers are further described below. It is understood that this description generally applies to biocompatible polymers. The carrier protein (such as albumin) in the composition generally serves as a carrier for the poorly water soluble pharmaceutical agent, ie, the carrier protein in the composition makes the pharmaceutical agent sparingly soluble in water more easily suspended in an aqueous medium or it helps maintain the suspension when compared to compositions that do not comprise a carrier protein. This can avoid the use of toxic solvents to solubilize the sparingly water soluble pharmaceutical agent, and thus one or more of the side effects of administration of the poorly water soluble pharmaceutical agent in an individual (such as an animal) can be reduced. human) . Accordingly, in some embodiments, the composition described herein is substantially free (such as free) of surfactants (such as Tween 20). A composition is "substantially free of the surfactant" if the amount of the surfactant in the composition is not sufficient to cause one or more secondary effect (s) in an individual when the composition is administered to the individual. In some embodiments, the carrier protein is associated with the poorly water soluble pharmaceutical agent, ie, the composition comprises the poorly water soluble pharmaceutical agent associated with the carrier protein. "Association" or "partner" is used herein in a general sense and refers to the carrier protein that affects a behavior and / or property of the pharmaceutical agent sparingly soluble in water in an aqueous composition. For example, the carrier protein and the poorly water soluble pharmaceutical agent are considered to be "associated" if the carrier protein renders the pharmaceutical agent sparingly soluble in water more easily suspended in an aqueous medium when compared to a composition without the carrier protein . As another example, the carrier protein and pharmaceutical agent poorly soluble in water are associated if the carrier protein stabilizes the poorly water soluble pharmaceutical agent in an aqueous composition. For example, the carrier protein and the pharmaceutical agent sparingly soluble in water may be present in a particle or a nanoparticle, which will be described here further. A pharmaceutical agent sparingly soluble in water is "stabilized" by a carrier protein in an aqueous suspension if it remains suspended in an aqueous medium (such as without visible precipitation or sedimentation) for a prolonged period of time, such as approximately any of 0.1, 0.2, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36, 48, 60, or 72 hours. The suspension is generally, but not necessarily, suitable for administration to an individual (such as a human being). As described above, the stability of the suspension is evaluated in some embodiments at room temperature (such as at 20-25 ° C) or in refrigerated conditions (such as 4 ° C)). The stability can also be evaluated under accelerated test conditions, such as at a temperature that is higher than about 40 ° C. As described above, the stability of the suspension can be further improved by the addition of the stabilizing agents described herein. The carrier protein and the sparingly water soluble pharmaceutical agent in the composition may be associated in various ways. For example, in some embodiments, the carrier protein is mixed with the poorly water soluble pharmaceutical agent. In some embodiments, the carrier protein encapsulates or entraps the pharmaceutical agent sparingly soluble in water. In some embodiments, the carrier protein is bound (as bound non-covalently) to the pharmaceutical agent poorly soluble in water. In some embodiments, the composition may exhibit one or more of the above aspects. In some embodiments, the composition comprises particles (such as nanoparticles) comprising (in various embodiments essentially consisting of) a pharmaceutical agent sparingly soluble in water and a carrier protein. When the pharmaceutical agent poorly soluble in water is in a liquid form, the particles or nanoparticles are also referred to as drops or nanogotes. In some embodiments, the poorly water soluble pharmaceutical agent is coated with the carrier protein. Particles (such as nanoparticles) of sparingly water-soluble pharmaceutical agents have been described in, for example, U.S. Pat. Nos. 5,916,596; 6,506,405; 6,537,579; and also in the U.S. patent application. in the publication No. 2005 / 0004002A1. In some embodiments, the composition comprises particles (such as nanoparticles) with an average or average diameter no greater than about 1000 nanometers (nm), such as no greater than about any of 900, 800, 700, 600, 500, 400, 300 , 200, and 100 nm. In some embodiments, the average diameters or averages of the particles are not greater than about 200 nm. In some embodiments, the mean or average diameter of the particles is between about 20 to about 400 nm. In some embodiments, the mean or average diameter of the particles is between about 40 to about 200 nm. In some modalities, the nanoparticles in the composition have a mean or average particle size no greater than about 200 nm. In some embodiments, the particles are filterable in sterile conditions. The particles (such as the nanoparticles) described herein may be present in a dry formulation (such as a lyophilized composition,) or suspended in a biocompatible medium. Suitable biocompatible medium includes, but is not limited to, water, a buffered aqueous medium, a saline solution, a buffered saline solution, optionally buffered amino acid solutions, optionally buffered solutions of proteins, optionally buffered solutions of sugars, optionally buffered solutions of vitamins, optionally buffered solutions of synthetic polymers, emulsions containing lipids, and the like. The amount of the carrier protein in the composition described herein will vary depending on the pharmaceutical agent poorly soluble in water and other components in the composition. In some embodiments, the composition comprises a carrier protein in an amount that is sufficient to stabilize the poorly water soluble pharmaceutical agent in an aqueous suspension, for example, in the form of a stable colloidal suspension (such as a stable suspension of nanoparticles) . In some embodiments, the carrier protein is in an amount that reduces the rate of sedimentation of the poorly soluble pharmaceutical agent in water in an aqueous medium. For compositions containing particles, the amount of the carrier protein also depends on the size and density of the particles of the poorly water soluble pharmaceutical agent. In some embodiments, the carrier protein is present in an amount that is sufficient to stabilize the poorly water soluble pharmaceutical agent in an aqueous suspension at a certain concentration. For example, the concentration of the sparingly water-soluble pharmaceutical agent in the composition is from about 0.1 to about 100 mg / ml, including for example any of from about 0.1 to about 50 mg / ml, about 0.1 to about 20 mg / ml, about 1 to about 10 mg / ml, about 2 mg / ml to about 8 mg / ml, about 4 to about 6 mg / ml. In some embodiments, the concentration of the sparingly soluble pharmaceutical agent in water is at least about either 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, and 50 mg / ml. In some embodiments, the carrier protein is present in an amount that avoids the use of surfactants (such as Tween 80 or Cremophor), so that the composition is free or substantially free of the surfactant (such as Tween 80 or Cremophor). In some embodiments, the composition, in the liquid form, comprises from about 0.1% to about 50% (w / v) (e.g., about 0.5% (w / v), about 5% (w / v), about 10% (w / v), approximately 15% (w / v), approximately 20% (w / v), approximately 30% (w / v), approximately 40% (w / v), or approximately 50% (w / v) )) of the carrier protein. In some embodiments, the composition, in the liquid form, comprises about 0.5% up to about 5% (w / v) of the carrier protein. In some embodiments, the weight ratio of the carrier protein, eg, albumin, to the poorly water soluble pharmaceutical agent is such that a sufficient amount of the poorly water soluble pharmaceutical agent binds to, or is transported by, the cell. . Although the proportion by weight of the carrier protein with respect to the pharmaceutical agent will have to be optimized for different combinations of the carrier protein and the drug, generally the weight ratio of the carrier protein, for example the albumin, to the pharmaceutical agent ( p / p) is approximately 0.01: 1 up about 100: 1, including for example any of from about 0.02: 1 to about 50: 1, about 0.05: 1 to about 20: 1, about 0.1: 1 to about 20: 1, about 1: 1 to about 18: 1, about 2: 1 to about 15: 1, about 3: 1 to about 12: 1, about 4: 1 hhasastata about 10: 1, about 5: 1 about about 9: 1, or about 9: 1. In some embodiments, the weight ratio of the carrier protein to the pharmaceutical agent is approximately either 18: 1 or less, 15: 1 or less, 14: 1 or less, 13: 1 or less, 12: 1 or less , 11: 1 or less, 10: 1 or less, 9: 1 or less, 8: 1 or less, 7: 1 or less, 6: 1 or less, 5: 1 or less, 4: 1 or less, and 3: 1 or less. In some embodiments, the carrier protein allows the composition to be administered to an individual (such as a human being) without significant side effects. In some embodiments, the carrier protein (such as albumin) is in an amount that is effective to reduce one or more side effects of administration of the poorly water soluble pharmaceutical agent to a human. The term "reduction of one or more side effects of administration of the sparingly soluble pharmaceutical agent in water" refers to the reduction, alleviation, elimination, or that one or more are avoided - undesirable effects caused by the poorly soluble pharmaceutical agent in water, as well as the side effects caused by the delivery vehicles (such as the solvents which render the pharmaceutical agents sparingly soluble) in water, suitable for injection) used to supply the pharmaceutical agent sparingly soluble in water. Such side effects include, for example, myelosuppression, neurotoxicity, hypersensitivity, inflammation, venous irritation, phlebitis, pain, skin irritation, peripheral neuropathy, neutropenic fever, anaphylactic reaction, venous thrombosis, extravasation, and combinations thereof. These side effects, however, are only exemplary and other side effects, or a combination of side effects, associated with various pharmaceutical agents, can be reduced. In some embodiments, the composition comprises particles (such as nanoparticles) comprising (in various embodiments consisting of or consisting essentially of) a poorly water soluble pharmaceutical agent and an albumin, wherein the weight ratio of the albumin to the pharmaceutical agent sparingly soluble in water in the composition (w / w) is from about 0.01: 1 to about 100: 1, including for example any of from about 0.02: 1 to about 50: 1, about 0.05: 1 to about 20: 1, about 0.1: 1 to about 20: 1, about 1: 1 to about 18: 1, about 2: 1 to about 15: 1, about 3: 1 to about 12: 1, about 4: 1 to about 10: 1, about 5: 1 to about 9: 1, or about 9: 1. In some embodiments, the weight ratio of the carrier protein to the pharmaceutical agent is approximately either 18: 1 or less, : 1 or less, 14: 1 or less, 13: 1 or less, 12: 1 or less, 11: 1 or less, 10: 1 or less, 9: 1 or less, 8: 1 or less, 7: 1 or less, 6: 1 or less, 5: 1 or less, 4: 1 or less, and 3: 1 or less. In some embodiments, the pharmaceutical agent poorly soluble in water is coated with albumin. In some embodiments, particles (such as nanoparticles) comprising a poorly water soluble pharmaceutical agent and albumin are suspended in an aqueous medium (such as an aqueous medium containing albumin). For example, the composition may be a colloidal suspension of the sparingly water soluble pharmaceutical agent particles (such as nanoparticles). In some embodiments, the composition is a dry composition (such as lyophilized) that can be reconstituted or suspended to a suspension stable of the particles described here. The concentration of the poorly water soluble pharmaceutical agent in the liquid composition or the reconstituted composition can be diluted (0.1 mg / ml) or concentrated (100 mg / ml), including for example any of about 0.1 to about 50 mg / ml, approximately 0.1 to about 20 mg / ml, about 1 to about 10 mg / ml, about 2 mg / ml to about 8 mg / ml, about 4 to about 6 mg / ml, and about 5 mg / ml. In some embodiments, the concentration of the sparingly soluble pharmaceutical agent in water (such as docetaxel) is greater than about 0.1 mg / ml. In some embodiments, the concentration of the poorly soluble pharmaceutical agent in water is greater than about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 mg / ml. In some embodiments, the poorly water soluble pharmaceutical agent is a taxane or derivative thereof (such as docetaxel or a derivative thereof). In some embodiments, the composition comprises particles (such as nanoparticles) comprising docetaxel, such as nanoparticles with an average or average diameter of about 20 to about 400 nm. In some embodiments, the particles have a average or average diameter between about 40 to about 200 nm. In some embodiments, the composition comprises particles (such as nanoparticles) comprising (in various embodiments consisting essentially of) docetaxel and albumin. In some modalities, docetaxel is coated with albumin. In some embodiments, the weight ratio of albumin to docetaxel (w / w) in the composition is from about 0.01: 1 to about 100: 1, including for example any of from about 0.02: 1 to about 50: 1, about 0.05: 1 to about 20: 1, about 0.1: 1 to about 20: 1, about 1: 1 to about 18: 1, about 2: 1 to about 15: 1, about 3: 1 to about 12: 1. In some embodiments, the ratio of albumin to docetaxel (w / w) is approximately 18: 1 or less, 15: 1 or less, 14: 1 or less, 13: 1 or less, 12: 1 or less , 11: 1 or less, 10: 1 or less, 9: 1 or less, 8: 1 or less, 7: 1 or less, 6: 1 or less, 5: 1 or less, 4: 1 or less or 3 : 1 or less. In some embodiments, particles (such as nanoparticles) comprising docetaxel and albumin are suspended in an aqueous medium (such as an aqueous medium containing albumin). For example, the composition can be a colloidal suspension of the particles containing docetaxel (such as nanoparticles). In some embodiments, the composition comprises a dry (such as lyophilized) composition that can be reconstituted to an aqueous suspension of particles containing docetaxel. In some embodiments, the concentration of docetaxel in the composition is between about 0.1 and about 100 mg / ml, including for example any of from about 0.1 to about 50 mg / ml, about 0.1 to about 20 mg / ml, about 1 to about 10. mg / ml, approximately 2 mg / ml to approximately 8 mg / ml, approximately 4 to approximately 6 mg / ml, and approximately 5 mg / ml. In some embodiments, the concentration of docetaxel is at least about either 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, and 50 mg / ml. Anhydrous Docetaxel In addition to the use of the stabilizing agents described herein, (such as sodium citrate and sodium citrate / sodium chloride), it has surprisingly been found that the use of docetaxel anhiro leads to a more stable formulation that can be made with a hydrated docetaxel such as docetaxel trihydrate or semi-hydrated. The anhydrous docetaxel formulations of the present invention further improve the stability of aqueous nanoparticle suspensions in such a way that the stability of the suspensions, either before or after lyophilization, exceeds 1 day. In addition, the benefits of an added stability of the anhydrous docetaxel also extend to conventional formulations such as a formulation in Tween 80, Cremophor or other known surfactants. Thus, according to the present invention, docetaxel can be dissolved in a pharmaceutically acceptable solvent or solvents at a final concentration in the range of about 1-99% v / v, more preferably in the range of about 5-25% p / p. Solvents include, for example, chlorinated solvents, ethyl acetate, ethanol, tetrahydrofuran, dioxane, acetonitrile, acetone, dimethyl sulfoxide, dimethyl formamide, methyl pyrrolidinone, oils such as soybean oil, safflower oil and other injectable oils. and similar. In some embodiments, a composition comprising docetaxel is provided, wherein the docetaxel used for the preparation of the composition is in an anhydrous form. In some embodiments, the invention provides a composition comprising docetaxel, wherein at least some of the docetaxel in the composition is in a anhydrous form. For example, in some embodiments, at least about 10% (such as at least about 20%, 30%, 40%, and 50%) of the docetaxel in the composition is in an anhydrous form. In some embodiments, the composition further comprises a stabilizing agent (such as the stabilizing agent described herein). In some embodiments, the composition comprises docetaxel and a biocompatible polymer (such as a carrier protein described herein, e.g., albumin), wherein the docetaxel used for the preparation of the composition is in an anhydrous form. In some embodiments, the composition comprises docetaxel, a biocompatible polymer (such as a carrier protein described herein, e.g. albumin) and a stabilizing agent (such as a stabilizing agent described herein), wherein the docetaxel used for the preparation of the composition It is in an anhydrous form. In some embodiments, the composition is substantially free (such as free) of surfactants. In some embodiments, the composition comprises a surfactant In some embodiments, the invention provides a composition comprising docetaxel and a biocompatible polymer (such as a carrier protein, e.g., albumin), wherein at least some of the docetaxel in the composition is in an anhydrous form, for example, in some embodiments, at least about 10% (such as at least about any 20%, 30%, 40% and 50%) of the docetaxel in the composition is in an anhydrous form. In some embodiments, the composition further comprises a stabilizing agent (such as the stabilizing agent described herein). In some embodiments, the invention provides a composition comprising docetaxel and a surfactant (such as an anhydrous surfactant), wherein the docetaxel used for the preparation of the composition is in an anhydrous form. In some embodiments, the surfactant used for the preparation of the composition is in an anhydrous form. Suitable surfactants include, for example, a polysorbate (such as Tweens) and Cremophor. In some embodiments, the composition may further comprise a stabilizing agent described herein. In some embodiments, the invention provides a composition comprising docetaxel and a surfactant, wherein at least some of the docetaxel in the composition is in an anhydrous form. For example, in some embodiments, at least about 10% (such as at least about any of 20%, 30%, 40%, and 50%) of the docetaxel in the composition is in an anhydrous form. In some embodiments, the composition described Here is a dry composition (such as lyophilized) that can be reconstituted, resuspended, or rehydrated generally to form a stable aqueous suspension of docetaxel. In some embodiments, the composition is a liquid (such as aqueous) composition obtained by the reconstitution or resuspension of a dry composition. In some embodiments, the composition is an intermediate liquid composition (such as aqueous) that can be dried (such as lyophilized). In some embodiments, a method of preparing the compositions comprising docetaxel and a surfactant is provided, wherein the method comprises combining an anhydrous docetaxel with the surfactant. In some embodiments, the surfactant used for the preparation of the composition is anhydrous. In some embodiments, there is provided a method of preparing a composition comprising docetaxel and a biocompatible polymer (such as carrier proteins, e.g., albumin), wherein the method comprises combining an anhydrous docetaxel with a biocompatible polymer (such as a protein). carrier, for example albumin). Compositions produced by the method described herein are also provided. Other components in the compositions The compositions described herein may include other agents, excipients, or stabilizers to improve the properties of the composition. Examples of suitable excipients and diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone. , cellulose, water, a saline solution, syrup, methylcellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate and mineral oil. The formulations may additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preservatives, sweetening agents or flavoring agents. Examples of emulsifying agents include tocopherol esters such as tocopheryl succinate and polyethylene glycol and the like, Pluronic®, emulsifiers based on polyoxyethylene compounds, Span 80 and related compounds and other emulsifiers known in the art and approved for use in the forms of dosage for animals and for humans. The compositions can be formulated to provide a rapid, sustained or delayed release of the active ingredient after administration to the patient employing procedures well known in the art. Preferred compositions for administration by injection include those which comprise a poorly soluble pharmaceutical agent in water as the ingredient active in association with a surface active agent (or wetting agent or surfactant), or in the form of an emulsion (for example, as a water-in-oil or oil-in-water emulsion). Other ingredients may be added, for example, mannitol or other pharmaceutically acceptable vehicles, if necessary. In some embodiments, the composition is suitable for administration to a human being. In some embodiments, the composition is suitable for administration to a mammal such as, in the veterinary context, including domestic pets and farm animals. There is a wide variety of suitable formulations of the inventive composition (see, for example, U.S. Patent Nos. 5,916,596 and 6,096,331). The following formulations and methods are only exemplary and are not limiting in any way. Formulations suitable for administration may comprise (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, a saline solution, or orange juice, (b) capsules, sachets or tablets, each containing, a predetermined amount of the active ingredient, such as solids or granules, (c) suspensions in an appropriate liquid, (d) suitable emulsions and (e) powders. The forms of the tablets may include one or more of lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talcum, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffers, wetting agents, preservatives, flavoring agents, and excipients pharmaceutically compatible The forms of the tablets may comprise the active ingredient in a flavor, usually sucrose or acacia or tragacanth, as well as tablets comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and similar which contain, in addition to the active ingredient, excipients such as those already known in the art. Formulations suitable for parenteral administration include isotonic, aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that make the formulation compatible with the blood of the proposed recipient, and sterile aqueous or non-aqueous suspensions that they may include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The formulations can be presented in single-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze dried condition (lyophilized) requiring only the addition of the sterile liquid excipient, for example, for injections, immediately prior to use. Solutions and suspensions for extemporaneous injection can be prepared from sterile powders, granules, and tablets of the kind previously described. Injectable formulations are preferred. Formulations suitable for aerosol administration comprise the inventive composition which includes isotonic, aqueous and non-aqueous sterile solutions, which may contain anti-oxidants, buffers, bacteriostats, and solutes as well as sterile aqueous and non-aqueous suspensions which may include suspending agents, solubilizers, thickeners, stabilizers, and preservatives, alone or in combination with other suitable agents, which can be manufactured in the aerosol formulations to be administered by inhalation. These aerosol formulations can be placed in acceptable pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They can also be formulated as pharmaceutical substances for non-pressurized preparations, such as in a nebulizer or an atomizer. In some embodiments, the composition is formulated to have a pH in the range of about 4.5 to about 9.0, including for example pH ranges of any of from about 5.0 to about 8.0, about 6.5 to about 7.5, and about 6.5 to about 7.0. In some embodiments, the pH of the composition is formulated to not less than about 6, including for example not less than about any of 6.5, 7, or 8 (such as about 7.5 or about 8). The composition can also be made to be isotonic with the blood by the addition of a suitable tonicity modifier, such as glycerol. Manufacturing articles comprising the compositions described herein in a suitable package are also provided. Suitable packaging for the compositions described herein is already known in the art and includes, for example, vials (such as sealed vials), containers, (such as sealed containers), ampoules, bottles, jars, flexible packaging (for example, sealed plastic or Mylar bags), and the like. These articles of manufacture can be sterilized and / or sealed additionally. Unitary dosage forms comprising the compositions described herein are also provided. These unit dosage forms can be stored in a suitable package in single or multiple unit dosages, and can also be sterilized and sealed further.

