MX2008002741A - Compositions comprising poorly water soluble pharmaceutical agents and antimicrobial agents - Google Patents

Abstract

The present invention provides compositions comprising a poorly water soluble pharmaceutical agent, a carrier protein, and an antimicrobial agent, wherein significant microbial growth is inhibited in the composition. The amount of the antimicrobial agent in the composition may be below the level that induces a toxicological effect or at a level where a potential side effect can be controlled or tolerated. Also provided are compositions comprising a poorly water soluble pharmaceutical agent, a carrier protein, a sugar, and optionally an antimicrobial agent. Methods of using the compositions are also provided.

Description

COMPOSITIONS COMPRISING SMALLLY SOLUBLE PHARMACEUTICAL AGENTS IN WATER AND ANTIMICROBIAL AGENTS Field of the Invention This application relates to compositions comprising pharmaceutical agents sparingly soluble in water, associated with proteins, for parenteral uses and other uses, which also comprise an antimicrobial agent. BACKGROUND OF THE INVENTION Many drugs for parenteral use, especially those administered intravenously, cause undesirable side effects. These drugs are often insoluble in water, and thus are formulated with solubilizing agents, surfactants, solvents, and / or emulsifiers which can be irritant, allergenic, or toxic when administered to patients (see for example, Briggs et al., Anesthesis 37: 1099 (1982), and Waugh et al., Am. J. Hoep. Phar acists, 48: 1520 (1991)). For example, the chemotherapeutic drug paclitaxel is active against carcinomas of the ovaries, breast, lung, esophagus and the head and neck. Paclitaxel, however, has been shown to induce toxicities associated with administration, as well as an acute and cumulative, significant toxicity, such as myelosuppression, neutropenic fever, anaphylactic reaction, and peripheral neuropathy. Paclitaxel is very sparingly soluble in water, and as a result, can not be formulated Ref .190431 practically with water for IV administration. Traditionally, paclitaxel is formulated for IV administration in a solution with polyethoxylated castor oil (Cremophor) as the primary solvent and high concentrations of ethanol as the cosolvent. Cremophor is associated with side effects that may be severe, including anaphylaxis and other regions of hypersensitivity that require pretreatment with corticosteroids, antihistamines, and H2 blockers, (see, eg, Gelderblom et al., Eur. J. of Cancer , 37: 1590-1598, (2001)). Similarly, docetaxel is used in the treatment of an anthracycline-resistant breast cancer, but it has also been shown to induce hypersensitivity side effects and fluid retention that can be severe. To avoid the problems associated with the side effects related to the administration of the drug formulations, alternative formulations have been developed. For example, Abraxane ™ is a protein-stabilized formulation, free of Cremophor, of paclitaxel, which was developed to resolve or minimize the side effects caused by the Cremophor EL / ethanol formulation. Formulations that contain similar proteins have also been developed for other taxanes such as docetaxel and ortataxel, as well as other drugs. Because the protein serves as a good substrate for microbial growth, a major challenge encountered when using these protein-containing formulations is potential microbial contamination. For example, to minimize the risk of microbial contamination, the common intravenous formulation of Abraxane ™ is stored in a lyophilized form, and must be injected immediately (eg, within hours) after it is reconstituted in a medium aqueous. Bacterial growth can result from inadvertent contamination in a container that contains a single dosage. Bacterial contamination is even more of a problem when multiple-dose withdrawals from containers are necessary. Antibacterial agents such as EDTA, pentetate, or sulfite-containing agents, are generally known and used in pharmaceutical compositions. See, for example, U.S. Nos. 5,714,520, 5,731,355, 5,731,356, 6,028,108, 6,100,302, 6,147,122, 6,177,477, 6,399,087, and 6,469,069, International Patent Application No. WO 99/39696, and U.S. Patent Publication. No. 20050004002. Many of the antibacterial agents, however, are considerably toxic. For example, the addition of sulphites to the drug formulations presents Potential adverse effects for the pediatric population and for its use in the general population that are allergic to sulfur. See, for example, Baker et al., Anesthesiology, 103 (4): 1-17 (2005); Mirejovsky, Am. J. Heal th Syst. Pharm. , 58: 1047 (2001). The toxicities of these bacterial agents become a significant problem in the formulation of the pharmaceutical compositions of the protein-containing drugs, which frequently require more antimicrobial agents than the non-protein-containing formulations, to counteract the significant microbial growth therein. In addition, many antimicrobial agents are known to interact with proteins and cause problems such as aggregation. See, for example, Lam et al., Pharm. Res. 14: 725-729 (1997). The effect of the antimicrobial agents on the stability of the protein enhances a matter of difficulty in the formulation of the protein-containing compositions of the sparingly soluble pharmaceutical agents in water, since the appropriate configuration of the proteins is generally required for stabilization of the pharmaceutical agents sparingly soluble in water in the composition. Therefore, there is a need to develop formulations containing protein from sparingly soluble pharmaceutical agents in water containing agents antimicrobials that provide a desired antimicrobial efficacy or that do not significantly affect the stability of the protein and / or do not cause unacceptable toxicological effects during administration. It is also necessary to develop protein-containing formulations of the sparingly water-soluble pharmaceutical agents that can be reconstituted more easily. The descriptions of all published publications, patents, patent publications and published patent applications, referred to herein, are incorporated herein for reference in their entireties. Brief Description of the Invention The invention provides compositions (such as pharmaceutical compositions) comprising a poorly water soluble pharmaceutical agent, a carrier protein (such as albumin, e.g., human serum albumin (HSA)). ), and an antimicrobial agent, wherein significant antimicrobial growth is inhibited in the composition. In some embodiments, significant antimicrobial growth in the compositions is inhibited for a given period of time, such as at least about 4 hours (including for example about any of 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108, or 120 hours). In some embodiments, the compositions are less susceptible to microbial contamination when compared to compositions that do not contain an antimicrobial agent. In some embodiments, the compositions of the invention comprise a poorly water soluble pharmaceutical agent, a carrier protein (such as albumin, e.g., HSA), and an antimicrobial agent, wherein the antimicrobial agent is in an amount effective to inhibit the significant microbial growth in the composition (s). In some embodiments, the pharmaceutical agent poorly soluble in water is an antineoplastic agent or a chemotherapeutic agent. 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 taxanes, geldanamycin, 17-allyl amine geldanamycin, thiocolchicine, and their dimers, rapamycin, cyclosporine, epothilone, radicicol, and combrestatin. For example, in some embodiments, a composition is provided comprising a taxane or a derivative thereof (such as paclitaxel, docetaxel, or ortataxel), a carrier protein (such as albumin, for example HSA), and an antimicrobial agent, in where significant microbial growth is inhibited in the composition. In some embodiments, a composition comprising a taxane or a derivative thereof is provided (Such as paclitaxel, docetaxel, or Ortataxel), a carrier protein (such as albumin, for example HSA), and an antimicrobial agent wherein the antimicrobial agent is in an amount effective to inhibit significant microbial growth in the composition. In some embodiments, the poorly water soluble pharmaceutical agent is an amorphous and / or non-crystalline taxane (such as paclitaxel). In some embodiments, the sparingly water-soluble pharmaceutical agent used to make the composition is in an anhydrous form (such as anhydrous docetaxel). In some embodiments, the antimicrobial agent is not deferoxamine (ie, it is different from deferoxamine). In some embodiments, a composition comprising a poorly soluble pharmaceutical agent in water, a carrier protein (such as albumin, for example HSA), and an antimicrobial agent wherein the antimicrobial agent is a chelating agent, and is provided where significant growth is inhibited in the composition. In some embodiments, a composition comprising a taxane or a derivative thereof (such as paclitaxel, docetaxel, or ortataxel), a carrier protein, is provided. (such as albumin, for example HSA), an antimicrobial agent, wherein the antimicrobial agent is a chelating agent, and wherein significant microbial growth is inhibited in the composition. In some modalities, the antimicrobial agent is a polidentate chelating agent. In some embodiments, the antimicrobial agent comprises one or more carboxylic acid groups. In some embodiments, the chelating agent is not deferoxamine (ie, it is different from deferoxamine). In some embodiments, the chelating agent is any of (and in some embodiments selected from the group consisting of) edetate, citrate, pentetate, tromethamine, sorbate, ascorbate, derivatives thereof, and mixtures thereof. In some embodiments, the chelating agent comprises citrate and EDTA. In some embodiments, a composition comprising a poorly soluble pharmaceutical agent in water, a carrier protein (such as albumin, for example HSA), and an antimicrobial agent wherein the antimicrobial agent is a chelating agent, and is provided where significant microbial growth is inhibited in the composition. In some embodiments, a composition comprising a taxane or a derivative is provided. thereof (such as paclitaxel, docetaxel, or Ortataxel), a carrier protein (such as albumin, for example HSA), and an antimicrobial agent wherein the antimicrobial agent is a chelating agent, and wherein significant microbial growth is inhibited in the composition. In some embodiments, the non-chelating antimicrobial agent functions as a pro-oxidant. In some modalities, the agent chemo antimicrobial works as an antioxidant. In some modalities, the non-chelating agent is either (and in some embodiments selected from the group consisting of) sulfites, benzoic acid, benzyl alcohol, chlorobutanol, paraben, and derivatives thereof. In some embodiments, the composition comprises a poorly soluble pharmaceutical agent in water, albumin, and an antimicrobial agent, wherein the weight ratio of albumin in the sparingly soluble pharmaceutical agent in water in the composition is from about 0.01: 1 to 100: 1, and where significant antimicrobial growth is inhibited in the composition. In some embodiments, the composition comprises a poorly water soluble pharmaceutical agent, an albumin, and an antimicrobial agent, wherein the weight ratio of the albumin to the poorly water soluble pharmaceutical agent 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, about 5: 1 to about 9: 1, and about 9: 1), and where significant microbial growth is inhibited in the composition. In some embodiments, the composition comprises a taxane or a derivative thereof (such as paclitaxel, docetaxel, or ortataxel) an albumin, and an antimicrobial agent, wherein the ratio by weight of the albumin to the taxane or derivative thereof in the composition is approximately 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, about 5: 1 to about 9: 1, and about 9: 1), and where significant microbial growth is inhibited in the composition. In some embodiments, the poorly water soluble pharmaceutical agent (such as the taxane or a derivative thereof) is coated with albumin. In some embodiments, the antimicrobial agent is a chelating agent, such as any of (and in some embodiments selected from the group consisting of) edetate, citrate, pentetate, tromethamine, sorbate, ascorbate, derivatives thereof, and mixtures thereof. . In some embodiments, the chelating agent is not deferoxamine (ie, it is different from deferoxamine). In some embodiments, the antimicrobial agent is not a chelating agent, such as any of (in some embodiments selected from the group consisting of) sulfites, benzoic acid, benzyl alcohol, chlorobutanol, parabens, derivatives thereof, and mixtures thereof. In some embodiments, the composition further comprises a sugar (such as the sugar described herein). In some embodiments, the composition comprises a poorly water soluble pharmaceutical agent associated with the protein and an antimicrobial agent, wherein significant microbial growth is inhibited in the composition. In some embodiments, the composition comprises a taxane associated with the protein or a derivative thereof (such as a paclitaxel associated with the protein, a docetaxel associated with the protein, or an ortataxel associated with the protein) and an antimicrobial agent, wherein significant microbial growth is inhibited in the composition. In some embodiments, the antimicrobial agent is a chelating agent, such as any of (and in some embodiments selected from the group consisting of) edetate, citrate, pentetate, tromethamine, sorbate, ascorbate, derivatives thereof, and mixtures thereof. . In some embodiments, the chelating agent is not deferoxamine (ie, it is different from deferoxamine). In some embodiments, the antimicrobial agent is a non-chelating agent, such as any of (and in some embodiments selected from the group consisting of) sulfites, benzoic acid, benzyl alcohol, chlorobutanol, paraben, derivatives thereof, and mixtures thereof. same.

