UA96273C2 - Docetaxel and citrate composition for the treatment of cancer - Google Patents

Abstract

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

Description

This application claims priority to prior US patent application Mo 60/712865, filed Aug. 31, 2005, prior US patent application Meb0/736962, filed Nov. 14, 2005, and prior patent application

US Mo. 60/736931, filed Nov. 14, 2005, all of which are incorporated herein by reference in their entirety.

Prior art of the invention

There is an ever-increasing number of pharmaceutical drugs available that are sparingly soluble or insoluble in aqueous solutions. Such drugs create complex problems when delivering them in the form of an injection, such as by parenteral administration. A well-chosen composition should at least provide a therapeutically effective amount of sparingly soluble drug at the desired absorption site in an absorbable form. In addition, these compositions tend to be unstable with precipitation and/or sedimentation occurring in less than 24 hours after rehydration or reconstitution.

Taxanes, in particular the two currently available taxane drugs, paclitaxel and docetaxel, are potent antitumor agents. Paclitaxel is very poorly soluble in water (less than 10 μg/ml) and as a result cannot be practically obtained in an aqueous environment for intravenous administration. At this time, paclitaxel is formulated for intravenous administration to cancer patients in a solution with polyoxyethylated castor oil (Roiuch! 35 or StetorpogF) as the parent solvent/surfactant with high concentrations of ethanol used as a co-solvent.

Major difficulties in the administration of paclitaxel are the manifestation of allergic reactions. These reactions, which include severe skin rashes, urticaria, flushing of the face, shortness of breath, tachycardia and others, can be explained, at least in part, by the high concentrations of ethanol and Stetorpogia used as solvents in the composition. Docetaxel, an analogue of paclitaxel, is semisynthetically prepared from 10-deacetyl bacatin I, a non-cytotoxic precursor extracted from the needles of Tahiye bBassaia and esterified with a chemically synthesized side chain (Sogpez and Ragdig, 1995, 9. Siip. Opsoi. 13(10):2643-55 ). Like paclitaxel, docetaxel is very poorly soluble in water. Currently, the most preferred solvent/surfactant used to dissolve docetaxel is polysorbate 80 (Pmueep 80) (Wizzegu et al. 1991 Sapseg Nev. 51(18):4845-52; Totiak et al. 1992). Similar to Stetorpog

Tmeep often causes allergic reactions in patients. Further, Tmeep 80 cannot be used with a PMC delivery device due to its tendency to decolorize diethylhexyl phthalate, which is highly toxic.

Purification of semi-synthetic paclitaxel and docetaxel is a difficult problem due to the formation of a number of degradation products during the synthetic process. In addition, purified taxanes were found to undergo degradation even under controlled storage conditions. Therefore, the desire to develop stable forms of these molecules that retain the desired antitumor properties becomes understandable. Previous attempts to obtain acceptable docetaxel have focused on methods of obtaining trihydrated forms of docetaxel, which can be considered to have significantly greater stability than those of the anhydrous product. See, e.g., U.S. Pat

MoMo 6022985; 6838569.

In order to achieve the expected therapeutic effects of poorly water-soluble agents such as paclitaxel and docetaxel, it is usually necessary that a solubilized form or nanodispersed form of the agent be administered to the patient.

Thus, a number of methods were developed, which are based on the use of: auxiliary solvents; surfactants; soluble forms of the drug, for example, salts and solvates; chemically modified forms of the drug, for example, prodrugs; soluble polymer-drug complexes; special medicinal carriers, such as liposomes; and others. Indeed, the use of amphiphilic block copolymer micelles has attracted much attention as a potentially effective drug carrier capable of solubilizing a hydrophobic drug in an aqueous environment.

The implementation of each of the above-mentioned methods is complicated by one or several specific problems. For example, the problems of the method based on the use of surface-active micelles with the solubilization of hydrophobic drugs are that some surface-active substances are relatively toxic and precipitation of hydrophobic drugs occurs when they are diluted.