The present invention also provides kits comprising the compositions (or the unit dosage forms and / or the articles of manufacture) described herein and may further comprise instruction (s) on the methods of use of the composition, such as the uses described herein. Additionally. In some embodiments, the kit of the invention comprises the package described above. In other embodiments, the kit of the invention comprises the package described above and a second package comprising a buffer. They may also include other desirable materials from a commercial and user's point of view, including other buffers, diluents, filters, needles, syringes, and packing inserts with instructions for performing any methods described herein. Kits may also be provided containing sufficient dosages of the sparingly water-soluble pharmaceutical agent (such as docetaxel) as described herein to provide an effective treatment for an individual over a prolonged period, such as any one week, 2 weeks, 3 weeks , 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or more. The kits may also include multiple unit doses of the sparingly soluble pharmaceutical agent in water and the pharmaceutical compositions and instructions for its use, and packed in sufficient quantities for storage and use in pharmacy, for example, hospital pharmacies and compounding pharmacies. Methods of making and using the compositions Methods of making and using the compositions described herein are also provided. For example, a method of preparing a composition comprising a pharmaceutical agent sparingly soluble in water is provided. (such as a taxane, e.g., paclitaxel, docetaxel or ortataxel), optionally a biocompatible polymer (such as a carrier protein, e.g., albumin), and a stabilizing agent, wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent, comprising the combination (such as mixing) of a composition containing a poorly water soluble pharmaceutical agent and optionally a biocompatible polymer (such as a carrier protein) with a stabilizing agent. Methods for the formation of docetaxel nanoparticles prepared under the conditions of high shear forces (eg, sonication, high pressure homogenization or the like) are also provided. The preparation of the nanoparticles from biocompatible polymers (e.g., albumin) are described in, for example, U.S. Pat. Nos. 5,916,596; 6,506,405; and 6,537,579 and also in the U.S. patent publication. No. 2005 / 0004002A1, incorporated here for reference. Briefly, the sparingly water soluble pharmaceutical agent (such as docetaxel) is dissolved in an organic solvent, and the solution can be added to an aqueous albumin solution. The mixture is subjected to high pressure homogenization. The organic solvent can then be removed by evaporation. The dispersion obtained can be lyophilized further. Suitable organic solvent includes, for example, ketones, esters, ethers, chlorinated solvents, and other solvents known in the art. For example, the organic solvent may be methylene chloride and chloroform / ethanol (for example, in a ratio of 1: 9, 1: 8, 1: 7, 1: 6, 1: 5, 1: 4, 1: 3, 1: 2, 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1). It was surprisingly found that docetaxel compositions, such as those prepared in the references cited above, have a stability that lasts less than 1 day. Indeed, when tested, many of the compositions were stable for only 4 to 8 hours. The present invention allows the increase of liquid stability and post-reconstitution stability by the addition of certain stabilizers before the formation of nanoparticles or after the nanoparticles have been formed.