In some embodiments, the pharmaceutical agent / protein is in a particulate form, which in various embodiments may be of the average diameters as described herein. 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 a carrier protein; and (2) an antimicrobial agent, wherein significant microbial growth is inhibited in the composition. In some embodiments, the sparingly water soluble agent is coated with the carrier protein. In some embodiments, the composition comprises particles (such as nanoparticles) comprising (in various embodiments consisting of or consisting essentially of) (1) taxane or a derivative thereof (such as paclitaxel, docetaxel, or ortataxel) and a protein carrier and (2) an antimicrobial agent, wherein significant microbial growth is inhibited in the composition. In some embodiments, the taxane or a derivative thereof is coated with the carrier protein. In some embodiments, the antimicrobial agent is a chelating agent, such as any of (and in some embodiments selected from the group consisting of) edetate, citrate, pentetate, tromethamine, sorbate, ascorbate, derivatives thereof, and mixtures thereof. In some embodiments, the chelating agent is not deferoxamine (ie, it is different from deferoxamine). In some embodiments, the antimicrobial agent is not a chelating agent such as any of (and in some embodiments selected from the group consisting of) sulfites or their derivatives, benzoic acid, benzyl alcohol, chlorobutanol, parabens, derivatives thereof, and mixtures thereof. thereof. In some embodiments, the composition comprises (1) particles (such as nanoparticles) that comprise. { in various embodiments consisting of or consisting essentially of) a pharmaceutical agent sparingly soluble in water and albumin; and (2) an antimicrobial 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 where significant microbial growth is inhibited. in the composition. 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) an antimicrobial agent, wherein the weight ratio of albumin to the sparingly soluble pharmaceutical agent in Water 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, about 5: 1 to about 9: 1, and about 9: 1), and where significant microbial growth is inhibited in the composition. In some embodiments, the composition comprises (such as consisting of or consisting essentially of) (1) particles (such as nanoparticles) comprising taxanes or a derivative thereof (such as paclitaxel, docetaxel, or ortataxel) and albumin; and (2) an antimicrobial agent, wherein the weight ratio of the albumin to the taxane or a derivative thereof in the composition is from 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, about 5:: 1 to about 9: 1, and about 9 : 1), and where significant microbial growth is inhibited in the composition. In some embodiments, the pharmaceutical agent poorly soluble in water (such as taxane or a derivative of it) is coated with albumin. In some embodiments, the antimicrobial agent is a chelating agent, such as one of (and in some embodiments selected from the group consisting of) edetate, citrate, pentetate, tromethamine, sorbate, ascorbate, derivatives thereof, and mixtures thereof. same. In some embodiments, the chelating agent is not deferoxamine (ie, it is different from deferoxamine). In some embodiments, the chelating agent is not citrate (ie, it is different from citrate). In some embodiments, the antimicrobial agent is a non-chelating agent, such as any of (and in some embodiments selected from the group consisting of) sulfites, benzoic acid, benzyl alcohol, chlorobutanol paraben, derivatives thereof, and mixtures thereof. . In some embodiments, the composition further comprises a sugar (such as the sugar described herein). In some embodiments, the poorly water soluble pharmaceutical agent is docetaxel or a derivative thereof. In some embodiments, the composition comprises (1) particles (such as nanoparticles) comprising (in various embodiments consisting of or consisting essentially of) paclitaxel and albumin; and (2) an antimicrobial agent, wherein the weight ratio of albumin to paclitaxel (w / w) is from about 0.01: 1 to about 100: 1, wherein the growth significant microbial is inhibited in the composition. In some embodiments, the composition comprises (1) particles (such as nanoparticles) comprising (in various embodiments consisting of or consisting essentially of) paclitaxel and albumin; and (2) an antimicrobial agent, wherein the weight ratio of albumin to paclitaxel (w / w) is approximately 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, about 5: 1 to about 9: 1, and about 9: 1), wherein significant microbial growth is inhibited in the composition. In some embodiments, the weight ratio of albumin to paclitaxel 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 modalities, paclitaxel is coated with albumin. In some embodiments, the composition is substantially free (such as free) from Cremophor. In some embodiments, the composition comprises a stable aqueous suspension of particles (such as nanoparticles) comprising paclitaxel and albumin (such as paclitaxel particles coated with albumin), wherein the composition further comprises an antimicrobial agent, wherein the weight ratio of albumin and paclitaxel in the composition is about 9: 1 or less, and in where significant microbial growth is inhibited in the composition. In some embodiments, the composition comprises a dry (such as lyophilized) composition, which can be reconstituted (or resuspended or rehydrated) to generally form a stable aqueous suspension of particles (such as nanoparticles) comprising paclitaxel and albumin (such as coated paclitaxel). with albumin), wherein the composition further comprises an antimicrobial agent, wherein the weight ratio of albumin and paclitaxel 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, about 5: 1 to about 9: 1, and about 9: 1), and wherein significant microbial growth is inhibited in the composition. In some embodiments, the antimicrobial agent is a chelating agent, such as any of (and in some embodiments selected from the group consisting of) edetate, citrate, pentetate, tromethamine, sorbate, ascorbate, derivatives thereof, and mixtures thereof. In some embodiments, the chelating agent is not deferoxamine (ie, it is different from deferoxamine). In some embodiments, the antimicrobial agent is a non-chelating agent, such as any of (and in some embodiments selected from the group consisting of) sulfites or their derivatives, benzoic acid, benzyl alcohol, chlorobutanol paraben, derivatives thereof, and mixtures thereof. thereof. In some embodiments, the composition further comprises a sugar (such as the sugar described herein). In some embodiments, the particles (such as nanoparticles) described herein 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 not greater than 200 nm. In some embodiments, the mean or average diameter of the particles is between about 20 nm to about 400 nm. In some embodiments, the mean or average diameter of the particles is between about 40 nm to about 200 nm. In some embodiments, the particles are filterable in sterile conditions. In some embodiments, the composition comprises a pharmaceutical agent poorly soluble in water (such as a taxane or a derivative thereof), a carrier protein (such as albumin), and an antimicrobial agent in an amount that is effective to inhibit significant microbial growth in the composition. In some embodiments, the composition comprises a sparingly water soluble pharmaceutical agent, (such as taxane or a derivative thereof) a carrier protein (such as albumin) in an amount that is effective to stabilize the poorly water soluble pharmaceutical agent in a aqueous medium, and an antimicrobial agent in an amount that is effective to inhibit the significant microbial agent in the composition. In some embodiments, the composition comprises a poorly water soluble pharmaceutical agent (such as a taxane or a derivative thereof), a carrier protein (such as albumin) in an amount that is effective to reduce one or more side effects of administration of the drug. a pharmaceutical agent sparingly soluble in water in a human being, and an antimicrobial agent in an amount that is effective to inhibit significant microbial growth in the composition. In some embodiments, the antimicrobial agent is a chelating agent, such as any of (and in some embodiments selected from the group consisting of) edetate, citrate, pentetate, tromethamine, sorbate, ascorbate, derivatives thereof, and mixtures thereof. . In some embodiments, the antimicrobial agent is an agent not chelant, such as any of (and in some embodiments selected from the group consisting of) sulfites, benzoic acid, benzyl alcohol, chlorobutanol, paraben, derivatives thereof, and mixtures thereof. The specific amounts of the antimicrobial agents are further described hereinafter. The compositions described herein can be a stable aqueous suspension of a sparingly water soluble pharmaceutical agent, such as a stable aqueous suspension of the poorly water soluble pharmaceutical agent at a concentration of from about 0.1 to about 100 mg / ml, about 0.1 to about 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, and about 5 mg / ml ml. In some embodiments, the concentration of the pharmaceutical agent sparingly soluble 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, 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), which can be reconstituted (or resuspended or rehydrated) to form a generally stable aqueous suspension of the pharmaceutical agent sparingly soluble in water. In some embodiments, the composition is a liquid (such as aqueous) composition obtained by reconstitution or resuspension of a dry composition. In some embodiments, the composition is an intermediate liquid composition (such as aqueous), which 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 the individual. In some embodiments, the compositions described herein are substantially free (such as free) of the surfactants. In some embodiments, the compositions described herein are substantially free (such as free of) Cremophor. The antimicrobial agent containing the compositions described herein may further comprise a sugar or other reconstitution or lyophilization adjuvants. In some embodiments, the amount of the antimicrobial agent in the composition is below the level that induces a toxicological effect (i.e., above a level). clinically acceptable toxicity) or is at a level where a potential side effect can be controlled or tolerated when the composition is administered to the individual. In some embodiments, the antimicrobial agent is present in an amount that does not adversely affect the stability or characteristics of the carrier protein in the composition. In another aspect, compositions (such as lyophilized compositions or intermediate liquid compositions that can be lyophilized) are provided which comprise a poorly water soluble pharmaceutical agent, a carrier protein (such as albumin), and a sugar. 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 (such as taxane or derivatives thereof) and an albumin; and (2) a sugar, 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. 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 sugar, 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, 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, about 5: 1 to about 9: 1, and about 9: 1). In some embodiments, the pharmaceutical agent poorly soluble in water is coated with albumin. In some embodiments, the composition is a dry composition (such as lyophilisate) wherein the lyophilized composition may be reconstituted (or resuspended or rehydrated) to form a stable aqueous suspension of a pharmaceutical agent sparingly soluble in water, and wherein the reconstitution of the composition in the aqueous solution is less than for the composition that is without sugar. In some embodiments, the concentration of the sugar in the composition or in a reconstituted suspension resulting from the composition is greater than about 50 mg / ml. In some embodiments, the composition further comprises an antimicrobial agent, such as the antimicrobial agents described herein. In some embodiments, the poorly water soluble pharmaceutical agent is docetaxel or a derivative thereof.