Previously, phospholipid-based liposomal compositions for paclitaxel, Tahoege and other active taxanes were developed (bZigasripdeg and colleagues 1993, 9. May. Sapseg Ipvi. Mopodg. (15):69-78;

Zmnaitsbripdeg with employees 1994; 5papta with employees 1993, Sapseg Nev. 53(24):557-81;. Zpapta and zngatsybipdeg 1994, Rpagt. Nez. I(6):889-96; A. ZNnapta with colleagues 1995, U. Rnagt. 5 84(12): 1400-4) and the physical properties of these and other taxane compositions were studied (Zpagta and 5igashbipdeg 1994, Rinapt. Nez. 11(6):889-96; USA ZNagpta et al. 1995, 9. RPagt. Osi. 84(10): 1223-30; Vaiiazibgatapiap and sggaiyripdeg 1994, Viospetivigu 33(30):8941-7; Vaiazibgatapiap and colleagues 1994, 9. RNnagpt. 5si. 83(10): 1470-86. The main utility of these compositions is the elimination toxicity associated with the Stetorpog EI excipient, and a reduction in the toxicity of the taxane itself, as demonstrated in some animal tumor models (Zpagta et al. 1993, Sapseg Nevz. 53(24):557-81; A. Zpagta et al. 1995, U.

Rpagt. 5 84(12): 1400-4; Zpapta with employees 1996, Sapseg I ey. 107(2):265-272). This observation extends to some taxanes in addition to paclitaxel (A. Zpapta et al. 1995, .). Rpagt.

All together. 84(12): 1400-4). In some cases, the antitumor activity of the drug appears to be slightly greater in liposome-based compositions (Zpagta et al. 1993, Sapseg Nev. 53(24):557-81).

These liposomal compositions include phospholipids and other additives in addition to the taxane and can be stored in a dried state. When the aqueous phase is added to the mixture, the particles are formed spontaneously and may take the form of liposomes (Zigasripdeg et al. 1993). Liposomes are closed vesicular structures consisting of a limited bilayer membrane surrounding an aqueous core.

The preferred composition of the composition (Zpagpta and Bigaybipdeg 1994) contains a neutral (zwitterionic) phospholipid such as lecithin (phosphatidylcholine, 80-90956 by molar ratio), along with a negatively charged phospholipid such as phosphatidylglycerol (10-2095). The latter prevents the aggregation of particles using electrostatic repulsion. The content of the most stable taxane is in the range of 3-4 mol.bo

(regarding the total phospholipid content); such liposomes may be physically and/or chemically stable for 2 months after hydration. Under most conditions, paclitaxel formulations containing higher (eg, 8 mol.Oo) drug concentrations are very unstable and may settle within minutes of administration (Zpapta and 5igasripdeg 1994).

The greatest concern in these compositions was caused by the relatively low content of taxane in acceptable stable compositions (3-5 mol.9o), which causes the need to introduce a large amount of phospholipid (5-10 g) to patients in order to give the calculated dose of the drug. Although humans are often given large amounts of lipids intravenously for Total Parenteral Nutrition (TPM), the main goal of development has been to produce taxane liposomes that have a high taxane content.

Other approaches to the development of a sparingly soluble drug for oral or parenteral delivery include, for example, compositions in which the sparingly soluble drug is an oil-in-water emulsion, microemulsion or micelle solution, or other multilamellar carrier particles. Because such approaches can be administered to some ionized as well as non-ionized hydrophobic therapeutic agents, they do not have the advantage of the unique acid-base chemical properties and associated solvent properties of ionized compounds.

Drugs that are insoluble in water can have considerable advantages in obtaining a stable suspension of submicron particles. Precise control of particle size is essential for the safe and effective use of these formulations. Particles must be less than seven microns in diameter to safely pass through the capillaries without causing embolism (Aiep et al., 1987; Oamiw and Tashibe, 1978; 5spgoedeg" et al., 1978; Walkei et al., 1981, Tohosoi. I ey. 9( 2): 165-70).

Another approach is disclosed in SILA Patent Mo 5118528, which discloses a method of producing nanoparticles. The method includes the following stages: 1) obtaining a liquid phase of a substance in a solvent or a mixture of solvents, to which one or more surface-active substances can be added; 2) obtaining the second liquid phase is not a solvent or a mixture of non-solvents, a non-solvent is mixed with a solvent or a mixture of solvents for a substance; 3) combining together solutions (1) and (2) with stirring; and 4) removal of excess solvents to obtain a colloidal suspension of nanoparticles. The 528 patent discloses obtaining particles of matter smaller than 500 nm without the input of energy. In particular, patent 528 notes that it is undesirable to use high-energy equipment, such as ultrasonic devices and homogenizers.