Thus, improved stabilization methods are provided for a composition comprising a poorly water soluble pharmaceutical agent, comprising the combination of the composition with a stabilizing agent, wherein the resulting composition is stable under the same condition under which the composition it is unstable prior to the addition of the stabilizing agent. In some embodiments, the method further comprises identifying and selecting a composition that is unstable under certain conditions. In some embodiments, the composition for selection comprises a pharmaceutical agent poorly soluble in water and a carrier protein (such as albumin). In some embodiments, the composition for screening comprises particles (such as nanoparticles) comprising the poorly water soluble pharmaceutical agent and a carrier protein (such as albumin). The pharmaceutically acceptable excipients may also be added to the composition. The pharmaceutically acceptable excipients may be a solution, emulsion or suspension. For example, an emulsion of propofol in oil and stabilized by lecithin is well known in the art. Another emulsion or formulations of nanoparticles of the invention can also be prepared. An emulsion is formed by homogenization under high pressure and high shear forces. Such homogenization is Conveniently carried out in a high pressure homogenizer, typically operated at pressures in the range of about 211.11 to 2111.1 kg / cm2 (3,000 to 30,000 psi). Preferably, such processes are carried out at pressures in the range of about 422.22 to 1759.25 kg / cm2 (3,000 to 30,000 psi). The resulting emulsion comprises very small nanogotes of the non-aqueous solvent containing the pharmacologically active agent, dissolved, and very small nanogotes of the stabilizing agent-protein. Acceptable methods of homogenization include processes that impart high shear and cavitation such as, for example, high pressure homogenization, high shear mixers, high shear impellers and the like. The colloidal systems prepared according to the present invention can be further converted to the powder form by the removal of water, for example, by lyophilization at an appropriate time-temperature profile. The protein (for example, HSA) by itself acts as a cryoprotectant, and the powder is easily reconstituted by the addition of water, a saline solution or a buffer, without the need to use conventional cryoprotectants such as mannitol, sucrose, glycine and similar. Although not required, it is assumed that conventional cryoprotectants can be added to the pharmaceutical compositions if so desired. The stabilizing agent can be either mixed with the sparingly water soluble pharmaceutical agent and / or the carrier protein during the preparation of the carrier protein / poorly water soluble pharmaceutical composition, or added after the carrier protein composition / agent Pharmaceutical sparingly soluble in water is prepared. For example, the stabilizing agent may be present in a protein solution prior to formation of the composition of the pharmaceutically poorly water soluble / carrier protein agent. For example, the stabilizing agent can also be added in the presence of an aqueous medium used for the reconstitution / suspension of the carrier protein / pharmaceutical agent composition poorly soluble in water or added to an aqueous suspension of the sparingly soluble pharmaceutical agent associated with water. the carrier protein. In some embodiments, the stabilizing agent is mixed with the carrier protein / pharmaceutical agent composition poorly soluble in water prior to lyophilization. In some embodiments, the stabilizing agent is added to the freeze-dried carrier protein / pharmaceutical composition poorly soluble in water. In some embodiments, when the composition comprises particles (such as nanoparticles), the stabilizing agent may be added either before or after the particles are formed. In some embodiments, when the addition of the stabilizing agent changes the pH of the composition, the pH in the composition is generally (but not necessarily) adjusted to a desired pH. Exemplary pH values of the composition include, for example, in the range of about 5 to about 8.5. In some embodiments, the pH of the composition is adjusted to no less than about 6, including for example not less than any of about 6.5, 7, or 8 (such as about 7.5 or 8). Also provided are methods of making the pharmaceutical compositions comprising combining any of the compositions described herein (including those described above) with a pharmaceutically acceptable excipient. Methods of using the compositions of the present invention are also provided herein. In some embodiments, a method is provided for the treatment of a disease or condition that functions in response to a poorly water soluble pharmaceutical agent, comprising administering a composition comprising an effective amount of the poorly water soluble pharmaceutical agent, optionally a biocompatible polymer (such as a carrier protein), and a stabilizing agent, in wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. For example, in some embodiments, there is provided a method of treating cancer in an individual (such as a human) comprising administering to the subject a composition comprising an effective amount of an antineoplastic agent sparingly soluble in water (such as docetaxel). ), a carrier protein, and a stabilizing agent, wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. In some embodiments, the amount of the stabilizing agent in the composition does not cause any toxicological effect when the composition is administered in an individual (such as a human). In some embodiments, the invention provides a method of treating cancer in an individual (such as a human) comprising administering to the individual an effective amount of docetaxel, wherein the docetaxel used for the preparation of the composition is in the anhydrous form . For example, docetaxel can be anhydrous prior to being incorporated into the composition. The term "effective amount" used herein, refers to an amount of a compound or composition sufficient to treat a specific disorder, condition or disease such as to improve, mitigate, reduce, and / or delay one or more of your symptoms. With reference to malignant tumors or other unwanted cell proliferation, an effective amount comprises an amount sufficient to cause a tumor to shrink and / or to reduce the rate of tumor growth (such as to suppress tumor growth). In some embodiments, an effective amount is an amount sufficient to retard development. In some embodiments, an effective amount is an amount sufficient to prevent presentation and / or recurrence. An effective amount can be administered in one or more administrations. Malignant tumors that are to be treated by the compositions described herein (such as a composition comprising a sparingly water-soluble antineoplastic agent such as docetaxel, rapamycin, and 17-AAG) include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. Examples of malignant tumors that can be treated by the compositions described herein include, but are not limited to, squamous cell cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, lung and squamous cell carcinoma of the lung), cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, cancer of the ovaries, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, melanoma, endometrial or uterine carcinoma, carcinoma of the salivary glands, renal or kidney cancer, liver cancer, prostate cancer, cancer vulvar, thyroid cancer, hepatic carcinoma, head and neck cancer, colorectal cancer, rectal cancer, soft tissue carcinoma, Kaposi's sarcoma, B-cell lymphoma (including non-Hodgkin's lymphoma, low grade) / follicular (NHL), small lymphocytic NHL (SL), follicular NHL / intermediate grade, intermediate-grade diffuse NHL, high-grade immunoblastic NHL, high-grade lymphoblastic NHL, NHL-cell non-segmented, small, high-grade, NHL of bulky disease, mantle cell lymphomas, AIDS-related lymphoma, and aldenstrom macroglobulinemia), chronic lymphocytic leukemia (CLL) in English), acute lymphoblastic leukemia (ALL), myeloma, hair cell leukemia, chronic myeloblastic leukemia, and post-transplant lymphoproliferative disease (PTLD), as well as abnormal vascular proliferation associated with fagomatosis, edema (such as that associated with brain tumors), and Meig's syndrome. In some modalities, a metastatic cancer treatment method is provided (ie, cancer that has metastasized from the primary tumor). In some embodiments, a method of reducing cell migration and / or cell proliferation is provided. In some embodiments, a method of treating hyperplasia is provided. In some modalities, cancer treatment methods in advanced stage (s) are provided. In some embodiments, treatment methods of breast cancer (which may be HER2-positive or HER2-negative) are provided, including, for example, advanced breast cancer, stage IV breast cancer, locally advanced breast cancer. , and metastatic breast cancer. In some embodiments, the cancer is lung cancer, including, for example, non-small cell lung cancer (NSCLC, such as advanced NSCLC), small cell lung cancer (SCLC), such as Advanced SCLC), and malignancies of advanced solid tumors in the tumor. In some modalities, cancer is cancer of the ovaries, cancer of the head and neck, gastric malignancies, melanoma (including metastatic melanoma), colorectal cancer, pancreatic cancer, and solid tumors (such as advanced solid tumors). In some modalities, the cancer is any of (and in some modalities is selected from the group consisting of) breast cancer, colorectal cancer, rectal cancer, lung cancer of non-small cells, non-Hodgkin's lymphoma (NHL), renal cell cancer, prostate cancer, liver cancer, pancreatic cancer, soft tissue sarcoma, Kaposi's sarcoma, carcinoid carcinoma, cancer of the head and neck, melanoma, cancer of the ovaries, mesothelioma, gliomas, glioblastomas, neuroblastomas, and multiple myeloma. In some modalities, cancer is a solid tumor. In some embodiments, the cancer is any of (in some embodiments, it is selected from the group consisting of) prostate cancer, colon cancer, breast cancer, cancer of the head and neck, pancreatic cancer, lung cancer, and cancer of the ovaries. Suitable individuals for the reception of these compositions depend on the nature of the poorly soluble pharmaceutical agent in water, as well as the disease / condition / disorder to be treated and / or prevented. Accordingly, the individual term includes any of the vertebrates, mammals and humans depending on the proper use. In some modalities, the individual is a mammal. In some embodiments, the individual is any one or more of a human, bovine, equine, feline, canine, rodent, or primate. In some modalities, the individual is a human being. In another aspect, a method is provided for the treatment of carcinoma (such as carcinoma of the colon) in an individual, wherein the method comprises administering to the individual a composition comprising an effective amount of docetaxel and a carrier protein (such as albumin). In some embodiments, the composition further comprises a stabilizing agent described herein, such as citrate. In some embodiments, the docetaxel used for the preparation of the composition that is administered to the individual is in an anhydrous form. The docetaxel and the carrier protein may be present in the forms of nanoparticles (such as the nanoparticles described herein). The compositions described herein can be administered alone or in combination with other pharmaceutical agents, including pharmaceutical agents sparingly soluble in water. For example, when the composition contains a taxane (such as docetaxel), it may be co-administered with one or more other chemotherapeutic agents including, but not limited to, carboplatin, navelpine® (vinorrelbine), anthracycline (Doxil) , lapatinib (GW57016), herceptin, gemcitabine (Gemzar®), capecitabine (Xeloda®), alimta, cisplatin, 5-fluorouracil, epirubicin, cyclophosphamide, avastin, velcade®, etc. In some embodiments, the taxane composition is administered with a chemotherapeutic agent selected from the group consisting of antimetabolites (including nucleoside analogs), platinum-based agents, alkylating agents, tyrosine kinase inhibitors, anthracycline antibiotics, vinca alkaloids, proteasome inhibitors, macrolides and topoisomerase inhibitors. These other pharmaceutical agents may be present in the same composition as the drug (such as the taxane), or in a separate composition which is administered simultaneously or consecutively with the composition containing the drug (such as the taxane). The methods of the combination therapy using the nanoparticle formulations of the taxane with other agents (or therapeutic methods) have been described in the international patent application No. PCT / US2006 / 006167. The dose of the inventive composition administered to an individual (such as a human) will vary with the particular composition, the method of administration, and the particular disease being treated. The dose should be sufficient to effect a desirable response, such as a therapeutic or prophylactic response against a particular disease or condition. For example, the dosage of docetaxel administered may be from about 1 to about 300 mg / m2, including for example about 10 to about 300 mg / m2, about 30 to about 200 mg / m2, and about 70 to about 150 mg / m2 .