In some embodiments, the invention provides a composition comprising paclitaxel, an albumin, and a sugar, wherein the weight ratio of albumin to paclitaxel is about 9: 1 or less, and wherein the sugar in the composition or in a reconstituted suspension resulting from the composition is greater than about 50 mg / ml. 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 sugar, wherein the weight ratio of the albumin to the poorly water soluble pharmaceutical agent 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, about 5: 1 to about 9: 1, and about 9: 1), and wherein the sugar in the composition or in a reconstituted suspension resulting from the composition is greater than about 50 mg / ml. In some embodiments, the sugar is in an amount that is effective to increase the stability of the pharmaceutical agent sparingly soluble in water in the composition when compared to a composition without the sugar. In some embodiments, the sugar is in an amount that is effective to improve the filterability of the compositions when compared to the composition of the sugar. In some embodiments, the sugar is in an amount that is effective to reduce foaming during reconstitution of the lyophilized composition when compared to a composition without the sugar. 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 (such as vials or containers (including vials or sealed containers and vials or sealed containers). sterile), and kits comprising the compositions The invention also provides methods of making and using these compositions as described herein It is to be understood that one, some, or all of the profiles of the various embodiments described herein may be combined to form other embodiments of the present invention Detailed Description of the Invention The present invention in one aspect provides compositions, including pharmaceutical compositions, comprising a poorly water soluble pharmaceutical agent, a carrier protein, and an antimicrobial agent. The carrier protein in the composition generally makes the pharmaceutical agent sparingly soluble in water more readily suspendable in an aqueous medium and / or helps maintain the suspension when compared to compositions that do not contain the carrier protein. The carrier protein is present generally, but not necessarily, in an amount that is sufficient to stabilize the sparingly soluble pharmaceutical agent in water in an aqueous suspension and / or in an amount that is effective to reduce one or more side effects of the administration of the pharmaceutical agent sparingly soluble in water in an individual (such as a human). The antimicrobial agent is generally present in an amount that is effective to inhibit (such as retard, reduce, slow down, and / or prevent) significant microbial growth in the composition. Preferably, the amount of the antimicrobial agent in the composition is below the level that induces a toxicological effect or a level at which a potential side effect can be controlled or tolerated. In another aspect, compositions are provided (such as lyophilized compositions or a composition intermediate liquid that can be lyophilized) comprising a poorly water soluble pharmaceutical agent, a carrier protein (such as albumin) and a sugar. The general reference to "the composition" or "compositions" includes and is applicable to the compositions of the invention. The invention also provides pharmaceutical compositions comprising the components described herein. The reference to paclitaxel here applies to paclitaxel or its derivatives and accordingly the invention contemplates and includes both of these modalities. The reference to "paclitaxel" is to simplify the description and is exemplary. The derivatives or analogs of paclitaxel include, but are not limited to, compounds that are structurally similar to paclitaxel or are of the same general chemical class as paclitaxel, eg, docetaxel. In some embodiments, the paclitaxel derivative or analog retains similar biological, pharmacological, chemical and / or physical properties (including, for example, functionality) of paclitaxel. Examples of the paclitaxel derivatives or analogs include docetaxel or ortataxel. The same principle of description applies to the other agents provided herein including, such as, for example, antimicrobial agents and pharmaceutical agents sparingly soluble in water (such as taxane (including docetaxel, ortataxel, or other taxanes), geldanamycin, 17-allyl amino geldanamycin, thiocolchicin and its dimers, rapamycin, cyclosporin, epothilone, radicicol and combrestatin). It is understood that the aspects and embodiments of the invention described herein include "consisting" and / or "consisting essentially of" aspects and modalities. Antimicrobial agents The term "antimicrobial agent" as used herein refers to an agent that is capable of inhibiting (such as retarding, reducing, slowing, and / or preventing) the growth of one or more microorganisms. Significant microbial growth can be measured or indicated by a number of ways well known in the art, such as one or more of the following: (1) microbial growth in a composition that is sufficient to cause one or more adverse effects to a individual when the composition is administered to the individual; (2) more than about a 10-fold increase in microbial growth over a certain period of time (eg, over a 24-hour period) during extrinsic contamination (such as exposure to 10-103 units. at a temperature in the range of 20 to 25 aC). Other signs of significant microbial growth are described here.

The antimicrobial agent described herein may be effective against the growth of one or more bacteria (including both gram positive and gram negative bacteria), fungi or molds. For example, in some embodiments, the antimicrobial agent is effective against the growth of one or any or more of the gram-positive cocci (such as Staphylococcus aureus and Staphylococcus epidermidie), gram-negative strains fermentative (such as species Klebeiella pneumoniae, Enterobacter cloaceae, Eecherichia coli, Proteus and Enterobacter gergoviae), non-fermentative gram-negative strains (such as Peeudomonas species aeruginoea, Peeudomonae cepacia, Peeudomonae fluorescene, Peeudomonas putida, Flavobacterium, and eepeciee Acinetobacter) and spore-forming bacteria ( such as Bacillue eubtilie). In some embodiments, the antimicrobial agent is effective against the growth of any one or more of the yeasts (such as Candida albicane, Candida parapeyloeia) and molds (such as Aepergillus niger and Penicillium notatum). Other bacteria whose growth can be inhibited include, for example, B. cerew, B. cohaerene, B. megatheri um, B. plicatue, B. ubicui tarius, Corynebacterium nicotinovarane, Enterobacter aerogenes, Lactobacill us arabinoeue, L. asei, Pe. effuee, and Pe. ovalie Other fungi whose growth can be inhibited include, for example Candida krusei, C. pseudotropicalie, abnormal Haneenula, Pichia membranaefaciens, S. anamensie, S. cerevisiae, S. ellipeoideus, S. EPEC, Torula lipolytica, abnormal Willia, and Z. nussbaumii. Other molds whose growth can be inhibited include, for example, Trichoderma lignorm, Fusarium epec, Gliocladium roeeum, Mucor epec, and Penicillium glaueum. The effectiveness of the antimicrobial agents against various microorganisms can be measured by methods known in the art, such as the conservative efficacy tests of USP / EP or modifications thereof. See Sutton and Porter, PDA J: Pharm. Sci. Tech, 2002; 56: 6, 300-311. See also U.S. patent publication No. 2004/0009168. For example, the ability of growth inhibition of antimicrobial agents in the final composition can be evaluated using filtration and culture techniques in a broth. Approximately 50-200 colony forming units (CFU) per ml of four standard organisms recommended by the United States Pharmacopeia (USP) for tests of conservative efficacy can be inoculated into each formulation. These four organisms are identified as: Staphylococcue aureue (ATCC 6538), Eechericha coli (ATCC 8739), Peeudomonae aeruginoea (ATCC 9027) and Candida albicane (ATCC 10231). In addition to these organisms, S. epidermidie (ATCC 12228) and S. aureue (coagulase negative, ATCC 27734). After the inoculation of the organisms, the test formulations can be incubated at 30-35 aC. The viable amount for the tested organism at the chosen time points (such as immediately after inoculation and after 24 hours of incubation at 30-35 aC) can be determined. In some embodiments, the antimicrobial agent is in an amount that is effective to inhibit significant microbial growth during at least about any of 4, 8, 12, 18, 24, 36, 48, 60, 72, 84, 96, or 108, or 120 hours. The antimicrobial agent is considered effective, for example, if the antimicrobial agent is capable of retarding the growth of the microorganisms in the compositions to no more than about 1 log increase (10 times) in about 24 hours after the extrinsic contamination. In some embodiments, the antimicrobial agent is effective if it causes at least a reduction of approximately 1.0 log from the initial count to approximately 7 days, approximately a reduction from 3.0 log to approximately 14 days, and / or no increase in approximately the day 28 in bacterial samples. In some embodiments, the antimicrobial is effective if it causes at least approximately a 2.0 log reduction from the initial count to approximately 6 hours, approximately a 3.0 log reduction to approximately 24 hours, and / or no recovery at approximately day 28 in the bacterial samples. In some embodiments, the antimicrobial agent is effective if it causes approximately a 2.0 log reduction from the initial count at about day 7 and / or no increase at about day 28 in the yeast and mold samples. In some embodiments, the antimicrobial agent is effective if it causes a reduction of at least about 1.0 log from the initial count to approximately 24 hours, a reduction of approximately 3.0 log approximately on day 7, and no increase approximately on day 28 in the bacterial samples. In some embodiments, the antimicrobial agent is effective if it causes a reduction of approximately 1.0 log from the initial count approximately on day 14 and no increase approximately on day 28 in the yeast and mold samples. In some embodiments, the amount of the antimicrobial agent in the composition is below the level that induces a toxicological effect (i.e., above a clinically acceptable level of toxicity), or at a level where a potential side effect can be controlled or tolerated when the composition is administered to an individual. The methods of determination of toxicity or Side effects of agents administered to an individual are generally known in the art, and depend on the particular antimicrobial agent in the composition. For example, any calcium chelating antimicrobial agents (such as EDTA) can cause heart problems (such as cardiac arrhythmia) when administered to an individual at elevated levels. The indications for cardiac arrhythmia can be verified in this way to evaluate the toxicity effect of the calcium-chelating agent. Other indications such as anemia (for ion burners), weight loss, and mortality can also be evaluated on animal models to determine the optimal amount of the antimicrobial agent. In some embodiments, the antimicrobial agent is present in an amount that does not adversely affect the stability or characteristics of the carrier protein in the composition. In some embodiments, the antimicrobial agent (such as EDTA and non-chelating antimicrobial agents that are antioxidants) is present in an amount that is effective to inhibit oxidation in the composition. The effective amount of the antimicrobial agents in the composition will vary depending on the particular antimicrobial agents or agent in the composition, and are further described in detail below.