US patent Mo 4826689 discloses a method of obtaining particles of uniform size from water-insoluble drugs or other organic compounds. First, an acceptable solid organic compound is dissolved in an organic solvent and the solution can be diluted in a non-solvent. Then an aqueous precipitating liquid is poured in, precipitating unaggregated particles with a substantially uniform average diameter. The particles are then separated from the organic solvent. Depending on the organic compound and the desired particle size, the parameters of temperature, non-solvent to organic solvent ratio, infusion rate, stirring rate and volume can be varied according to the patent. The 689 patent discloses that this method forms a drug in a metastable state that is thermodynamically unstable and that is ultimately converted to a more stable crystalline state. The 689 patent discloses a system for trapping a drug in a metastable state in which the free energy is conserved between that of the initial drug solution and the stable crystalline form. The '689 patent discloses the use of crystallization inhibitors (e.g., polyvinylpyrrolidone) and surface-active agents (e.g., poly(oxyethylene-co-oxypropylene)), making the precipitate stable even when separated by centrifugation, membrane filtration, or reverse osmosis.

Another approach to providing insoluble drugs for parenteral delivery is disclosed in Pat

US Mo. 5145684. The 684 patent discloses the wet milling of an insoluble drug in the presence of a surface modifier to provide a drug particle having an average effective particle size of less than 400 nm. The 684 patent discloses that the surface modifier is adsorbed on the surface of the drug particle in an amount sufficient to prevent agglomeration into large particles. Nanoparticles of insoluble drugs prepared under high shear conditions (eg, sonication, high pressure homogenization, or the like) with biocompatible polymers (eg, albumin) are disclosed, for example, in US Pat. US 2005/0004002 A1.

Taking into account the above, there is a need for pharmaceutical compositions that include poorly water-soluble drugs with increased physical and chemical stability, which eliminates the use of physiologically harmful solvents and excipients, and methods of their preparation. It is desirable that such pharmaceutical compositions do not degrade, remain stable under storage conditions and remain physically and/or chemically stable after rehydration. It would also be desirable to have a pharmaceutical composition comprising an anhydrous form of a poorly water-soluble drug that has increased solubility in conventionally used solvents and excipients and in solvents and excipients that are not physiologically harmful. The present invention provides such pharmaceutical compositions and methods.

The disclosures of all publications, patents, patent applications, and references to published patent applications in this specification are incorporated herein by reference in their entirety.

Brief summary of the invention

The invention presents compositions and methods of obtaining stable pharmaceutical compositions of docetaxel. In one embodiment of the invention, the invention provides pharmaceutical compositions of docetaxel comprising citrate or its derivatives. In the second embodiment of the invention, the invention provides pharmaceutical compositions of docetaxel that include sodium pyrophosphate. In a third embodiment of the invention, the invention provides pharmaceutical compositions of docetaxel including EDTA or its derivatives. In the fourth embodiment of the invention, the invention offers pharmaceutical compositions of docetaxel, including sodium gluconate. In the fifth embodiment of the invention, the invention offers pharmaceutical compositions of docetaxel, including citrate and sodium chloride. In the sixth embodiment of the invention, the invention provides a composition of docetaxel, including a surfactant, where the docetaxel used to prepare the composition is in an anhydrous form before its inclusion in the composition.

Accordingly, in one aspect, the invention provides compositions (such as pharmaceutical compositions) comprising a poorly water-soluble pharmaceutical agent (such as docetaxel) and a stabilizing agent, wherein the stability of the composition is increased compared to such a composition without the stabilizing agent. In some embodiments of the invention, the compositions further include a biocompatible polymer (such as the carrier proteins described herein). The stabilizing agent includes, for example, complexing agents (such as citrate, malic acid, edetate and pentetate), sodium pyrophosphate and sodium gluconate.

In another aspect, various compositions (such as pharmaceutical compositions) comprising docetaxel are provided, wherein the docetaxel used to form the composition is in an anhydrous form (eg, the docetaxel may be anhydrous prior to incorporation into the composition). In some embodiments of the invention, the composition further includes a biocompatible polymer (such as a carrier protein described herein). In some embodiments of the invention, the composition further includes a stabilizing agent (such as the stabilizing agents described herein). In some embodiments of the invention, the composition includes a biocompatible polymer (such as the carrier proteins described herein) and a stabilizing agent. In some embodiments, the invention provides compositions (such as pharmaceutical compositions) comprising docetaxel and a surfactant, where the docetaxel used to prepare the composition is in an anhydrous form (eg, the docetaxel may be anhydrous prior to inclusion in the composition). In some embodiments of the invention, the composition further includes a stabilizing agent (such as the stabilizing agents described herein).

Also offered are standard dosage forms of the compositions described herein, articles comprising the compositions according to the invention or standard dosage forms in acceptable packaging, and kits comprising the compositions.

The invention also provides methods of preparation and use of these compositions as described herein.