Typically, the dosage of docetaxel in the composition may be in the range of about 50 to about 200 mg / m2 when provided in a 3-week schedule, or approximately 10 to approximately 100 mg / m2 when provided in a weekly schedule. In addition, if provided in a metronomic method (eg, daily or sometimes weekly), the dosage may be in the range of about 1-50 mg / m2. The frequency of the dosage for the composition includes, but is not limited to, at least approximately any one time every three weeks, once every two weeks, once a week, twice a week, three times a week. , four times a week, five times a week, six times a week, or daily. In some embodiments, the interval between each administration is less than about one week, such as less than about any of 6, 5, 4, 3, 2, or 1 day. In some modalities, the interval between each administration is constant. For example, the administration can be carried out daily, every two days, every three days, every four days, every five days, or per week. In some embodiments, the administration may be carried out twice daily, three times daily or more frequently.

The administration of the composition can be extended for a prolonged period of time, such as from about one month to about three years. For example, the dosage regimen may be prolonged for a period of any of approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, and 36 months. In some modalities, there is no interruption in the dosing program. In some embodiments, the interval between each administration is not greater than about one week. The compositions described herein can be administered to an individual (such as a human) by means of several routes, for example, intravenous, intraarterial, intraperitoneal, intrapulmonary, oral, by inhalation, intravesicular, intramuscular, intratracheal, subcutaneous, intraocular, intrathecal , transmucosal, and transdermal. For example, the inventive composition can be administered by inhalation to treat respiratory tract conditions. The composition can be used to treat respiratory conditions such as pulmonary fibrosis, bronchiolitis obliterans, lung cancer, bronchoalveolar carcinoma, and the like. In one embodiment of the invention, the nanoparticles (such as the albumin nanoparticles) of the compounds of the invention can be administered by any acceptable route including, but not limited to, orally, intramuscularly, transdermally, intravenously, by means of an inhaler or other delivery systems carried by air and the like. When preparing the composition for injection, particularly for intravenous delivery, the continuous phase preferably comprises an aqueous solution of tonicity modifiers, buffered at a pH range of about 5 to about 8.5. The pH may also be below 7 or below 6. In some embodiments, the pH of the composition is not less than about 6, including for example not less than about any of 6.5, 7, or 8 (such as about 7.5 u. 8). The nanoparticles of this invention can be enclosed in a hard or soft capsule, can be compressed into tablets, or can be incorporated with beverages or foods or otherwise incorporated into the diet. The capsules can be formulated by mixing the nanoparticles with an inert pharmaceutical diluent and inserting the mixture into a hard gelatin capsule of the appropriate size. If soft capsules are desired, a suspension of the nanoparticles with an acceptable vegetable oil, light petroleum or other inert oil, can be encapsulated by means of a machine in a capsule of jelly . Also provided here are methods of reducing side effects associated with the administration of a poorly water soluble pharmaceutical agent to a human, which comprises administering to a human being a pharmaceutical composition comprising the poorly water soluble pharmaceutical agent, a polymer biocompatible (such as a carrier protein), and a stabilizing agent, wherein the stability of the composition is improved when compared to that of a composition without the stabilizing agent. For example, the invention provides methods of reducing various side effects associated with administration of the poorly water soluble pharmaceutical agent, including, but not limited to, myelosuppression, neurotoxicity, hypersensitivity, inflammation, venous irritation, phlebitis, pain, irritation of the skin, peripheral neuropathy, neutropenic fever, anaphylactic reaction, hematological toxicity, and cerebral or neurological toxicity, and combinations thereof. In some embodiments, methods are provided for reducing the hypersensitivity reactions associated with administration of the sparingly water-soluble pharmaceutical agent, which includes, for example, severe skin rashes, hives, flushes, dyspnea, tachycardia and others. In addition, a method of improving the stability of the composition comprising a poorly water soluble pharmaceutical agent and optionally a biocompatible polymer (such as a carrier protein), which comprises adding to the composition a stabilizing agent in an amount that is effective to improve the stability of the composition. In some embodiments, there is provided a method of preparing a composition comprising a sparingly water-soluble agent (such as docetaxel), a compatible biopolymer (such as a carrier protein, e.g., albumin), and a stabilizing agent, comprising combining (such as mixing) the poorly water soluble agent and the biocompatible polymer with the stabilizing agent. In some embodiments, the composition is a liquid composition. In some embodiments, the composition is a post-reconstitution composition. The stabilizing agent can be either mixed with the pharmaceutically sparingly water soluble agent and / or the carrier protein during the preparation of the composition of the pharmaceutically poorly water soluble / carrier protein agent, or added in the company of an aqueous medium used for the reconstitution of the carrier / pharmaceutical protein composition. In a further aspect of the invention, there is provided the use of the compositions described herein in the manufacture of a medicament. In particular, the manufacture of a medication for use in the treatment of the conditions described herein. In addition, the pharmaceutical composition thereof, variably described herein, is also proposed for use in the manufacture of a medicament for use in the treatment of conditions and, in accordance with the methods described herein, unless noted otherwise. Those skilled in the art will recognize that various variations are possible within the scope and spirit of this invention. The invention will now be described in greater detail by reference to the following non-limiting examples. Unless stated otherwise, the stabilities of the compositions in the following examples are evaluated at either 25 ° C or 4 ° C. Example 1 This example demonstrates the instability of a preparation of the pharmaceutical compositions comprising docetaxel and albumin, prepared as described in U.S. Patent Publication. 2005/0004002 Al. 30 mg of docetaxel are dissolved in 2 ml of chloroform / ethanol. The solution was then added in 27.0 ml of the HSA solution (3%, w / v). The mixture is homogenized for 5 minutes at low RPM (model homogenizer Tempest I.Q. from Vitris) to form an unrefined emulsion, and then transferred to a high pressure homogenizer (Avestin). The emulsification is carried out at 633.33-2814.80 kg / cm2 (9000-40,000 psi). The resulting system is transferred to a Rotavap apparatus and the solvent is rapidly removed under reduced pressure. The resulting dispersion was translucent and the typical average diameter of the resulting particles was in the range of 50-220 nm (Z-average apparatus, from Malvern Zetasizer). The dispersion was lyophilized further for 48 hours. The resulting cake was easily reconstituted to the original dispersion by the addition of sterile water or a saline solution. The particle size after reconstitution was the same as before lyophilization. When the liquid suspension prior to lyophilization was stored, it was surprisingly found that although the suspension was stable at 4-8 hours after the preparation, at 24 hours, there was some sedimentation indicating instability. Similarly, for the lyophilized reconstituted suspension it was surprising to find that although the suspension was stable at 4-8 hours after the preparation, at 24 hours, there was some sedimentation indicating instability. This instability at 24 hours was not previously observed by the inventors because the verification period after the preparation of the initial formulation and reconstitution was typically only 4-8 hours.

Example 2 This example demonstrates the instability of the docetaxel nanoparticles prepared by sonication. 25.9 g of docetaxel were added to a vial for the 20 ml scintillation count and dissolved in 0.3 ml of chloroform. 4.7 ml of HSA (3%, w / v) were added to the dissolved docetaxel mixture. The composition was sonicated (Sonic Dismembrator, model 550, Fisher Scientific Company, Pittsburgh, PA 155275) at a power of 50% for 1 minute. The mixture is transferred to a rotary evaporator, and the chloroform-ethanol was quickly removed to 45 ° C, at reduced pressure. The diameter of the resulting docetaxel particles was 250-300 nm (Z-average, Malvern Zetasizer). The suspension is precipitated in less than 1 day. Example 3 This example demonstrates the instability of the docetaxel nanoparticles prepared by sonication of the test soybean oil with a stabilizer. 18.0 mg of docetaxel were added to a vial for the 20 ml scintillation count and dissolved in 0.1 ml of a chloroform-ethanol mixture. 0.05 ml of soybean oil and 2.35 ml of HSA (5.0%, w / v) were added to the previous organic solvent. The sample was sonicated (Sonic Dismembrator, model 550, Fisher Scientific Company, Pittsburgh, PA 155275) for 2 minutes. The mixture transferred to a rotary evaporator, and the chloroform-ethanol was removed rapidly at 45 ° C, under reduced pressure. The diameter of the resulting docetaxel particles was -270 nm (Z-average, Malvern Zetasizer). The suspension is precipitated in less than 1 day. Example 4 This example demonstrates the instability of the docetaxel nanoparticles prepared by sonication using a mixture of ethyl acetate-n-butyl acetate. 22.7 mg of docetaxel were added to a vial for the 20 ml scintillation count and dissolved in 1.0 ml of the ethyl acetate-n-butyl acetate mixture. 2.4 ml of HSA (5.0%, w / v) were added to docetaxel dissolved in the organic solvent. The sample was sonicated (Sonic Dismembrator, model 550, Fisher Scientific Company, Pittsburgh, PA 155275) at 50% power for 1 minute. The mixture is transferred to a rotary evaporator, and ethyl acetate and n-butyl acetate are removed under reduced pressure. The composition was precipitated within the course of one hour. Example 5 This example demonstrates the instability of the docetaxel nanoparticles prepared by high pressure homogenization. 49.0 mg of docetaxel were dissolved in 0.56 ml of chloroform. The solution is added to 9.6 ml of HSA (5%, w / v). The mixture is pre-homogenized to give an unrefined emulsion, and then transferred to a high pressure homogenizer (Avestin). The emulsification is carried out at 1266.66-1407.40 kg / cm2 (18,000-20,000 psi). The resulting system is transferred to a rotary evaporator, and the chloroform and t-butyl alcohol were removed under reduced pressure. The diameter of the resulting docetaxel particles was 160-175 nm (Z-average, Malvern Zetasizer). The precipitation was observed in < 1 day. During the microscopic examination, crystalline precipitates were observed. Example 6 This example demonstrates the instability of the docetaxel nanoparticles prepared by high pressure homogenization using lecithin. 55.3 mg of docetaxel and 48.8 mg of egg lecithin were dissolved in 0.56 ml of the mixture of chloroform and t-butyl alcohol. The solution was added to 9.6 ml of HSA (5%, w / v). The mixture was pre-homogenized to form an unrefined emulsion, and transferred to a high pressure homogenizer (Avestin). The emulsification was carried out at 1266.66-1407.40 kg / cm2 (18,000-20,000 psi). The resulting system is transferred to a rotary evaporator, and the chloroform and t-butyl alcohol are removed under reduced pressure. The diameter of the particles of The resulting docetaxel was 190-220 nm (Z-average, Malvern Zetasizer). The precipitation was observed in < 24 hours . Example 7 This example demonstrates the instability of the docetaxel nanoparticles prepared by the high pressure homogenization test of polylacticoglycolic acid (PLGA). 56.3 mg of docetaxel and 40.8 mg PLGA (50:50) were dissolved in 0.56 ml of the chloroform mixture. The solution was added to 9.6 ml of HSA (5%, w / v). The mixture is pre-homogenized to form an unrefined emulsion, and transferred to a high pressure homogenizer (Avestin).