Chelating agents In some embodiments, the antimicrobial agent is a chelating agent. Chelating agents function as antimicrobial agents mainly by the removal of essential metal ions (such as calcium, zinc, magnesium, etc.) and make them unavailable for essential metabolic processes. 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 embodiments, 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, pentetate, tromethamine, sorbate, ascorbate, derivatives thereof, and mixtures thereof. An antimicrobial agent contemplated herein is an edetate, ie, ethylenediaminetetraacetic acid (EDTA) and derivatives thereof. Suitable derivatives for use in the present invention include disodium edetate, trisodium edetate, tetrasodium edetate and disodium calcium edetate. The nature of edetate is not critical, provided that it satisfies the function of inhibiting the significant growth of microorganisms during a period of prolonged time (such as at least about 24 hours). In some embodiments, the edetate is present in the compositions at a concentration of about 0.001 mg / ml to about 1 mg / ml, including for example any of 0.01 mg / ml to about 1 mg / ml, about 0.01 mg / ml to about 0.5 mg / ml, approximately 0.01 mg / ml to approximately 0.3 mg / ml, approximately 0.02 mg / ml to approximately 0.2 mg / ml, approximately 0.03 mg / ml to approximately 0.1 mg / ml, and approximately 0.05 mg / ml. In some embodiments, the edetate concentration is less than about 1 mg / ml, such as less than about any of 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, or 0.001 mg / ml. In some embodiments, the weight ratio of the edetate to the sparingly water soluble pharmaceutical agent in the composition is from about 0.002: 1 to about 0.2: 1, including for example about 0.002: 1 to about 0.1: 1, about 0.002: 1 to about 0.06: 1, about 0.004: 1 to about 0.04: 1, about 0.006: 1 to about 0.02: 1, and about 0.01: 1. In some modalities, the. proportion by weight of the edetate and the poorly soluble pharmaceutical agent in water in the composition is less than about 0.2: 1, 1.5: 1, 0.1: 1, 0.05: 1, 0.01: 1, and 0.005: 1. Another antimicrobial agent contemplated herein is a citrate, such as sodium citrate and citric acid. Suitable citrate concentrations include, for example, about 0.1 mg / ml to about 200 mg / ml, about 0.2 mg / ml to about 100 mg / ml, about 0.3 mg / ml to about 50 mg./ml, about 0.5 mg. / ml to about 10 mg / ml, and about 1 mg / ml to about 5 mg / ml. In some embodiments, the concentration of the citrate is greater 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 citrate to the sparingly water soluble pharmaceutical agent is from about 0.02: 1 to about 40: 1, including, for example, about 0.04: 1 to about 20: 1, about 0.06: 1 to about 10: 1, about 0.1: 1 to about 2: 1, about 0.2: 1 to about 1 mg / ml. In some embodiments, the weight ratio of the citrate to the poorly soluble pharmaceutical agent in water is less than about any of 40: 1, 30: 1, 20: 1, 10: 1, 5: 1, 1: 1, 0.5: 1, and 0.1: 1. In other embodiments, the antimicrobial agent is not citrate, (ie, different from citrate). The antimicrobial agent can also be a pentetate, (including trisodium calcium pentetate). In some embodiments, the amount of pentetate is less than about 3 mg / ml (including for example less than about any of 2, 1.5, 1, 0.5, 0.3, 0.1, 0.09, 0.08, 0.7, 0.6, 0.5, 0.4, 0.3 , 0.2, 0.1, and 0.05 mg / ml). For example, the pentetate may also be present in the range of either from about 0.005 to about 3 mg / ml, about 0.005 to about 0.1 mg / ml, or about 0.005 to about 0.05 mg / ml. In some embodiments, the weight ratio of the pentetate to the sparingly water soluble pharmaceutical agent is from about 0.001: 1 to about 0.6: 1, including for example about 0.001: 1 to about 0.2: 1, and about 0.01: 1 to about approximately 0.1: 1. In some embodiments, the weight ratio of the pentetate to the sparingly soluble pharmaceutical agent in water is less than about any of 0.6: 1, 0.3: 1, 0.1: 1, 0.05: 1, and 0.01: 1. Another antimicrobial agent contemplated herein is tromethamine.

The tromethamine when used herein refers to 2-amino-2-hydroxymethyl-l, 3-propanediol, also known as TRIS. In some embodiments, tromethamine is present in the compositions in amounts no greater than about 2.5 mg / ml (including for example less than about any 2.5, 2, 1.5, or 1 mg / ml). For example, tromethamine is present in the range of either from about 1.5 to about 2.5 mg / ml, such as about 2 mg / ml. Another exemplary amount of tromethamine is about 2.4 mg / ml. In some embodiments, the weight ratio of the tromethamine to the sparingly soluble pharmaceutical agent in water is about 0.1: 1 to about 0.5: 1, including for example. about 0.2: 1 to about 0.5: 1, and about 0.2: 1 to about 0.4: 1. In some embodiments, the weight ratio of the tromethamine to the sparingly water soluble pharmaceutical agent in the composition is less than about any of 0.5: 1, 0.4: 1, 0.3: 1, 0.2: 1, and 0.1: 1. In some embodiments, the chelating antimicrobial agent is a sorbate (such as potassium sorbate). In some embodiments, the sorbate is present in the composition in amounts not greater than about 2.5 mg / ml (including for example less than about either 2.5, 2, 1.5, or 1 mg / ml). For example, sorbate is present in an amount of about 0.5 mg / ml. In some embodiments, the weight ratio of the sorbate and the sparingly water soluble pharmaceutical agent in the composition is less than about either 0.5: 1, 0.4: 1, 0.2: 1, or 0.1: 1. In some embodiments, the chelating antimicrobial agent is an ascorbate (such as sodium ascorbate). In some embodiments, ascorbate is present in the composition in amounts of no greater than about 5 mg / ml (including for example less than about any of 2.5, 2, 1.5, or 1 mg / ml). For example, ascorbate may be present in the amount of 1 mg / ml. In some embodiments, the weight ratio of the sorbate and the sparingly water soluble pharmaceutical agent in the composition is less than about any of 1: 1, 0.5: 1, 0.4: 1, 0.2: 1, or 0.1: 1. Other suitable metal chelating antimicrobial agents and their exemplary amount include, but are not limited to, sodium formaldehyde sulfoxylate (0.1 mg / ml) and monothioglycerol (5 mg / ml). Non-chelating agents In some embodiments, the antimicrobial agent is not a chelating agent (ie, it is not a chelating antimicrobial agent), which includes, but is not limited to, a, sulfites, benzoic acid, benzyl alcohol, chlorobutanol, and derivatives thereof. These non-chelating antimicrobial agents work by a variety of mechanisms. In some embodiments, the non-chelating antimicrobial agent functions as a pro-oxidant. In some embodiments, the non-chelating antimicrobial agent functions as an antioxidant. An antimicrobial agent contemplated herein is a sulfite. The term "sulfites" refers to all pharmaceutically acceptable derivatives of sulfurous acid (orthosulfuric acid) and metasulfuric acid. Suitable sulfites include, but are not limited to, sodium sulfite, sodium bisulfite, potassium sulfate, potassium bisulfite, sodium metabisulfite, potassium metabisulfite, or combinations thereof. In some embodiments, the sulfite is present from about 0.075 to about 6.6 mg / ml, including for example any of from about 0.075 to about 1 mg / ml and about 0.25 mg / ml. In some embodiments, the sulfite is present in an amount that is less than about 5 mg / ml, 3 mg / ml, and 1 mg / ml. In some embodiments, the weight ratio of the sulfite and the sparingly soluble pharmaceutical agent in water is from about 0.01: 1 to about 1.5: 1, including for example 0.02: 1 to about 1: 1, and about 0.05: 1 to about 0.5: 1. In some embodiments, the weight ratio of the sulfite and the sparingly soluble pharmaceutical agent in water is less than about any of 1.5: 1, 1: 1, 0.5: 1, 0.1: 1, and 0.05: 1. In some embodiments, the antimicrobial agent is benzoic acid, benzyl alcohol, or derivatives thereof. In some embodiments, the antimicrobial agent selected from the group consisting of benzyl alcohol, benzethonium chloride, sodium benzoate, potassium benzoate, benzyl benzoate, or various combinations thereof. In some embodiments, the amount of benzyl alcohol is in the range of about 0.175 to about 9 mg / ml, including for example any of from about 0.7 to about 4.5 mg / ml, about 1.5 mg / ml and about 1 mg / ml. In some embodiments, the amount of benzyl alcohol is from about 0.7 to about 9 mg / ml, optionally including an EDTA amount of about 0.05 mg / ml. In some embodiments, the composition comprises a benzoic acid or a derivative thereof in the range of about 2 mg / ml to about 50 mg / l, including for example any of from about 1 mg / ml to about 20 mg / ml, about 2 mg / ml. mg / ml to approximately 10 mg / ml, and approximately 5 mg / ml. In some embodiments, the composition comprises a benzyl benzoate or sodium benzoate in the range of about 0.1 mg / ml to about 460 mg / ml, including for example about 0.5 mg / ml to about 200 mg / ml, about 1 mg / ml to about 100 mg / ml, about 1 mg / ml to about 50 mg / ml, and 1 mg / ml. In some embodiments, the composition comprises an amount of benzethonium chloride from about 0.1 to about 1 mg / ml. In some embodiments, the weight ratio of the benzoic acid or benzyl alcohol and the sparingly water soluble pharmaceutical agent in the composition is from about 0.02: 1 to about 150: 1, including for example about 0.1: 1 to about 40: 1. , approximately 0.2: 1 to approximately 20: 1, and approximately 0.2: 1 to approximately 10: 1. In some embodiments, the weight ratio of benzoic acid or benzyl alcohol, and the sparingly water soluble agent in the composition is less than about any of 150: 1, 100: 1, 50: 1, 10: 1, 5: 1, 1: 1, and 0.5: 1 and 0.1: 1. In some embodiments, the antimicrobial agent is a chlorobutanol or derivative thereof (such as chlorobutanol hemihydrate). Suitable amounts of chlorobutanol include, for example, about 2.5 mg / ml up to about 50 mg / ml, about 5 mg / ml to about 20 mg / ml. In some embodiments, the antimicrobial agent is a phenol or a derivative thereof. The appropriate amount of phenol (or a derivative thereof) includes, for example, about 0.7 to about 25 mg / ml, about 1 mg / ml to about 20 mg / ml. In some embodiments, the antimicrobial agent is a cresol (such as m-cresol) or a derivative thereof. Suitable amounts of the cresol (or a derivative thereof) include, for example, any of from about 1.5 mg / ml to about 31 mg / ml and about 5 mg / ml to about 15 mg / ml. In some embodiments, the non-chelating agent is the paraben that includes, but is not limited to, methyl paraben, butyl paraben, and propyl paraben. An adequate amount of paraben (such as methyl paraben) includes, for example, any of from about 0.05 mg / ml to about 5 mg / ml, about 0.08 mg / ml to about 3 mg / ml, about 0.1 mg / ml to about 2. mg / ml, approximately 0.2 mg / ml to approximately 1.5 mg / ml, and approximately 1 mg / ml. Other suitable antimicrobial agents include, but are not limited to, nitrates and nitrites (such as phenyl mercuric nitrate), esters of p-hydroxybenzoic acid, propionic acid and propionates, diacetates of sodium, sorbic acid and sorbates, sulfur dioxide, diethylpyrocarbonate (DEPC), sodium hypochlorite, sodium iodide, thimerosal, and the like. 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 antimicrobial agents (such as at least two of the antimicrobial agents described herein). These antimicrobial agents may be of the same class (for example, different from sulfite) or of different classes (for example, a sulfite and a benzyl alcohol). For example, combinations of methylparaben and propylparaben (1-2 mg / ml) are found to be particularly good against fungi. When multiple antimicrobial agents are present in the composition, the effective amount of each antimicrobial agent depends on the combined effects of the antimicrobial agents. For example, if the antimicrobial agents work synergistically, the effective amount of each antimicrobial agent may be much less than that which is required when the antimicrobial is present in only one composition. In some embodiments, the composition comprises both citrate and EDTA. Citrate and EDTA were found to be particularly good against E. coli. In some embodiments, the composition comprises 200 mM citrate and. EDTA In some modalities, the composition comprises 200 mM citrate and either 0.001%, 0. 01%, 0.1% and 0.2% (w / v) of EDTA. Pharmaceutical agent 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 SC 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, or 0.01 mg / ml. Poorly soluble pharmaceutical agents in water described herein can be, for example, anticancer or antineoplastic agents, antimicrobial agents, immunosuppressive agents, anesthetics, hormones, agents for use in cardiovascular disorders, antiarrhythmics, antibiotics, antifungals, antihypertensives, antiasthmatics, antiinflammatory agents , antiarthritic agents,. vasoactive agents, analgesics / antipyretics, antidepressants, antidiabetics, antifungals, antiinflammatories, antianxiety agents, immunosuppressive agents, antimigraine agents, sedatives, antianginal agents, antipsychotic agents, antimanic agents, antiarthritic agents, antigout agents, anticoagulants, thrombolytic agents, antifibrinolytic agents, hemorheological agents, antiplatelet agents, anticonvulsants, antiparkinson agents, antihistamines / antipruritics useful for calcium regulation, antiviral agents, antimicrobials, anti-infectives, bronchodilators, hormones, hypoglycemic agents, hypolipidemic agents, antiulcer / antireflux agents, antinauseants / anti-vomiting agents, and oil soluble vitamins (e.g., vitamins agents 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. Pharmaceutical agents poorly soluble in water, suitable include, but are not limited to, taxanes (such as paclitaxel, docetaxel and other taxanes), epothilones, campototecinas, colchicines, geladanamicinas, amiodaronas, thyroid hormones, amphotericin, corticosteroids, propofol , melatonin, cyclosporin, rapamycin (sirolimus) and derivatives, tacrolimus, mycophenolic acids, ifosfamide, vinorelbine, vancomycin, gemcitabine, SU5416, thiotepa, bleomycin, diagnostic radiocontrast agents, and derivatives thereof. Other poorly water soluble 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 Pharmaceutical agents sparingly soluble in water include those compounds which 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 and other taxane or taxane analog, 17-allyl amino geldanamycin (17-AAG) , geldanamycin 18-derivative, camptothecin, propofol, amiodariona, cyclosporine, epothilone, radicicol, combretastatin, amphotericin rapamycin, liothyronine, epothilone, colchicine, thiocolchicine and its dimers, thyroid hormone, vasoactive intestinal peptide, corticosteroids, melatonin, tacrolimus, acids mycophenolic, epothilones, radicicols, combrestatins, and analogues or derivatives thereof. 