It should be understood that one, several or all features of various embodiments of the invention described in this description may be combined to form other embodiments of the present invention.

A brief description of the figures

Fig. 1 shows the loss of body weight in rats at a dose of 5 mg/kg of docetaxel for the composition of docetaxel with nanoparticles of albumin (Mab-docetaxel) and Tueep 80-docetaxel (Tahoegef)). Administration of doses took place in days 0.4 units.

Fig. 2 shows a comparison of neutropenia in rats at a dose of 5 mg/kg for Mar-docetaxel and Puyeep 80-docetaxel (Tahoegef). Doses were administered on days 0, 4, and 8.

Figures 3A-3O0 show a pharmacokinetic comparison of Mar-docetaxel and Tahoege. FigZA-3C show the plasma concentration of Mar-docetaxel and TahoegeF in doses of 10 mg/kg, 20 mg/kg and 30 mg/kg, respectively. Fig.30 shows a linear relationship between the AOS (section under the curve) and the dose of Mar-docetaxel and a non-linear relationship between the AOS and the Tahoeige dose. Mar-docetaxel shows a linear relationship corresponding to the equation of AOS-218"Dose; Tahoeige shows an exponential curve corresponding to the equation of AOS-722"exp(0.10"Dose).

Fig. 4 shows the inhibition of the binding of the drug to albumin in the presence of the surfactant Tmeep 80 and Stetorpog EI F/EUN.

Figures 5A and 5B show the antitumor activity (5A) and loss of body weight (58) with Mar-docetaxel in H29 colon cancer xenograft mice. Mice were administered Mab-docetaxel at a dose of 15 mg/kg, Dach.

Fig. bA and 6B show antitumor activity (6bA) and loss of body weight (68) in HST116 colon cancer xenograft mice treated with saline, Mardocetaxel (22 mg/kg), and Tahoeige (15 mg/kg).

Fig. 7A and 7B show body weight loss (7A) and antitumor activity (78) in prostate cancer ROZ xenograft mice treated with saline, Mar-docetaxel (10, 15, 20, 30 mg/kg) and Tmeep 80-docetaxel (10 mg/kg).

Detailed description of the invention

The present invention, in one of its variants of implementation of the invention, offers compositions and methods for obtaining docetaxel and other poorly water-soluble pharmaceutical agents or drugs that retain the desired therapeutic effects and remain physically and/or chemically stable when stored under certain conditions, such as long-term storage, elevated temperature or dilution for parenteral administration.

A stable composition is, for example, one that remains physically and/or chemically stable and therefore shows no signs of sedimentation or precipitation for at least about 8 hours, including, for example, at least about any of 24 hours, 48 hours or up to approximately 96 hours after reconstitution or rehydration. For example, the compositions may remain stable for at least 24 hours after reconstitution or rehydration.

The stability of the suspension is usually (but not necessarily) evaluated under normal conditions of transport and storage pending sale of the product (such as room temperature (such as 20-257°C) or under refrigeration conditions (such as 4°C)). For example, a suspension is stable at storage temperature if it does not exhibit flocculation or agglomeration of particles visible to the naked eye or visible under an optical microscope at 1000x magnification (or other acceptable particle characterization techniques) within approximately fifteen minutes of receiving the suspension. Stability can also be evaluated under particularly adverse conditions of temperature, humidity, light and/or others by testing the stability of compositions in accelerated testing. For example, stability can be assessed at a temperature that is higher than about 40°C. The stability of a composition can also be assessed, for example, by the ability of the composition to remain suspended without showing signs of settling or delamination, or by the ability of the composition to remain unchanged (ie, without apparent differences ) color or consistency.

The stability of a dry (such as lyophilized) composition can be evaluated based on the behavior of a liquid suspension obtained from a reconstituted or rehydrated dry suspension.

The purpose of the invention is to provide pharmaceutical compositions capable of maintaining physically and/or chemically stabilized, therapeutically effective amounts of poorly water-soluble pharmaceutical agents. Another object of the invention is to provide pharmaceutical compositions capable of maintaining physically and/or chemically stabilized, poorly water-soluble pharmaceutical agents when diluted for administration to a patient. A further object of the invention is to provide pharmaceutical compositions capable of maintaining physically and/or chemically stabilized, therapeutically effective amounts of poorly water-soluble pharmaceutical agents with reduced toxicity.

A further object of the invention is to provide stable pharmaceutical compositions using anhydrous docetaxel, as well as compositions obtained using anhydrous docetaxel.