The emulsification was carried out at 1266.66-1407.40 kg / cm2 (18,000-20,000 psi). The resulting system is transferred to a rotary evaporator, and the chloroform and t-butyl alcohol were removed under reduced pressure. The diameter of the resulting docetaxel particles was 575 nm (Z-average, Malvern Zetasizer). The precipitation was observed in < 24 hours. Example 8 This example demonstrates the instability of the docetaxel nanoparticles prepared by the high pressure homogenization test of benzoic acid. 50.3 mg of docetaxel and 3.0 mg of benzoic acid were dissolved in 0.56 ml of a mixture of chloroform and t-butyl alcohol. The solution was added to 10.0 ml of HSA (5%, w / v). The mixture was pre-homogenized to form an unrefined emulsion, and transferred to a high pressure homogenizer (Avestin). The emulsification was carried out at 1266.66-1407.40 kg / cm2 (18,000-20,000 psi). The resulting emulsion is transferred to a rotary evaporator, and the chloroform and t-butyl alcohol are removed under reduced pressure. The diameter of the resulting docetaxel particles was 160 nm (Z-average, Malvern Zetasizer). The precipitation was observed in <; 24 hours. Example 9 This example demonstrates the instability of the docetaxel nanoparticles prepared by the high pressure homogenization test of cholesterol. 51.0 mg of docetaxel and 16.5 mg of cholesterol dissolve in 0.56 ml of the mixture of chloroform and t-butyl alcohol. The solution is added to 10.0 ml of HSA (5%, w / v). The mixture is pre-homogenized to form an unrefined emulsion, and transferred to a high pressure homogenizer (Avestin). The emulsification is carried out at 1266.66-1407.40 kg / cm2 (18,000-20,000 psi). The resulting emulsion is transferred to a rotary evaporator, and the chloroform and t-butyl alcohol are removed under reduced pressure. The precipitation was observed in < 24 hours.

EXAMPLE 10 This example demonstrates the stability of the docetaxel nanoparticles prepared by the high pressure homogenization test of sodium citrate. 50.0 mg of docetaxel are dissolved in 0.56 ml of a mixture of chloroform and t-butyl alcohol (10.2: 1 (v / v)). The solution is added to 9.6 ml of HSA (5%, w / v) containing 100 mM trisodium citrate (2.94% w / v). The mixture is pre-homogenized to form an unrefined emulsion, and transferred to a high pressure homogenizer (Avestin). The emulsification is carried out at 1266.66-1407.40 kg / cm2 (18,000-20,000 psi). The resulting emulsion is transferred to a rotary evaporator, and the chloroform and t-butyl alcohol are removed under reduced pressure. The diameter of the resulting docetaxel particles was 150-225 nm (Z-average, Malvern Zetasizer). The formulation was surprisingly stable > 24 hours without an observable precipitate. EXAMPLE 11 This example demonstrates the stability of the preparation of docetaxel nanoparticles with citrate (3.9%, 133 mM) and sodium chloride (1.75%, 300 mM). The aqueous phase is prepared by adding HSA (5% by weight), sodium citrate (3.9% by weight) and sodium chloride (1.75% by weight) in water for injection and stirring until it dissolves. The organic phase is prepared by dissolving docetaxel (7% by weight) in a mixture of solvents (6% by volume) containing chloroform and ethanol and stirring until dissolved. Slowly, the organic phase is added to the aqueous phase and mixed with the rotor-stator mixer. The lot size was 20 mi. The unrefined emulsion was homogenized at high pressure at 1407.40 kg / cm2 (20,000 psi). The chloroform and ethanol in the emulsion were removed using a rotary evaporator, at a reduced pressure. The suspension is filtered by serial filtration (1.2 μm, 0.8 μm, and 0.45 μm) and then lyophilized (FTS Tray Freeze Dryer). The liquid suspension is homogeneous and matt white. The particle size analysis was performed using a Malvern Zetasizer apparatus. The particles have an average size of 165.6 nm. The mixture was also examined by microscopy and most of the particles were from < 0.5 μm. the suspension is stored at both 4 ° C and 25 ° C. Surprisingly, the suspension was stable for 3 days at 4 ° C and > 1 day at 25 ° C. The suspension exhibited no sedimentation or precipitation, and did not change color or consistency. In addition, the lyophilized product looked like a solid cake. The reconstitution of the lyophilized cake took < 5 minutes. After reconstitution, the particles had an average particle size of 164.6 nm. The reconstituted suspension was stored at 4 ° C and surprisingly remained stable > 1 day. Example 12 This example demonstrates the stability of the preparation of docetaxel nanoparticles with citrate (2.9%, 100 mM) and sodium chloride (1.75%, 300 mM). The aqueous phase is prepared by adding HSA (5% by weight), sodium citrate (2.9% by weight) and sodium chloride (1.75% by weight) in water for injection and stirring until dissolved. The organic phase is prepared by dissolving docetaxel (7% by weight) in a solvent mixture (6% by volume) containing chloroform and ethanol and stirring until dissolved. The organic phase is added to the aqueous phase and mixed with the rotor-stator mixer. The unrefined emulsion was homogenized at high pressure at 1407.40 kg / cm2 (20,000 psi). The chloroform and ethanol in the emulsion were removed using a rotary evaporator, at a reduced pressure. The suspension is filtered by serial filtration (1.2 μm, 0.8 μm, and 0.45 μm) and lyophilized (FTS Tray Freeze Dryer). The liquid suspension is homogeneous and matt white. The particle size analysis was performed using a Malvern Zetasizer apparatus. The particles have an average size of 157.1 nm. The sample was also examined by microscopy and most of the particles were from < 0.5 μm. The suspension was stored at 4 ° C as at 25 ° C. Surprisingly, the suspension was stable for 3 days at 4 ° C and > 1 day at 25 ° C. The suspension exhibited no sedimentation or creaming, nor did it change in color or consistency. The lyophilized product looked like a solid cake. The reconstitution of the lyophilized cake took < 5 minutes. After reconstitution, the particles had an average particle size of 150.9 nm. The reconstituted suspension was stored at 4 ° C and remained stable > 1 day. Example 13 This example demonstrates the stability of the preparation of docetaxel nanoparticles with citrate (3.9%, 133 mM). The aqueous phase was prepared by adding HSA (5% by weight), and sodium citrate (3.9% by weight) in water for injection and stirring until dissolved. The organic phase was prepared by dissolving docetaxel (5% by weight) in a solvent mixture (6% by volume) containing chloroform and ethanol and stirring until dissolved. Slowly, the organic phase was added to the aqueous phase and mixed using a rotor-stator mixer. The lot size was 20 mi. The unrefined emulsion was homogenized at high pressure at 1407.40 kg / cm2 (20,000 psi). The chloroform and ethanol in the emulsion were removed using a Rotary evaporator, at reduced pressure. The suspension was filtered by serial filtration (1.2 μm, 0.8 μm, 0.45 μm and 0.22 μm) and then lyophilized (FTS Tray Freeze Dryer). The liquid suspension was homogenized and matt white. The particle size analysis was performed using a Malvern Zetasizer apparatus. The particles had a size of 131 nm. The sample was also examined by microscopy and most of the particles were < 0.5 μm. Surprisingly, the suspension was stable during > 1 day. Example 14 This example demonstrates the stability of the docetaxel nanoparticle preparation (11.7%, 400 mM). The aqueous phase was prepared by adding HSA (5% by weight) and sodium citrate (11.7% by weight) and in water for injection and stirring until dissolved. The organic phase was prepared by dissolving docetaxel (5% by weight) in a solvent mixture (6% by volume) containing chloroform and ethanol and stirring until dissolved. Slowly, the organic phase was added to the aqueous phase and mixed using a rotor-stator mixer. The lot size was 20 mi. The unrefined emulsion was homogenized at high pressure at 1407.40 kg / cm2 (20,000 psi). The chloroform and ethanol in the suspension were then removed using a rotary evaporator, under reduced pressure. The suspension it was filtered by serial filtration (1.2 μm, 0.8 μm, 0.45 μm and 0.22 μm) and then lyophilized (FTS Tray Freeze Dryer). The liquid suspension was homogeneous and colored - matte white. The particle size analysis was performed using a Malvern Zetasizer apparatus. The particles had an average size of 143.5 nm. The sample was also examined by microscopy and most of the particles were < 0.5 μm. The suspension was stored at both 4 ° C and 25 ° C. Surprisingly, the suspension was stable up to 3 days at 4 ° C and during > 1 day at 25 ° C. The suspension did not exhibit any sedimentation or cream formation, nor did it change color or consistency. The lyophilized product appeared as a solid cake. The reconstitution of the lyophilized cake took < 5 minutes. After reconstitution, the particles had an average particle size of 151.8 nm. Surprisingly, the reconstituted suspension was stored at 4 ° C and remained stable > 1 day. Example 15 This example demonstrates the stability of the preparation of docetaxel nanoparticles with citrate (7.7%, 200 mM). The aqueous phase was prepared by adding HSA (5% by weight) and sodium citrate (7.7% by weight) and in water for injection and stirring until dissolved. The organic phase was prepared by dissolving docetaxel (5% by weight) in a solvent mixture (6% by volume) containing chloroform and ethanol and stirring until dissolved. Slowly, the organic phase was added to the aqueous phase and mixed using a rotor-stator mixer. The lot size was 20 mi. The unrefined emulsion was homogenized at high pressure at 1407.40 kg / cm2 (20,000 psi). The chloroform and ethanol in the emulsion were removed using a rotary evaporator, under reduced pressure. The suspension is filtered by serial filtration (1.2 μm, 0.8 μm, 0.45 μm and 0.22 μm) and then lyophilized (FTS Tray Freeze Dryer). The liquid suspension was homogeneous and matt white. The particle size analysis was performed using a Malvern Zetasizer apparatus. The particles had an average size of 226.4 nm. The sample was also examined by microscopy and most of the particles were <; 0.5 μm. The suspension was stored at both 4 ° C and 25 ° C. Surprisingly, the suspension was stable up to 3 days at 4 ° C and during > 1 day at 25 ° C. The suspension did not exhibit any sedimentation or cream formation, nor did it change color or consistency. The lyophilized product appeared as a solid cake. The reconstitution of the lyophilized cake took < 5 minutes. After reconstitution, the particles had an average particle size of 211.4 nm. The reconstituted suspension was stored at 4 ° C and remained stable > 1 day. Example 16 This example demonstrates the stability of the preparation of docetaxel nanoparticles with citrate / NaCl. The aqueous phase was prepared by adding HSA (5% by weight) and sodium citrate (5.88%, 200 mM) and NaCl (1.75%, 300 mM) and in water for injection and stir until dissolved. The organic phase was prepared by dissolving docetaxel (5% by weight) in a solvent mixture (6% by volume) containing chloroform and ethanol and stirring until dissolved. Slowly, the organic phase was added to the aqueous phase and mixed using a rotor-stator mixer. The lot size was 20 mi. The unrefined emulsion was homogenized at high pressure at 1407.40 kg / cm2 (20,000 psi). The solvents in the emulsion were removed using a rotary evaporator, under reduced pressure. The suspension is filtered by serial filtration and then lyophilized (FTS Tray Freeze Dryer). The liquid suspension was homogeneous and matt white. The particle size analysis was performed using a Malvern Zetasizer apparatus. The particles had an average size of < 200 nm. The sample was also examined by microscopy and most of the particles were < 0.5 μm. The suspension was stored and surprisingly, the suspension was stable without precipitates or sediments during > 1 day. The lyophilized product appeared as a cake, solid. The reconstitution of the lyophilized cake took < 5 minutes. The reconstituted suspension was stored and surprising remained stable > 1 day. Example 17 This example demonstrates the stability of the preparation of docetaxel nanoparticles with citrate / NaCl. The aqueous phase was prepared by adding HSA (5% by weight) and sodium citrate (2.94%, 100 mM) and NaCl (2.9%, 500 mM) and in water for injection and stir until dissolved. The organic phase was prepared by dissolving docetaxel (5% by weight) in a solvent mixture (6% by volume) containing chloroform and ethanol and stirring until dissolved. Slowly, the organic phase was added to the aqueous phase and mixed using a rotor-stator mixer. The lot size was 20 mi. The unrefined emulsion was homogenized at high pressure at 1407.40 kg / cm2 (20,000 psi). The solvents in the emulsion were removed using a rotary evaporator, under reduced pressure. The suspension is filtered by serial filtration and then lyophilized (FTS Tray Freeze Dryer). The liquid suspension was homogeneous and matt white. The particle size analysis was effected using a Malvern Zetasizer device. The particles had an average size of < 200 nm. The sample was also examined by microscopy and most of the particles were < 0.5 μm. The suspension was stored and surprisingly, the suspension was stable without precipitates or sediments during > 1 day. The lyophilized product appeared as a solid cake. The reconstitution of the lyophilized cake took < 5 minutes. The reconstituted suspension was stored and surprising remained stable > 1 day. Example 18 This example demonstrates the stability of the preparation of docetaxel nanoparticles with citrate / NaCl. The aqueous phase was prepared by adding HSA (5% by weight) and sodium citrate (2.94%, 100 mM) and NaCl (3.5%, 600 mM) and in water for injection and stir until dissolved. The organic phase was prepared by dissolving docetaxel (5% by weight) in a solvent mixture (6% by volume) containing chloroform and ethanol and stirring until dissolved. Slowly, the organic phase was added to the aqueous phase and mixed using a rotor-stator mixer. The lot size was 20 mi. The unrefined emulsion was homogenized at high pressure at 1407.40 kg / cm2 (20,000 psi). The solvents in the emulsion were removed using a rotary evaporator, under reduced pressure. The suspension is filtered by serial filtration and then lyophilized (FTS Tray Freeze Dryer). The liquid suspension was homogeneous and matt white. The particle size analysis was performed using a Malvern Zetasizer apparatus. The particles had an average size of <; 200 nm. The sample was also examined by microscopy and most of the particles were < 0.5 μm. The suspension was stored and surprisingly, the suspension was stable without precipitates or sediments during > 1 day. The lyophilized product appeared as a solid cake. The reconstitution of the lyophilized cake took < 5 minutes. The reconstituted suspension was stored and surprising remained stable > 1 day. Example 19 This example demonstrates the stability of the preparation of docetaxel nanoparticles with citrate / NaCl. The aqueous phase was prepared by adding HSA (5% by weight) and sodium citrate (1.47%, 50 mM) and NaCl (2.9%, 500 mM) and in water for injection and stir until dissolved. The organic phase was prepared by dissolving docetaxel (5% by weight) in a solvent mixture (6% by volume) containing chloroform and ethanol and stirring until dissolved. Slowly, the organic phase was added to the aqueous phase and mixed using a mixer with rotor-stator. The lot size was 20 mi. The unrefined emulsion was homogenized at high pressure at 1407.40 kg / cm2 (20,000 psi). The solvents in the emulsion were removed using a rotary evaporator, under reduced pressure. The suspension is filtered by serial filtration and then lyophilized (FTS Tray Freeze Dryer). The liquid suspension was homogeneous and matt white. The particle size analysis was performed using a Malvern Zetasizer apparatus. The particles had an average size of < 200 nm. The sample was also examined by microscopy and most of the particles were < 0.5 μm. The suspension was stored and surprisingly, the suspension was stable without precipitates or sediments during > 1 day. The lyophilized product appeared as a solid cake. The reconstitution of the lyophilized cake took < 5 minutes. The reconstituted suspension was stored and surprising remained stable > 1 day. EXAMPLE 20 This example demonstrates the effect of the preparation of nanoparticles of docetaxel anhydrous against those hydrated with citrate / NaCl. The aqueous phase was prepared by the addition of HSA (5% by weight) and sodium citrate (200 mM) and NaCl (300 mM) and in water for injection and stir until dissolved. The Organic phase for three different formulations was prepared by the solution of either docetaxel anhydrous, docetaxel trihydrate or docetaxel semi-hydrated (partial hydration) (5% by weight) in a mixture of solvents (6% by volume) containing chloroform and ethanol and stir until it dissolves. Slowly, the organic phase was added to the aqueous phase and mixed using a rotor-stator mixer. The unrefined emulsion was homogenized at high pressure at 1407.40 kg / cm2 (20,000 psi). The solvents in the emulsion were removed using a rotary evaporator, under reduced pressure. The suspension is filtered by serial filtration and then lyophilized (FTS Tray Freeze Dryer). The liquid suspension was homogeneous and matt white. The particle size analysis was performed using a Malvern Zetasizer. The particles had an average size of < 200 nm. The three suspensions were stored and surprisingly, the suspension containing the anhydrous docetaxel was stable without precipitates or sediments during > 1 day. Both of the hydrated docetaxel preparations showed precipitates or sediments in < 1 day. The same observation was detected for the lyophilized suspension during reconstitution. Thus, it was determined that the anhydrous form of docetaxel was the most suitable for the preparation of docetaxel from nanoparticles.