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 taxanes, geldanamycin, 17-allyl amino geldanamycin, thiocolchicin and their 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 In some embodiments, the pharmaceutical agent poorly soluble in water is a thiocolchicine dimer (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). Anhydrous docetaxel has been shown to produce a more stable formulation than can be done with a hydrated docetaxel such as the trihydrate or docetaxel hemihydrate. Carrier protein The compositions described herein also comprise carrier proteins. 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 which will be interrupted by substances other than those 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 chemically synthesized or synthesized by recombinant DNA techniques). Examples of suitable carrier proteins include proteins normally found in plasma or blood, including, but not limited to, albumin, immunoglobulins including IgA, lipoproteins, apolipoproteins B, alpha-acid glycoprotein, beta-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 carrier proteins can be either naturally occurring or they 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. HSA is the most abundant protein in 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 Obetetrics, 150, 811-816, (1980)) and in conjunction with exchange transfusion in the treatment of neonatal hyperbilirubinemia (see, for example, 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 diverse set of drugs, especially neutral and negatively charged hydrophobic compounds (Goodman et al. al., The Pharmacological Baeic of Therapeutice, 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 arginine residues that function as fixation points for polar ligand characteristics (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., Nat. = * Truct. Biol., 5, 827-35 (1998), Emerged 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 ttelforechung, 45, 1053-6 (1995), and Garrido et al., Rev. Eep.Anestestiol. Reanim, 41, 308 -12 (1994)). In addition, docetaxel has been shown to bind to proteins in human plasma (see, for example, Urien et al., Jnvest, New Druge, 14 (2), 147-51 (1996)). 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 agent a sparingly water-soluble pharmaceutical that is more easily suspended in an aqueous medium or 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) from Cremophor, such as Cremophor EL® (BASF). In some embodiments, the composition is substantially free (such as free) from the surfactants. A composition is "substantially free of Cremophor" or "substantially free of the surfactant" if the amount of Cremophor or 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 sparingly water soluble pharmaceutical agent associated with the carrier protein. "Association" or "associate" is used here 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 sparingly water soluble pharmaceutical agent are considered to be "associated" if the carrier protein makes 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 poorly water soluble pharmaceutical agent are associated if the carrier protein stabilizes the sparingly water soluble pharmaceutical agent in an aqueous composition. For example, the carrier protein and the poorly water soluble pharmaceutical agent may be present in a particle or a nanoparticle, which will be described here further. A pharmaceutical agent sparingly soluble in water is "stabilized" 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 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). The stability of the suspension is generally (but not necessarily) evaluated at a storage temperature (such as at room temperature (such as at 20-25 eC) or in refrigerated conditions (such as 4 SC)). 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 viewed under the optical microscope at 1000 times of amplification, approximately fifteen minutes after the preparation of the suspension. The stability can also be evaluated under accelerated test conditions, such as at a temperature that is higher than about 40 BC. The carrier protein and the poorly 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 pharmaceutical agent poorly soluble in water. In some embodiments, the carrier protein encapsulates or entraps the pharmaceutical agent sparingly soluble in water. In some embodiments, the carrier protein is bound (such as non-covalently bound) 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 consisting essentially of) a pharmaceutical agent sparingly soluble in water and a carrier protein. When the poorly soluble pharmaceutical agent in water is in a liquid form, the particles or nanoparticles are also referred to as droplets 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 a mean 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 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. The 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 protein solutions, optionally buffered solutions of sugars, optionally buffered solutions of vitamins. , optionally buffered solutions of synthetic polymers, lipid-containing emulsions, 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 sparingly 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 settling of the poorly water soluble pharmaceutical agent 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 sparingly 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, about 5 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 Cremophor), so that the composition is free or substantially free of the surfactant (such as 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% 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, with respect to the pharmaceutical agent ( p / p) is from about 0.01: 1 to about 100: 1, 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 until 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, 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 reduction, alleviation, elimination, or to the avoidance of one or more undesirable effects caused by the poorly soluble pharmaceutical agent in water, as well as the side effects caused by the delivery vehicles (such as solvents which render pharmaceutical agents sparingly soluble in water, suitable for injection) used to deliver 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 (w / w) is from about 0.01: 1 to about 100: 1, 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 up 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 less than about any of 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 sparingly water soluble pharmaceutical agent is a taxane or a derivative thereof, such as paclitaxel, docetaxel, ortataxel, or derivatives thereof. In some embodiments, the poorly water soluble pharmaceutical agent is coated with albumin. In some embodiments, the particles (such as nanoparticles) comprising a sparingly 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 stable suspension 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, about 5 mg / ml. In some embodiments, the concentration of the poorly soluble pharmaceutical agent in water is approximately any of 1,2,3,4,5,6,7,8,9,11,12,13,14,15,16,17. , 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 paclitaxel, docetaxel, ortataxel or derivatives thereof. In some embodiments, the composition comprises particles (such as nanoparticles) comprising paclitaxel, such as particles with a mean or average diameter of about 20 to about 400 nm, including for example about 40 to about 200 nm. In some embodiments, the composition comprises particles (such as nanoparticles) that comprise (in various embodiments consisting of essentially of) paclitaxel and albumin. In some modalities, paclitaxel is coated with albumin. In some embodiments, the weight ratio of albumin to paclitaxel (w / w) is anywhere from about 0.01: 1 to about 100: 1, 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 albumin to paclitaxel is less than about any of 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 particles (such as nanoparticles) comprising paclitaxel 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 particles (such as nanoparticles) containing paclitaxel. In some embodiments, the composition comprises a dry composition (such as lyophilized) which can be reconstituted to an aqueous suspension of paclitaxel-containing particles. In some embodiments, the concentration of paclitaxel in the composition is between 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, 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 paclitaxel 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 composition comprises a formulation of nanoparticles containing paclitaxel albumin (hereinafter referred to as NaJ-paclitaxel). NaJb-paclitaxel such as Capxol ™ (also known as Abraxane ™) has been described in U.S. Pat. or. 6,096,331. Capxol ™ is a formulation of paclitaxel stabilized by human albumin USP, which can be dispersed in a physiological solution that can be injected directly. When dispersed in a suitable aqueous medium such as a 0.9% sodium chloride injection or a 5% dextrose injection, Capxol ™ forms a stable colloidal suspension of paclitaxel. The size (ie, average or average diameter) of the particles in the colloidal suspension can vary from 20 nm to 8 microns with a preferred range of about 20-400 nm. Since HSA is freely soluble in water, Capxol ™ can be reconstituted in a wide range of concentrations ranging from diluted (0.1 mg / ml paclitaxel) to concentrated (20 mg / ml paclitaxel), including for example about 2 mg / ml to approximately 8 mg / ml, approximately 5 mg / ml. In some embodiments, the concentration of paclitaxel is approximately either 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 mg / ml. Sugar Containing Compositions The present invention also provides compositions (such as pharmaceutical compositions) comprising a sparingly water soluble agent, a carrier protein (such as albumin) and a sugar. The composition may further comprise an antimicrobial agent as described herein. The composition described herein includes, for example, dry compositions (such as lyophilized), liquid compositions (such as aqueous) obtained by reconstitution or resuspension of a dry composition, or intermediate liquid compositions (such as aqueous), which can be dried (such as lyophilized). "Sugar" when used herein, includes, but is not limited to, monosaccharides, disaccharides, polysaccharides, and derivatives or modifications thereto. Suitable sugars for the compositions described herein include, for example, mannitol, sucrose, fructose, lactose, maltose, and trehalose. In some embodiments, the sugar serves as a reconstitution enhancer which causes a lyophilized composition to dissolve or suspend in water and / or an aqueous solution, more rapidly than the lyophilized composition could dissolve without the sugar. For example, the composition can be a dry composition (such as lyophilized) wherein the composition can be reconstituted (or resuspended or rehydrated) to a stable aqueous suspension of the poorly water soluble pharmaceutical agent, and wherein the reconstitution time of the composition in an aqueous solution is less than that for the composition without the sugar. In some embodiments, the composition can be reconstituted (such as by mixing, applying light strokes, or swirling) within less than about any of 8 minutes, 5 minutes, or 2 minutes. In some modalities, the sugar is in a sufficient amount that is effective to increase the Chemical stability of the pharmaceutical agent sparingly soluble in water in the composition. In some embodiments, the sugar is in an amount that is effective to improve the filterability of the composition. In some embodiments, the sugar is in an effective amount to reduce foaming during reconstitution of the dry composition (such as lyophilized). These compositions are improved when compared to the compositions without the sugar. In some embodiments, the concentration of the sugar in a liquid suspension (such as the suspension prior to lyophilization or the reconstituted suspension) is greater than approximately either 50, 60, 70, 80, 90, or 100 mg / ml. In some embodiments, the sugar is present in an amount of any of from about 20 to about 100 mg / ml, about 50 mg / ml to about 100 mg / ml, about 90 mg / ml. The proportion (w / w) of the sugar with respect to the poorly water soluble pharmaceutical agent in the composition can vary depending on the pharmaceutical agent poorly soluble in water. Exemplary proportions of the sugar with respect to the sparingly water soluble pharmaceutical agent (such as paclitaxel) include, for example, approximately any of 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, or greater.

In some embodiments, the composition comprises (1) particles (such as nanoparticles) comprising the pharmaceutical agent poorly soluble in water (such as taxane or derivatives thereof) and albumin and (2) a sugar, wherein the proportion by weight of the albumin with respect to the pharmaceutical agent (w / w) is from about 0.01: 1 to about 100: 1, including, for example, 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 approximately 9: 1, or approximately 9: 1. In some embodiments, the weight ratio of the albumin to the pharmaceutical agent is about 18: 1 or less, including for example about any of 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 minor, and 3: 1 or less. The pharmaceutical agent sparingly soluble in water can be coated with albumin. In some embodiments, the invention provides a composition comprising paclitaxel, an albumin, and a sugar, wherein the weight ratio of albumin to paclitaxel (w / w) is from about 0.01: 1 to about 100: 1, including for example 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 about 12: 1, about 4: 1 hhaassttaa about 10: 1, about 5: 1 hiaastasis about 9: 1, or about 9: 1. In some embodiments, the weight ratio of albumin to paclitaxel is about 18: 1 or less, including for example about any of 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 minor, and 3: 1 or less. In some embodiments, the composition comprises (1) particles (such as nanoparticles) comprising paclitaxel and albumin and (2) - a sugar, wherein the weight ratio of albumin to paclitaxel (w / w) is about 0.01: 1 to about 100: 1, including for example 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 albumin to paclitaxel is about 18: 1 or less, including for example about 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. Paclitaxel can be coated with albumin. In some embodiments, the composition is a dry composition (such as lyophilized) that can be reconstituted (or resuspended or rehydrated) to form a generally stable aqueous suspension of a pharmaceutical agent sparingly soluble in water, and wherein the reconstitution time of the composition in an aqueous solution is less than that for the composition that does not have sugar. In some embodiments, the concentration of the sugar in the composition or in a reconstituted suspension resulting from the composition is greater than either approximately 50, 60, 70, 80, 90, or 100 mg / ml. In some embodiments, sugar is present at a concentration of any of from about 20 to about 100 mg / ml, about 50 mg / ml to about 100 mg / ml, or about 90 mg / ml. The sugar-containing compositions, described herein, may further comprise one or more antimicrobial agents, such as the antimicrobial agents described herein. In addition to sugar, other reconstitution enhancers (such as those described in U.S. Patent Application Publication No. 2005/0152979) may also be added to the compositions. Other components in the compositions The compositions described herein may include other agents, excipients, or stabilizers to improve the properties of the composition. For example, to increase the stability by increasing the negative zeta potential of the nanoparticles, certain negatively charged components can be added. Such negatively charged components include, but are not limited to, bile salts, bile acids, glycocholic acid, cholic acid, chenodeoxycholic acid, taurocholic acid, glycokenedeoxycholic acid, taurokenedeoxycholic acid, lithocholic acid, ursodeoxycholic acid, dehydrocholic acid, and others; phospholipids, including lecithin-based phospholipids (for example egg yolk) that they include the following phosphatidylcholines: palmitoylolethylphosphatidylcholine, palmitoylolinoleylphosphatidylcholine, stearoyl-linoleylphosphatidylcholine stearoyloleylphosphatidylcholine, stearoyl arachidylphosphatidylcholine, and dipalmitoylphosphatidylcholine. Other phospholipids include L-α-dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), distearoylphosphatidylcholine (DSPC), hydrogenated soy phosphatidylcholine (HSPC), and other related compounds. Negatively charged surfactants or emulsifiers are also suitable as additives, for example cholesteryl sodium sulfate and the like. 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, 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 quantity 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 "Dyes, Diluents, Buffering Agents, Wetting Agents, Preservatives, Flavoring Agents, and Pharmaceutically Compatible Excipients The forms of the lozenges may comprise the active ingredient in a flavor, usually sucrose or acacia or tragacanth, as well as lozenges comprising the ingredient active in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, excipients such as those already known in the art Formulations suitable for parenteral nistration include isotonic, aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffer Iguadores, bacteriostatos, and solutes that make the formulation compatible with the recipient's blood proposed, and sterile aqueous or non-aqueous suspensions which may include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The formulations can be presented in single dose or multiple 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, eg, 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 nistration comprise the inventive composition which includes isotonic, aqueous and non-aqueous sterile solutions, which may contain antioxidants, 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 nistered 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 range of from about 4.5 to about 9.0, including for example the pH ranges of either 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 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, ampoules, bottles, jars, flexible packaging (e.g., plastic or Mylar bags, sealed ), and similar. These manufacturing items 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 unit dosage forms and / or articles of manufacture) described herein and may further comprise instruction (s) on methods of using 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. In some embodiments, the invention comprises a kit comprising (1) a composition comprising a pharmaceutical agent sparingly soluble in water and a carrier protein; and (2) an antimicrobial agent, wherein the poorly water soluble protein / pharmaceutical composition and the antimicrobial agent are present in separate packages, and wherein significant microbial growth in the composition is inhibited during the addition of the antimicrobial agent. to the protein / agent composition Pharmaceutical sparingly soluble in water. In some embodiments, the kit further comprises an instruction on the addition of the antimicrobial agent to the protein / drug composition. The kits described herein may further include other desirable materials from a commercial and user standpoint, 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 paclitaxel) 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 water-soluble pharmaceutical agent and the pharmaceutical compositions and instructions for use, and packaged in amounts sufficient for storage and use in pharmacy, eg, hospital pharmacies and composition pharmacies. Methods of making and using the compositions Methods of making and using the compositions described herein are also provided. For example, it provides a method of preparing a composition comprising a poorly water soluble pharmaceutical agent (such as a taxane, for example, paclitaxel, docetaxel or ortataxel), a carrier protein (such as albumin), and an antimicrobial agent, wherein the Significant microbial growth is inhibited in the composition, which comprises the combination (such as mixing) of a composition containing a poorly water soluble pharmaceutical agent and a carrier protein with an antimicrobial agent. The methods of making the compositions containing the carrier proteins and the pharmaceutical agents sparingly soluble in water are already known in the art. For example, nanoparticles containing poorly water soluble pharmaceutical agents (such as paclitaxel) and the carrier protein (such as albumin) can be prepared under conditions of high shear forces (eg, sonication, high pressure homogenization or the like). ). These methods are described, for example, in U.S. Pat. Nos. 5,916,596; 6,506,405; and 6,537,579 and also in U.S. Patent Publication. No. 2005 / 0004002A1. Briefly, the sparingly water-soluble drug (such as docetaxel) is dissolved in an organic solvent, and the solution can be added to a solution of human serum albumin. The mixture is subjected to high homogenization Pressure. 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). The antimicrobial 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 / agent protein composition. Pharmaceutical sparingly soluble in water is prepared. For example, the antimicrobial agent can be added in the presence of an aqueous medium used for the reconstitution / suspension of the carrier protein / pharmaceutical agent composition sparingly soluble in water or added to an aqueous suspension of the sparingly soluble pharmaceutical agent associated with water. carrier protein In some embodiments, the antimicrobial agent is mixed with the carrier protein / pharmaceutical agent composition poorly soluble in water prior to lyophilization. In some modalities, the agent Antimicrobial is added to the composition of carrier protein / pharmaceutical agent sparingly soluble in water, lyophilized. In some embodiments, when the addition of the antimicrobial 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 not less than about 6, including for example not less than any of about 6.5, 7, or 8 (such as about 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 pharmaceutical agent sparingly. soluble in water, a carrier protein, and an antimicrobial agent, wherein significant microbial growth is inhibited in the composition. 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 taxane). ), a carrier protein, and an antimicrobial agent, wherein significant microbial growth is inhibited in the composition. In some embodiments, the antimicrobial agent is in an amount that is sufficient to inhibit significant microbial growth in the composition. In some embodiments, the antimicrobial agent in the composition is additionally in an amount that does not cause any toxicological effect when the composition is administered in an individual (such as a human). 