Example 20A This example provides a comparison of anhydrous docetaxel, docetaxel trihydrate and docetaxel hemihydrate by Differential Scanning Calorimetry (DSC). The three different types of docetaxel were subjected to DSC using standard techniques. All showed an endotherm in the melt at approximately 162-166 ° C. However only the 2 hydrated materials showed an endothermic dehydration of water between about 74-80 ° C. Example 20B This example provides a comparison of anhydrous docetaxel, docetaxel trihydrate and docetaxel hemihydrate by the X-ray powder diffraction (XRD) (for its acronym in English). The three different types of docetaxel were subjected to XRD using standard techniques. All three materials showed a variety of sharp peaks that indicate crystallinity. However, the anhydrous material showed a different spectrum when compared to the two hydrated materials. In particular there was a peak that was present in 2-theta of 7-8 for the anhydrous sample that was absent from the hydrated material. This indicated a different crystal structure for anhydrous docetaxel against the hydrated docetaxel. Example 21 This example demonstrates that the degree of hydration affects the solubility of docetaxel and provides a comparison of the solubility of anhydrous docetaxel, docetaxel trihydrate and docetaxel hemihydrate. To compare whether the different types of docetaxel material had different solubility profiles as a result of their different structures, their solubility rates were compared in the acetonitrile solvent. Acetonitrile was added to a fixed amount of docetaxel from different suppliers to obtain a concentration of 5 mg / ml (anhydrous base). The speed at which the dissolution of the different docetaxel occurred, was observed. It was observed that the anhydrous docetaxel (from 2 different suppliers) completely dissolved in less than 1 minute. In contrast to the hydrated materials (trihydrate and partially hydrated from 2 different suppliers) they do not dissolve easily and additional solvent had to be added to a final concentration of 2.5 mg / ml. Under these additional diluted conditions, the time for dissolution was between 5 and 10 minutes for the hydrated materials. A similar observation was made when chloroform is used as a solvent. Consequently, it was surprisingly found that the degree of hydration or the Anhydrous nature can substantially affect the solubility of docetaxel. EXAMPLE 22 This example demonstrates that the degree of hydration of docetaxel affects stability and provides a comparison of the formulations of docetaxel trihydrate, in docetaxel hemihydrate and the docetaxel anhydrous in Tween 80. It is well known that docetaxel is formulated with Tween 80 as a solubilizer or emulsifier for the commercial product Taxotere. The different docetaxel are dissolved in Tween 80 at a concentration of 40 mg / ml (on an anhydrous basis). 2 ml of these solutions were observed to verify stability over time. It was surprisingly found that after some days a sediment or precipitate for the docetaxel hydrate was observed but no precipitate was observed with the anhydrous docetaxel. Accordingly, anhydrous docetaxel is preferred in the Tween formulation. In addition, it may be useful to use a Tween 80 surfactant or equivalent that is anhydrous or of a very low water content because the anhydrous form of docetaxel can observe water to form the hydrated form which could lead to precipitation.

Example 23 This example demonstrates the stability of the preparation of docetaxel nanoparticles with anhydrous docetaxel and are aggregate stabilizers. The aqueous phase was prepared by adding HSA (5% by weight) and in water for injection. The organic phase was prepared by dissolving anhydrous docetaxel (5% by weight) in a solvent mixture (6% by volume) containing chloroform and ethanol and stirring until dissolved. Slowly, the organic phase was added to the aqueous phase and mixed using a rotor-stator mixer. The unrefined emulsion was homogenized at high pressure at 1407.40 kg / cm2 (20,000 psi). The solvents in the emulsion were removed using a rotary evaporator, under reduced pressure. The suspension was filtered by serial filtration and then lyophilized (FTS Tray Freeze Dryer). The liquid suspension was homogeneous and matt white. The particle size analysis was performed using a Malvern Zetasizer apparatus. The particles had an average size of < 200 nm. The sample was also examined by microscopy and most of the particles were < 0.5 μm. The suspension was stored and surprisingly, the suspension was stable without precipitates or sediments during > 1 day. Therefore, in the absence of stabilizers War-docetaxel prepared with Anhydrous docetaxel appears to be more stable than when prepared with a hydrated form of docetaxel for which stability is much less than 1 day, typically only a few hours. Example 24 This example demonstrates the stability of the nanoparticle preparation of anhydrous docetaxel with citrate / NaCl. The aqueous phase was prepared by adding HSA (8.5% by weight) and sodium citrate (200 mM) and NaCl (300 mM) and in water for injection and stirring until it dissolves. The organic phase was prepared by dissolving anhydrous docetaxel (133 mg / ml) in a solvent mixture containing chloroform and ethanol (1: 1) and stirring until dissolved. Slowly, the organic phase (6% by volume) was added to the aqueous phase and mixed using a rotor-stator mixer. The lot size was 200 mi. The unrefined emulsion was homogenized at high pressure at 1407.40 kg / cm2 (20,000 psi). The solvents in the emulsion were removed using a rotary evaporator, under reduced pressure. The suspension is filtered by serial filtration and then lyophilized (FTS Tray Freeze Dryer). The liquid suspension was homogeneous and matt white. The particle size analysis was performed using a Malvern Zetasizer apparatus. The particles had an average size of < 200 nm. The suspension was stored and surprisingly, the suspension was stable without precipitates or sediments during > 1 day. The same observation was noted for the lyophilized suspension during reconstitution. Example 25 This example demonstrates the preparation of nanoparticles of anhydrous docetaxel with citrate / NaCl. The aqueous phase was prepared by adding HSA (5% by weight) and sodium citrate (200 mM) and NaCl (300 mM) and in water for injection and stirring until dissolved. The organic phase was prepared by dissolving anhydrous docetaxel (160 mg / ml) in a mixture of chloroform and ethanol containing solvents (1: 1) and stir until dissolved. Slowly, the organic phase (8% by volume) was added to the aqueous phase and mixed using a rotor-stator mixer. The lot size was 200 mi. The unrefined emulsion was homogenized at high pressure at 1407.40 kg / cm2 (20,000 psi). The solvents in the emulsion were removed using a rotary evaporator, under reduced pressure. The suspension is filtered by serial filtration and then lyophilized (FTS Tray Freeze Dryer). The liquid suspension was homogeneous and matt white. The particle size analysis was performed using a Malvern Zetasizer apparatus. The particles had a size smaller than 200 nm. The suspension was stored and, surprisingly, the suspension was stable without precipitates or sediments for more than one day. The same observation was noted for the lyophilized suspension during reconstitution. EXAMPLE 26 This example demonstrates the preparation of nanoparticles of anhydrous docetaxel with citrate / NaCl. The aqueous phase was prepared by adding HSA (5% by weight) and sodium citrate (200 mM) and NaCl (300 mM) and in water for injection and stirring until dissolved. The organic phase was prepared by dissolving anhydrous docetaxel (160 mg / ml) in a mixture of chloroform and ethanol containing solvents (1: 1) and stir until dissolved. Slowly, the organic phase (8% by volume) was added to the aqueous phase and mixed using a rotor-stator mixer. The lot size was 200 mi. The unrefined emulsion was homogenized at high pressure at 1407.40 kg / cm2 (20,000 psi). The solvents in the emulsion were removed using a rotary evaporator, under reduced pressure. Additional albumin was added to the evaporated suspension to increase the ratio of albumin: drug to 8: 1 by weight. The suspension is filtered by serial filtration and then lyophilized (FTS Tray Freeze Dryer). The liquid suspension was homogeneous and colored matte white. The particle size analysis was performed using a Malvern Zetasizer apparatus. The particles had a size smaller than 200 nm. The suspension was stored and, surprisingly, the suspension was stable without precipitates or sediments for more than one day. The same observation was noted for the lyophilized suspension during reconstitution. Example 27 This example demonstrates the effect of pH on the stability of the nanoparticle suspension as well as the chemical degradation of docetaxel. The formulations of docetaxel nanoparticles were prepared as described in the previous examples. The effect of pH on these formulations was tested between pH 4 and pH 9. The increase in pH above pH 6 was found to increase the physical stability measured in terms of the size of the nanoparticle and sedimentation of the formulation while at the same time the amount of the degradation of docetaxel to 7-epi-docetaxel at room temperature is increased. An optimal pH range in which both physical stability and chemical stability were acceptable, was found to be between 6-8.5. A more preferable pH range was 6.5-8 and a more preferred range was found to be from pH 7.25 to 7.75.