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 retard one or more of its symptoms. With reference to cancers or other unwanted cell proliferation, an effective amount comprises an amount sufficient to cause a tumor to shrink and / or to reduce the speed 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. Cancers to be treated by the compositions described herein (such as a composition comprising an antineoplastic agent such as a taxane, rapamycin, and 17-AAG) include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. Examples of cancers 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, lung adenocarcinoma, 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, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, melanoma, endometrial or uterine carcinoma, carcinoma of the salivary glands, kidney or kidney cancer, liver cancer, prostate cancer, vulvar cancer, cancer thyroid, liver carcinoma, head and neck cancer, colorectal cancer, rectal cancer, soft tissue carcinoma, Kaposi's sarcoma, B-cell lymphoma (including non-Hodgkin's lymphoma, low / follicular lymphoma (NHL by its acronym in English), small lymphocytic NHL (SL for its acronym in English), follicular NHL / intermediate grade, intermediate-grade diffuse NHL, high-grade immunoblastic NHL, high-grade lymphoblastic NHL, non-segmented, small-cell NHL , high grade, NHL of bulky disease, mantle cell lymphomas, AIDS-related lymphoma, and Waldenstrom's macroglobulinemia), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) ), myeloma, hair cell leukemia, chronic myeloblastic leukemia, and post-transplant lymphoproliferative disease (PTLD), as well as vascular proliferation abnormally 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, methods of treating hyperplasia are 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 SCLC. advanced), 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 embodiments, the cancer is any of (and in some modalities is selected from the group consisting of) breast cancer, colorectal cancer, rectal cancer, non-small cell lung cancer, non-Hodgkin's lymphoma (NHL), cancer. kidney cells, 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, glio as, glioblastomas, neuroblastomas, and multiple myeloma. In some modalities, cancer is a solid tumor. Suitable individuals for the reception of these compositions depend on the nature of the pharmaceutical agent poorly soluble in water, as well as the disease / condition / disorder that is to be treated and / or prevented. Consequently, the individual term includes any of the vertebrates, mammals and humans. In some embodiments, the individual is a mammal, including, but not limited to, a human, bovine, equine, feline, canine, rodent, or primate. In some modalities, the individual is a human being. 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 paclitaxel), 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 an agent chemotherapeutic 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). Combination therapy methods using taxane nanoparticle formulations with other agents (or therapeutic methods) have been described in International Patent Application No. PCT / US006 / 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. For example, the dosage of paclitaxel in the composition may be in the range of 100-400 mg / m2 when provided in a 3-week schedule, or 50-250 mg / m2 when provided in a schedule per week. In addition, if it is provided in a metronomic regime (for example, daily or sometimes per week), the dosage may be in the range of about 5-75 mg / m2. The compositions described herein can be administered to an individual (such as a human) by means of several routes, for example, intravenous, intraarterial, 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. Also provided here are methods of reducing the side effects associated with the administration of a poorly water soluble pharmaceutical agent to a human, which comprise administering to a human being a pharmaceutical composition comprising the poorly water soluble pharmaceutical agent, a carrier protein, and an antimicrobial agent, wherein significant microbial growth is inhibited in the composition. For example, the invention provides methods of reducing various side effects associated with the administration of the poorly soluble pharmaceutical agent in water, including, but not limited to, myelosuppression, neurotoxicity, hypersensitivity, inflammation, venous irritation, phlebitis, pain, skin irritation, peripheral neuropathy, neutropenic fever, anaphylactic reaction, haematological toxicity, and cerebral or neurological toxicity, and combinations thereof. In some embodiments, methods are provided for reducing the hypersensitivity reactions associated with the administration of the poorly water soluble pharmaceutical agent, which includes, for example, severe skin rashes, hives, flushes, dyspnea, tachycardia and others. In some embodiments, the antimicrobial agent is present in an amount that is effective to inhibit significant microbial growth in the pharmaceutical composition. In some embodiments, the antimicrobial agent in the composition is also in an amount that does not cause any toxicological effect or a. a level where a potential side effect can be controlled or tolerated when the composition is administered to an individual. In addition, a method for increasing the storage life of a liquid composition comprising a poorly water soluble pharmaceutical agent and a carrier protein is provided. For example, in some embodiments, the invention provides a method for maintaining to a composition (such as a pharmaceutical composition), comprising a pharmaceutical agent sparingly soluble in water and a carrier protein, preserved against microbial growth (ie, sterile or substantially free of significant microbial growth) for at least 24 hours in a aqueous medium, which comprises adding to the composition an antimicrobial agent in an amount that is effective to inhibit significant microbial growth in the composition. In some embodiments, methods of inhibiting microbial growth are provided in a composition (particularly in a pharmaceutical composition) comprising a carrier protein and a poorly water soluble pharmaceutical agent, which comprises adding to the composition an antimicrobial agent in an amount that is effective to inhibit significant microbial growth in the composition. The antimicrobial agent can be either mixed with the sparingly water soluble pharmaceutical agent and / or the carrier protein during the preparation of the carrier protein / pharmaceutical agent composition poorly soluble in water, or added in the company of an aqueous medium used for reconstitution the pharmaceutical composition / carrier protein. In some embodiments, methods for maintaining a composition preserved against bacterial (ie, sterile or substantially growth-free) growth significant bacterial) during at least any of 24, 36, 48, 60, 72, 84, or 96 hours are provided. In a further aspect of the invention there is provided the use of the compositions described herein in the manufacture of a medicament. Particularly, the manufacture of a medicament for use in the treatment of the conditions described herein. In addition, the pharmaceutical composition thereof, here described variably, is also proposed for use in the manufacture of a medicament for use in the treatment of the conditions and, according to the methods, described herein, unless is signaled in another way. The following examples are provided to illustrate, but not to limit, the invention. Example 1 This example illustrates the formulations of paclitaxel / albumin and the preservatives. The compositions are prepared essentially as described in U.S. Patents. Nos. 5,439,686 and 5,916,596. Briefly, paclitaxel is dissolved in an organic solvent (such as methylene chloride or a mixture of chloroform / ethanol), and the solution is added to a solution of human serum albumin. A suitable amount of an antimicrobial agent is then added to the mixture. The mixture is then homogenized for 5 minutes at low RPM to form a Unrefined emulsion, and then transferred to a high pressure homogenizer. The emulsification is effected at 633.33-2814.80 kg / cm2 (9000-40,000 psi) while the emulsion is recycled for at least 5 cycles. The resulting system is transferred to a rotary evaporator, and the organic solvent is rapidly removed at 40 fiC, under reduced pressure (30 mm HG) for 20-30 minutes. The dispersion is then lyophilized further for 48 hours. The resulting cake can be easily reconstituted to the original dispersion by the addition of sterile water or a saline solution, which may contain additional antimicrobial agent (s). Exemplary formulations of the compositions that can be prepared are provided later (only the concentrations of paclitaxel, albumin and the antimicrobial agent are provided). Formulation 1: 5 mg / ml paclitaxel; 56 mg / ml human albumin; 0.25 ml of sodium metabisulfite. ' Formulation 2: 5 mg / ml paclitaxel; 56 mg / ml human albumin; 0.05 mg / ml disodium edetate. Formulation 3: 5 mg / ml paclitaxel; 56 mg / ml human albumin; 0.5 mg / ml potassium sorbate. Formulation 4: 5 mg / ml paclitaxel; 56 mg / ml human albumin; 1 mg / ml sodium benzoate. Formulation 5: 7 mg / ml paclitaxel; 56 mg / ml of human albumin; 1 mg / ml sodium ascorbate. Formulation 6: 7 mg / ml paclitaxel; 56 mg / ml human albumin; 1 mg / ml of methyl paraben. Formulation 7: 7 mg / ml paclitaxel; 56 mg / ml human albumin; 1 mg / ml of benzyl alcohol. Example 2 This example demonstrates how to determine the efficacy of the antimicrobial agents in a composition described in Example 1. The growth inhibition capabilities of the antimicrobial agents in the formulations described in Example 1 are evaluated using membrane filtration techniques and cultures. in a broth. Approximately 50-200 colony forming units (CFU) per ml of four organisms - standards recommended by the United States Pharmacopeia (USP) for conservative efficacy tests are inoculated into each formulation. These four organisms are identified as: Staphylococcus aureue (ATCC 6538), Eechericha Coli (ATCC 8739), Pseudomonas aeruginosa (ATCC 9027), and Candida albicane (ATCC 10231). In addition to these organisms, S. epidermidie (ATCC 12228) and S. aureue (coagulase negative, ATCC 27734) can also be tested. After inoculation of the test organisms, the test formulations are incubated at 30-35 SC. Viable counts for the organism Test at the selected times of the time (such as immediately after inoculation and after 24 hours of incubation at 30-35 SC) are determined. The antimicrobial agent is considered effective if the antimicrobial agent is capable of retarding the growth of the microorganisms in the composition to no greater than about 1 log (10 times) in 24 hours after the extrinsic contamination. EXAMPLE 3 This example demonstrates the improved reconstitution time in the sugar-containing formulations of paclitaxel and albumin. The compositions were prepared essentially as described in U.S. Pat. Nos. 5,439,686 and 5,916,596, in the presence or absence of sugar. Briefly, paclitaxel was dissolved in a mixture of chloroform / ethanol (1: 1), and the solution was added to a solution of human serum albumin. The mixture was homogenized for 5 minutes at low RPM to form an unrefined emulsion, and then transferred to the high pressure homogenizer. The emulsification was carried out at 633.33-2814.80 kg / cm2 (9000-40,000 psi) while the emulsion is recycled for at least 5 cycles. The resulting system was transferred to a rotary evaporator, and the chloroform / ethanol was rapidly removed at 40 SC, under reduced pressure (30 mm HG) for 20-30 minutes. The dispersion was lyophilized then additionally for 48 hours. The resulting cake was easily reconstituted to the original dispersion by the addition of sterile water or a saline solution, which may contain the additional antimicrobial agent (s). The sugar was added either in a solution of human serum albumin or added to the dispersion prior to lyophilization. Antimicrobial agents were not added in this particular experiment, but they can be added. The following formulations were prepared: Formulation 1: the suspension prior to lyophilization contained 5 mg / ml paclitaxel; 56 mg / ml human albumin; 10 mg of mannitol. The suspension is filled into vials with 250 mg paclitaxel per vial. Formulation 2: the suspension prior to lyophilization contained 5 mg / ml of paclitaxel; 56 mg / ml human albumin; 10 mg / ml sucrose. The suspension is filled into vials with 250 mg paclitaxel per vial. Formulation 3: the suspension prior to lyophilization contained 7 mg / ml paclitaxel; 56 mg / ml human albumin; 90 mg / ml sucrose. The suspension is filled in vials with 300 mg paclitaxel per vial. Formulation 4: the suspension prior to lyophilization contained 7 mg / ml of paclitaxel; 56 mg / ml of human albumin; 50 mg / ml mannitol. The suspension is filled in vials with 300 mg paclitaxel per vial. Formulation 5: the suspension prior to lyophilization contained 7 mg / ml paclitaxel; 56 mg / ml human albumin. The suspension is filled in vials with 3.0 mg of paclitaxel per vial. The lyophilized products of formulations 3 and 4 were reconstituted in less than 2 minutes. The reconstitution times for the formulation products 1, 2 and 5 were similar and between approximately 8-12 minutes. It was surprisingly found that 10 mg / ml of the sugars were not sufficient to significantly reduce the reconstitution time for nab-paclitaxel. Approximately 50-90 mg / ml of sugars were required to reduce the reconstitution time. EXAMPLE 4 This example demonstrates the advantageous properties of the albumin / paclitaxel formulations. that contain sugar. In one experiment, the composition of paclitaxel and albumin (naJ-paclitaxel) was prepared with and without the presence of the sugars as described above. The lyophilized vials of albumin-paclitaxel were prepared containing 300 mg per vial for both of the formulations. The sugar-based formulation contained sucrose at a concentration of 90 mg / ml. The lyophilized products were subjected to conditions of accelerated stability at 55 SC for up to 30 days. The percentage of the impurity of 7-epitaxol was determined in the case of each of the formulations and at time zero it was approximately 0.1%. At 15 days and 30 days at 55 SC, the impurity level for the sugar-free formulation was found to be 0.6% and 0.8% respectively and the level of impurity for the sugar-based formulation was found to be to be 0.4 and 0.6% respectively. Based on the surprisingly lower generation of impurities in the sugar-based formulation, its shelf life must be substantially longer than the sugar-free formulations. In another experiment, approximately 1500 ml of the liquid suspension of each formulation containing approximately 7 mg / ml of paclitaxel, 56 mg / ml of human albumin, and 90 mg / ml of sucrose were subjected to filtration through a series of filters with a final filter of 0.2 μm (EKV capsule of 200 cm2). The filtration capacity of each formulation was evaluated based on the volume amount of the nanoparticle suspension that can be filtered through the filter. For the sugar-free formulation, the maximum volume that can be filtered was 1300 ml, at which time the filtration pressure increased beyond 1.7592 kg / cm2 (25 psi) indicating plugging or saturation of the filter membrane. For the sugar-based formulation, the substantially increased filtration capacity was indicated without increasing the pressure for 1500 ml filtered. This surprisingly demonstrates that the sugar-based naj-paclitaxel formulation is more easily filtered with minimal loss of potency when compared to the formulation without the sugars. Example 5 This example demonstrates that nab formulations can serve as a growth medium for microorganisms in the case of accidental contamination. The formulations contained 5 mg / ml of docetaxel, paclitaxel, and 17-AAG, respectively. Four strains of microorganisms were used in the experiment. E. coli (ATCC lot # 97-08 / lot # 483284); S aureus (ATCC Lot # 1836394 / lot # 485823); C. albicans (ATCC lot # 98-0lA / lot # 443131): P. aeruginosa (ATCC lot # 378667 / lot # 484882). 100-600 μl (approximately 100-200 CFU / ml) of each strain, were inoculated in 2 ml of the sample tube of the test batch (see table 1, each sample was duplicated) and 2 ml of TSB as the control. Tryptic soy agar plates (TSA) were inoculated with 10% of the samples (20 drops, disposable syringe of 10 μl), duplicated for each sample. The TSA plates were incubated aerobically at 25 SC + 1 SC in the temperature controlled incubator. The colony counts for the test organism and the CFU / ml were determined at 0 hours, 24 hours and 48 hours after the microbial inoculation. The formulation is rated "yes" (ie, the formulation passed the test) if the formulation does not show a more than 10-fold increase in microbial growth over a 24-hour period or a 48-hour period. Table 1. Microbial growth 48 hours post-inoculation.

Pass = yes (Y) or not (N). Naip-paclitaxel (albumin formulation in paclitaxel nanoparticles) without antimicrobial agents (Abraxane), najb-docetaxel (albumin formulation in docetaxel nanoparticles) without antimicrobial agents and na > -17AAG (albumin formulation in 17-AAG nanoparticles) without the antimicrobial agent, all showed a substantial bacterial growth (> 10 times) over a period of either 24 or 48 hours over at least 3 of the 4 bacterial strains tested. See Table 1. This confirms that accidental contamination of a nab formulation without any of the growth inhibitors can lead to an increase > 10 times in the growth of the microorganism during 24 or 48 hours. Nao-docetaxel with 200 mM citrate, on the other hand, showed microbial suppression at 24 and 48 hours except in the case of ß. coli This was remedied with the addition of EDTA. Supplementation of EDTA with nao-docetaxel with citrate at either 0.001%, 0.01%, 0.1% and 0.2% (w / v) suppressed the growth of E. coli completely. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, it is evident to those skilled in the art that certain modifications and minor changes 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 (34)

1. Claims Having described the invention as above, the content of the following claims is claimed as property. A composition comprising a poorly water soluble pharmaceutical agent, a carrier protein, and an antimicrobial agent other than deferoxamine, characterized in that significant microbial growth is inhibited in the composition.
2. 2. The composition according to claim 1, characterized in that the carrier protein is albumin.
3. 3. The composition according to claim 2, characterized in that the proportion by weight of the albumin with respect to the pharmaceutical agent poorly soluble in water in the composition is about 18: 1 or less.
4. 4. The composition according to claim 1, characterized in that it comprises nanoparticles of the pharmaceutical agents sparingly soluble in water, coated with the carrier protein.
5. 5. The composition according to claim 4, characterized in that the carrier protein is albumin.
6. 6. Composition in accordance with claim 5, characterized in that the weight ratio of the albumin to the poorly water soluble pharmaceutical agent in the composition is about 18: 1 or less.
7. The composition according to claim 4, characterized in that the nanoparticles in the composition have an average diameter no greater than 200 nm.
8. 8. The composition according to claim 7, characterized in that it can be filtered in sterile conditions.
9. 9. The composition according to claim 1, characterized in that it is an aqueous suspension of the pharmaceutical agent sparingly soluble in water at a concentration of about 0.1 to about 20 mg / ml.
10. 10. The composition according to claim 1, characterized in that it is a lyophilized composition that can be reconstituted to an aqueous suspension of the poorly soluble pharmaceutical agent in water at a concentration of about 0.1 to about 20 mg / ml.
11. 11. The composition according to claim 1, characterized in that it is suitable for parenteral administration.
12. 12. The composition according to claim 1, characterized in that it is substantially free of Cremophor®.
13. The composition according to any of claims 1-12, characterized in that the amount of the antimicrobial agent in the composition does not cause a toxicological effect when the composition is administered to an individual.
14. 14. The composition according to any of claims 1-12, characterized in that the antimicrobial agent is a chelating agent.
15. 15. The composition according to claim 14, characterized in that the chelating agent is selected from the group consisting of edetate, citrate, pentetate, tromethamine, derivatives thereof, and mixtures thereof.
16. 16. The composition according to claim 15, characterized in that the chelating agent comprises citrate and edetate.
17. 17. The composition according to claim 16, characterized in that the chelating agent comprises 200 mM citrate and EDTA.
18. 18. The composition according to any of claims 1-12, characterized in that the antimicrobial agent is a non-chelating agent.
19. 19. The composition according to claim 18, characterized in that the non-chelating agent is selected from the group consisting of sulfites, benzoic acid, benzyl alcohol, chlorobutanol, paraben, derivatives thereof, and mixtures thereof.
20. The composition according to any of claims 1-12, characterized in that the poorly water soluble pharmaceutical agent is selected from the group consisting of paclitaxel, docetaxel, ortataxel, or other taxanes, geldanamycin, 17-allyl amino geldanamycin, a Thiocolchicine dimer, rapamycin, cyclosporine, epothilone, radicicol and combrestatin.
21. 21. The composition according to claim 20, characterized in that the pharmaceutical agent poorly soluble in water is a taxane or a derivative thereof.
22. 22. The composition according to claim 21, characterized in that the pharmaceutical agent poorly soluble in water is paclitaxel.
23. 23. The composition according to claim 17, characterized in that the pharmaceutical agent poorly soluble in water is paclitaxel.
24. 24. Use of a composition according to any of claims 1-12, for the manufacture of a medicament for treating cancer, wherein the agent Pharmaceutically sparingly soluble in water is an antineoplastic agent.
25. 25. The use according to claim 24, wherein the amount of the antimicrobial agent in the composition does not cause a toxicological effect when the composition is administered to an individual.
26. 26. A method of preserving a composition comprising a poorly water soluble pharmaceutical agent and a carrier protein against significant microbial growth, characterized in that it comprises adding to the composition an antimicrobial agent other than deferoxamine in an amount that is effective to inhibit significant microbial growth in the composition.
27. 27. A dry composition comprising a poorly water soluble pharmaceutical agent, a carrier protein, and a sugar, characterized in that it can be reconstituted to a stable aqueous suspension of the poorly water soluble pharmaceutical agent, and wherein the reconstitution time of the composition is less than for the composition that does not have sugar, wherein the concentration of sugar in the reconstituted suspension is greater than about 50 mg / ml.
28. The composition according to claim 27, characterized in that it also comprises an antimicrobial agent, wherein the microbial growth significant is inhibited in the composition.
29. 29. The composition according to claim 27, characterized in that the sugar is sucrose or mannitol.
30. 30. The composition according to claim 27, characterized in that the pharmaceutical agent sparingly soluble in water is paclitaxel.
31. 31. The composition according to claim 27, characterized in that the carrier protein is albumin.
32. 32. A composition, characterized in that it comprises paclitaxel, an albumin and a sugar, wherein the weight ratio of albumin to paclitaxel is about 9: 1 or less, and wherein the sugar in the composition or a reconstituted suspension resulting from the composition is greater than about 50 mg / ml.
33. 33. The composition according to claim 32, characterized in that the composition comprises nanoparticles comprising albumin and paclitaxel.
34. 34. The composition according to claim 32 or 33, characterized in that the sugar is sucrose or mannitol.