Example 28 This example compares the stability of Najb-docetaxel prepared with either the hydrated forms of docetaxel or anhydrous docetaxel in the presence or absence of suitable stabilizers. The stability of these preparations was examined visually prior to lyophilization as well as during the reconstitution of the lyophilized preparations. In addition, the stability of lyophilized preparations (containing stabilizers) during reconstitution was evaluated at different concentrations of docetaxel in the reconstituted suspension. The results are described in tables 1-3 below. Table 1. Evaluation of the stability of the nanoparticle suspension of Na £ > -cetataxel prior to lyophilization.

As shown in table 1, the stability of Na £ > -cetataxel prepared using anhydrous docetaxel was significantly better than Na £ > -cetataxel prepared using the hydrated forms of docetaxel whether or not the stabilizers were present in the formulation. The addition of the stabilizers (200 mM citrate / 300 mM NaCl) significantly improved the stability of the Nab-docetaxel comparisons that do not contain the stabilizer. The addition of the stabilizers improved the stability of the Nab-docetaxel preparations made from docetaxel trihydrate. Table 2. Stability of the reconstitution of the freeze-dried powder of Na > -cetataxel containing the stabilizer (200 mM citrate / 300 mM NaCl) reconstituted at 5 mg / ml docetaxel in water for injection.

Code: 1 - without sedimentation 2 - . 2 - Light sedimentation 3 - Greater sedimentation 4 - Sedimentation thick 5 - Complete sedimentation. Table 3. Stability of the reconstitution of the lyophilized Nah-docetaxel powder, containing the stabilizer (200 mM citrate / 300 mM NaCl) reconstituted at 1 mg / ml docetaxel in water for injection.

Code: 1 - No sedimentation 2 - Light sedimentation 3 - Higher sedimentation 4 - Sedimentation thick 5 - Complete sedimentation. As shown in tables 2 and 3, the stability of the stabilizers containing reconstituted Naj-docetaxel is significantly improved at a higher concentration of 5 mg / ml of docetaxel against a lower concentration of about 1 mg / ml of docetaxel. The stability of the reconstituted Nab-docetaxel formulation containing stabilizers prepared with anhydrous docetaxel is significantly better than Nab-docetaxel prepared with the docetaxel trihydrate. Example 29 This example demonstrates the toxicity profiles of the albumin formulation of docetaxel nanoparticles (Najb-docetaxel) against Taxotere. The maximum tolerated dose (MTD) for Nab-docetaxel and Taxotere® (Tween-8-docetaxel) was determined during a study of dose increase in hairless mice. Hairless mice, in a group size of 10 per group, were treated with an increasing dose of Taxotere (0 mg / kg, 7 mg / kg, 15 mg / kg, 22 mg / kg, 33 mg / kg, and 50 mg / kg), using a q4dx3 program. Hairless mice, in a group size of 6 per group, were treated with an increasing dose of Naj-docetaxel (0 mg / kg, 15 mg / kg, 22 mg / kg, 33 mg / kg, 50 mg / kg, and 75 mg / kg), using a q4dx3 program. The animals were weighed every third day. The maximum body weight loss was plotted against the dose and adjusted using an equation of Hill. The BAT defined as the weight loss equal to 20% was calculated using the adjusted data. BAT was 2.3 times higher for Nab-docetaxel versus Taxotere (Tween 80 docetaxel). The MTDs were 47.2 mg / kg and 20.6 mg / kg for Najb-docetaxel and Taxotere, respectively. EXAMPLE 30 This example demonstrates the anti-tumor efficacy of docetaxel of the nanoparticles of the invention (Nab-docetaxel) with the stabilizer against Taxotere. The efficacy of NaJ-incetaxel (prepared with citrate 200 mM and 300 mM NaCl) was compared against Taxotere in a xenoincule tumor model in nude mice bearing human HCT-116 colon tumor. 10 mice per group were used for the study. Taxotere was dosed at 15 mg / kg and Nab-docetaxel was dosed at 22 mg / kg, both to a q4dx3 program. Na-docetaxel (22 mg / kg) was more effective in tumor pressure than Taxotere (15 mg / kg, MTD) with p < 0.0001. In addition, Najb-docetaxel exhibited a therapeutic Index greater than Taxotere when the maximum weight loss in the Taxotere group was 20%, whereas for Na £ > -ceacetaxel was approximately 17%, despite a 50% higher dose. Example 31 This example demonstrates an infusion study of Na £ > -cetataxel (200 mM citrate / 300 mM NaCl). A study was carried out in rats with an infusion minutes of Najb-docetaxel, with increasing infusion rates of the Najb-docetaxel formulation containing approximately 200 mM of 300 mM citrate /? aCl. A 5-minute infusion in rats can be considered equivalent to a 30-minute infusion in humans. The maximum safe infusion rate was ~ 0.5 ml / min. This is equivalent to 0.23 mmol / kg / min or 68 mg / kg / min of citrate during a 5 minute infusion in the rats. Transferred to the human dose, this was equivalent to approximately 170 mg docetaxel / m2 in a 30 minute infusion. EXAMPLE 32 This example demonstrates the blood biocompatibility of 5 mg / ml Nab-docetaxel (200 mM citrate /? 300 mM aCl). As in the study of in vitro hemolysis in the blood of the rats was carried out using a formulation of placebo (all components except docetaxel) and the formulation of Najb-docetaxel. The placebo does not cause hemolysis even at the highest ratio of placebo / blood of the rat of 1: 1. The formulation of NaJb-docetaxel interfered with the reading of the absorption due to the dispersion of the characteristic light by the nanoparticles, but when the appropriate controls / bases were taken, no hemolysis was detected at the ratio highest Najb-docetaxel: rat blood of 1: 1. This demonstrates that Najb-docetaxel with the stabilizer as indicated, is compatible with the blood of the rat. Example 33 This example provides a study of the multiple dose increase, pilot, in the rats. All the Najb-docetaxel formulations described herein contain 200 mM citrate and 300 mM? ACl. To compare the severity of the Na b-docetaxel formulation with the Taxotere formulation, the rats were dosed with either Tween 80 docetaxel (the same formulation as Taxotere) or Najb-docetaxel at 5.0, 10.0, 15.0, 30.0 and 50 mg / kg using a 10-minute infusion through jugular catheters resident on days 0, 4, and 8 for a total of three treatments. Saline solution (1 / mg / kg / min) was used as a control. Each animal was observed and weighed daily during days 0-25. Body weight was recorded daily for each animal treated. The signs of clinical stress were recorded daily. The blood was collected on days 13, 16 and 25 in the EDTA treatment tubes and subjected to differential analysis. The necropsy was carried out on day 25. The result of the study is shown in table 4. As shown in the table, the animals in all groups of the dose tolerated the first treatment without acute related toxicities or infusion even at the highest dose of 50 mg / kg. However, only the animals at the lowest dose level of 5 mg / kg and the control saline solution survived until the end of the experiment (in all three treatments). All animals receiving higher doses died either between the second and third doses or after the third dose. Table 4: Weight loss and mortality in the study of dose increase.

The weight loss of the treated animals is shown in Figure 1. The comparison of neutropenia in the docetaxel dose of 5 mg / kg for Najb-docetaxel and Tween 80-docetaxel is shown in Figure 2. Weight loss for the surviving group of 5 mg / kg of Najb-docetaxel was significantly lower than that of the group of 5 mg / kg of Tween-docetaxel (p = 0.02+, A? OVA). This was paralleled by the significantly higher severe neutropenia for Tween-docetaxel (5 mg / kg) against Nab-docetaxel (5 mg / kg), p < 0.0001, A? OVA, figure 2) on day 13. Necropsy at the end of the experiment (day 25) in the groups of 5 mg / kg survivors revealed abnormalities in 2/3 animals in the "Tween-docetaxel" group (one case of accumulation of milky fluid in the thoracic cavity and a case of adherence of the abnormal spleen to the abdominal wall, stomach and pancreas) Animals provided with Nab-docetaxel (5 mg / kg) and saline solutionThey remained normal. This pilot study showed a significant improvement in safety for Najb-docetaxel in terms of body weight loss. Neutropenia was significantly higher for Tween-docetaxel. EXAMPLE 34 This example demonstrates the kinetic characteristics of Najb-docetaxel blood. All the Najb-docetaxel formulations described herein contained 200 mM citrate and 300 mM? ACl. The rats were divided into six groups (3 per group). On day 1, each animal was weighed and administered with a single intravenous dose of the appropriate article shown below: Group A: Taxotere, jl0 mg / kg Group B: Taxotere, 20 mg / kg Group C: Taxotere, 30 mg / kg Group D: Najb-docetaxel, 10 mg / kg Group E: Nab-docetaxel, 20 mg / kg Group F: Nab-docetaxel, 30 mg / kg. The test articles were administered during an infusion period of 10 +/- 1 minute. Blood samples were collected (200 μl) from the tail of each rat in the following intervals: pre-infusion (baseline); during the infusion (5 minutes in the infusion, t = -5 minutes); and in the complement of the infusion (t = 0). The blood was also collected in the following moments of the time after the infusion complement: 5, 10, and 20 minutes; 40 + 3 minutes, 2 hours + 5 minutes; 3 hours + _ 10 minutes; 4 hours + 10 minutes; 8 hours + 10 minutes; 24 + 1 hour; 48 + 1 hour; and 120 + 2 hours. Blood samples were collected in tubes with green top (sodium heparin) and processed for plasma collection by centrifugation at approximately 2,000 rpm for approximately 10 minutes. The samples in the plasma were stored frozen until they were shipped on dry ice from ALTA Analytical (El Dorado Hills, CA) for LC / MS analysis of docetaxel levels. The results of the experiments are shown in Figures 3A-3D and Table 5. There were no significant differences between the PK profiles of Nab-docetaxe I against Taxotere at 10 mg / kg. However, the differences between Nab-docetaxe I and Taxotere were significant at 20 mg / kg with Cmax and AUC, 53% and 70% of Taxotere respectively and Vz and Vss were 177% and 243% Taxotere respectively. At 30 mg / kg, once again the differences were significant with Cmax and with AUC for Na-docetaxel 46% and 47% of Taxotere respectively and Vz and Vss were 225% and 375% Taxotere respectively. Table 5: PK parameters for NaJb-docetaxel and Taxotere Tsbla 5 (Cont.) When AUC was plotted against the dose, the non-linearity for Taxotere was clearly evident, with the AUC of Najb-docetaxel being linear with respect to the dose (Figure 3D). This can be explained by the micellar formation property of Tween 80, the high solubility of docetaxel in the "core of hydrophobic micelles and corresponding to the capture of docetaxel in the plasma (6). Najb-docetaxel it can also be explained by the use of transcytosis mediated by albumin / venae cavae by means of endothelial cells, a process previously described by Abraxane (Najb-paclitaxel). The PK data suggest that Tween 80 in Taxotere exhibited the capture of docetaxel in the plasma in a manner similar to that observed with Cremophor EL in the case of taxol. This led to higher Cmax and AUC and lower volumes of distribution for Taxotere than for Nab-docetaxel. The PK of Nab-docetaxel is linear while for Tween 80-docetaxel (Taxotere) it is not linear with respect to the dose. The dosages described herein, ie, 10 mg / kg, 20 mg / kg, and 30 mg / kg, are equivalent to a dosage to a human of approximately 60 mg / m2, approximately 120 mg / m2, and approximately 180 mg / m2. mg / m2. Typically, the linear PK range of Najb-docetaxel is about 10-180 mg / m2. Example 35 This example demonstrates the inhibition of drug-albumin interaction by surfactants such as Tween 80. The experiment was done using a fluorescent labeled paclitaxel (Flutax) as a substitute for paclitaxel / docetaxel. Flutax was shown to have a similar agglutination to albumin as paclitaxel.

HSA was immobilized on 96-well plastic microplates. Immobilized albumin was reacted for 1 h with a constant concentration of Flutax and an increasing concentration of the solvents (Cremophor EL / EtOH, Tween 80, and TPGS). The unbound ligands were removed by washing with the buffer. The solid ligands were quantified using a fluorometer. The IC50 was determined using an exponential decay equation. The results of the experiment were shown in Figure 4. As shown in Figure 4, the albumin-paclitaxel interaction was inhibited by the solvent commonly used in the formulation of the water-insoluble drug such as Cremophor EL / EtOH, Tween 80, and TPGS (IC50 of 0.009%, 0.003%, and 0.008%, respectively). Complete inhibition occurred at 0.02% or 0.2 μl of Tween 80 / ml. This is clinically relevant when patients treated with Taxotere exhibited 0.07-0.41 μl of Tween 80 / ml of blood at the end of the drug infusion. This experiment demonstrates that Tween 80 in the Taxotere formulation can inhibit the agglutination of docetaxel to albumin and prevent its endothelial transcytosis by means of a caveolar / gp60 mechanism. The PK data in the previous studies also support this observation.

EXAMPLE 36 This example provides the evaluation of the antitumor activity of Nab-docetaxel against the xenoincule of H29 colon carcinoma in athymic nude mice. Mice were divided into the control group and the Nab-docetaxel group (? = 4 mice per group, each with bilateral tumors). All of the Najb-docetaxel formulations described herein contained 200 mM citrate and 300 mM? ACl. Briefly, H29 tumors were implanted subcutaneously in athymic nude mice, allowed to grow to 100 mm3 and then treated with either the control (without drug) or with Nab-docetaxel (15 mg / kg, q4dx3, bolus iv ). Measurements of tumor size and body weight were obtained three times per week and were plotted in Figures 5A-5B. As shown in Figures 5A-5B, there was significant inhibition of the HT29 tumor, in vivo, p < 0.0001 against the control, A? OVA. At a dose of 15 mg / kg Nab-docetaxel, the average weight loss between 10-20% suggests that this dose may be close to BAT for Najb-docetaxel. The MTD for Taxotere has been reported to be 15 mg / kg in this program. Example 37 This example compares the antitumor activity of Nab-docetaxel and Taxotere using the HCT116 colon carcinoma xenoin in athymic nude mice with a dose higher than 50% Nab-docetaxel when compared to Taxotere. The mice were divided into the control group, the Nab-docetaxel group and the Taxotere group (? = 10 mice per group). All the Najb-docetaxel formulations described herein contain 200 mM citrate and 300 mM? ACl. Briefly, the antitumor activity of Nab-docetaxel and Taxotere was compared at the doses of 22 mg / kg of q4dx3 and 15 mg / kg of q4x3, respectively, in the xenograft of the carcinoma of the colon of HCT116. The results of the experiment are shown in Figures 6A-6B. As shown in Figures 6A-6B, both NaJb-docetaxel and Taxotere showed tumor inhibition with respect to the control. As shown below, tumor inhibition was improved with Najb-docetaxel against Taxotere (p = 0.03, A? OVA) and weight loss was somewhat lower but not statistically significant (p = ns, A? OVA) among the two groups. In this pilot study, the anti-tumor activity of Najb-docetaxel was superior to that of Taxotere. The mice tolerated a dose of docetaxel 50% higher for Najb-docetaxel with a somewhat lower, total body weight loss, when compared to Taxotere.

Example 38 This example compares the toxicity of the Nab-docetaxel preparation with the stabilizers (citrate /? ACl) against Taxotere (Tween-docetaxel) in the rats provided with a single dose of each preparation. Male Sprague-Dawley rats (160-180 g, n = 3 / group) were infused with Taxotere, or Najb-docetaxel (citrate /? aCl) with the infusion time was 10 minutes and the following docetaxel dosage levels were used: 25, 50, 75, 100, and 125 mg / kg. The animals were weighed and checked daily to verify signs of toxicity / mortality. Percentage mortality (%) at 7 days after treatment was shown in Table 6. Table 6. Percentage mortality in rats treated by Taxotere and Najb-docetaxel As shown in table 6, the formulation of Najb-docetaxel was significantly less toxic than Taxotere (Tween-docetaxel). This effect was particularly pronounced at doses of 25 and 50 mg / kg. The LD50 was calculated to be 63 mg / kg for Nab-docetaxel against approximately 12.5 mg / kg for Tween-docetaxel. Example 39 This example shows the efficacy of Najb-docetaxel in the treatment of prostate cancer in a tumor model of the PC3 prostate xenograft. The PC3 tumor was implanted subcutaneously in athymic nude mice, allowed to grow to 100 mm3 and then treated with q4 x 3, i.v. with either saline or Najb-docetaxel (10, 15, 20, or 30 mg / kg) or Tween-docetaxel (10 mg / kg). Six mice in each group were evaluated. The results of the study are shown in Figures 7A-7B. All of the six mice treated with Tween-docetaxel died during the course of the study. In contrast, Najb-docetaxel was well tolerated at all dose levels. There was only one death at 15 mg / kg, and none was observed at the highest doses of 20 mg / kg and 30 mg / kg. The suppression of the tumor was observed at all levels of the Najb-docetaxel dose. In particular, at the dose of 30 mg / kg, there were six out of six complete regressions. Although the preceding invention has been described in some detail by way of illustration and example for For purposes of clarity and understanding, it is evident to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention. It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (36)

1. Claims Having described the invention as above, the content of the following claims is claimed as property: 1. A composition comprising docetaxel and a stabilizing agent, characterized in that the stability of the composition is improved when compared to that of a composition without the agent stabilizer 2. The composition according to claim 1, characterized in that it also comprises a biocompatible polymer. 3. The composition according to claim 1, characterized in that the biocompatible polymer is a carrier protein. 4. The composition according to claim 3, characterized in that the carrier protein is albumin. 5. The composition according to claim 4, characterized in that the ratio of albumin to docetaxel is about 18: 1 or less. 6. The composition according to claim 1, characterized in that it comprises docetaxel nanoparticles coated with a biocompatible polymer. 7. The composition according to claim 1, characterized in that the biocompatible polymer is a carrier protein. 8. The composition according to claim 7, characterized in that the carrier protein is albumin. 9. The composition according to claim 8, characterized in that the ratio of albumin to docetaxel is about 18: 1 or less. 10. The composition according to claim 6, characterized in that the nanoparticles in the composition have a mean or average particle size no greater than about 200 nm. The composition according to claim 1, characterized in that it is a liquid suspension of docetaxel at a concentration of at least about 1 mg / ml. 12. The composition according to claim 11, characterized in that it is a liquid suspension of docetaxel at a concentration of at least about 15 mg / ml. 13. The composition according to claim 1, characterized in that it is a dry composition that can be reconstituted to a liquid suspension. with at least about 1 mg / ml docetaxel. The composition according to claim 13, characterized in that the dry composition is a lyophilized composition. 15. The composition according to any of claims 1-14, characterized in that the stabilizing agent is a chelating agent. 16. The composition according to claim 15, characterized in that the stabilizing agent is any of citrate, edetate, malic acid, pentetate, tromethamine, derivatives thereof, and mixtures thereof. 17. The composition according to claim 16, characterized in that the stabilizing agent is citrate. 18. The composition according to claim 17, characterized in that the composition further comprises sodium chloride. 19. The composition according to claim 18, characterized in that the composition comprises approximately 200 mM sodium citrate and approximately 300 mM sodium chloride. 20. The composition according to any of claims 1-14, characterized in that the stabilizing agent is sodium pyrophosphate or sodium gluconate. 21. A pharmaceutical composition comprising docetaxel, characterized in that the docetaxel used for the preparation of the composition is in an anhydrous form. 22. The pharmaceutical composition according to claim 21, characterized in that it also comprises a biocompatible polymer. 23. The pharmaceutical composition according to claim 22, characterized in that the biocompatible polymer is albumin. 24. The pharmaceutical composition according to claim 22, characterized in that it comprises nanoparticles comprising docetaxel coated with the carrier protein. 25. The pharmaceutical composition according to claim 24, characterized in that the carrier protein is albumin. 26. The pharmaceutical composition according to claim 25, characterized in that the weight ratio of docetaxel and albumin in the composition is about 18: 1 or less. 27. The pharmaceutical composition according to claim 21, characterized in that it also comprises a surfactant. 28. The pharmaceutical composition according to claim 27, characterized in that the agent surfactant is Tween 80. 29. The pharmaceutical composition according to claim 27, characterized in that the surfactant is anhydrous. 30. A method of stabilizing a poorly water soluble pharmaceutical agent in a composition, characterized in that it comprises combining the composition comprising a poorly water soluble pharmaceutical agent with a stabilizing agent, wherein the resulting composition is stable under the same condition under which composition is unstable prior to the addition of the stabilizing agent. 31. The method according to claim 30, characterized in that it also comprises the identification and selection of a composition that is unstable under one or more conditions. 32. The method according to claim 30, characterized in that the stabilizing agent is selected from the group consisting of citrate, edetate, malic acid, pentetate, sodium pyrophosphate and sodium gluconate. 33. Use of the composition according to claim 1, for the manufacture of a medicament for the treatment of cancer. 34. The use according to claim 33, where the cancer is any of prostate cancer, colon cancer, breast cancer, cancer of the head and neck, pancreatic cancer, lung cancer, and cancer of the ovaries. 35. Use of a composition according to any of claims 1-14 and 21-29, for the manufacture of a medicament for the treatment of cancer. 36. The use according to claim 33, wherein the cancer is any of prostate cancer, colon cancer, breast cancer, cancer of the head and neck, pancreatic cancer, lung cancer, and cancer of the ovaries