A further aim of the invention is to provide improved methods of obtaining pharmaceutical compositions capable of maintaining physically and/or chemically stabilized, therapeutically effective amounts of poorly water-soluble pharmaceutical agents. A further aim of the invention is to provide improved methods of obtaining pharmaceutical compositions capable of maintaining a physically and/or chemically stabilized poorly water-soluble pharmaceutical agent when diluted for administration to a patient. A further aim of the invention is to provide improved methods of obtaining pharmaceutical compositions capable of maintaining physically and/or chemically stabilized, therapeutically effective amounts of poorly water-soluble pharmaceutical agents with reduced toxicity.

In one embodiment, the invention provides a sterile pharmaceutical composition for parenteral administration that includes a poorly water-soluble pharmaceutical agent that is physically and/or chemically stabilized by adding excipients to the composition. Prior to this invention, the relative stability of certain sparingly soluble pharmaceutical agents was limited to their use in parenteral pharmaceutical compositions due to degradation under storage conditions and/or precipitation during dilution. Many different pharmaceutical agents cannot be satisfactorily prepared as parenteral agents due to the lack of a stable formulation.

The present invention leads to the surprising discovery that common excipients such as citrate are able to stabilize poorly water-soluble pharmaceutical agents such as docetaxel. Therefore, the primary purpose of the invention is to provide compositions that include docetaxel (and other poorly water-soluble pharmaceutical agents) and excipients to obtain stable parenteral pharmaceutical compositions. Therefore, in one embodiment, the invention provides a pharmaceutical composition comprising docetaxel and citrate. In another embodiment, the invention provides a pharmaceutical composition comprising docetaxel, citrate and sodium chloride.

Different implementation options according to the invention

The invention provides compositions (such as pharmaceutical compositions) that include a poorly water-soluble pharmaceutical agent and a stabilizing agent, where the stability of the composition is increased compared to such a composition without a stabilizing agent. For example, the composition may include docetaxel and a stabilizing agent, where the stability of the composition is increased compared to such a composition without the stabilizing agent. In some embodiments of the invention, the compositions further include a biocompatible polymer. In some embodiments of the invention, the biocompatible polymer is a carrier protein (such as albumin, for example, human serum albumin (HSA)). In some embodiments of the invention, the stability of the composition is at least 1.5 times (including, for example, at least about any of: 2x, 3x, 4x, bh, bh, 7x, 8x, Ux, 10x, 15x, 20x, 25x, 3x, or more) is greater compared to such a composition without a stabilizing agent. In some embodiments of the invention, the poorly water-soluble pharmaceutical agent is unstable in a composition that does not include a stabilizing agent.

In some embodiments, the invention provides a composition that includes a poorly water-soluble pharmaceutical agent and a stabilizing agent, where the stabilizing agent is a complexing agent and where the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments, the invention provides a composition including docetaxel and a stabilizing agent, where the stabilizing agent is a complexing agent and where the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments of the invention, the composition further includes a biocompatible polymer. In some embodiments of the invention, the biocompatible polymer is a carrier protein (such as albumin, for example, H5BA). In some embodiments of the invention, the stabilizing agent is a polydentate complexing agent. In some embodiments of the invention, the stabilizing agent includes one or more carboxylic acid groups. In some embodiments of the invention, the complexing agent is not deferoxamine (ie, other than deferoxamine). In some embodiments of the invention, the complexing agent is any of (and in some embodiments is selected from the group consisting of) edetate, citrate, malic acid, pentetate, tromethamine, derivatives thereof, and mixtures thereof. In some embodiments of the invention, the stabilizing agent is citrate or its derivative (such as sodium citrate, and in some embodiments, citric acid). In some embodiments of the invention, the composition includes sodium citrate and sodium chloride. In some embodiments of the invention, the composition includes approximately 200 mM citrate and approximately 300 mM sodium chloride. In some embodiments of the invention, the stabilizing agent is edetate or its derivative (such as

EDTA).

In some embodiments, the invention provides a composition including a poorly water-soluble pharmaceutical agent and a stabilizing agent, where the stabilizing agent is sodium gluconate and where the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments, the invention provides a composition comprising docetaxel and a stabilizing agent, where the stabilizing agent is sodium gluconate and where the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments of the invention, the composition further includes a biocompatible polymer. In some embodiments of the invention, the biocompatible polymer is a protein

carrier (such as albumin, for example, NBZA).

In some embodiments, the invention provides a composition that includes a poorly water-soluble pharmaceutical agent and a stabilizing agent, where the stabilizing agent is sodium pyrophosphate and where the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments, the invention provides a composition including docetaxel and a stabilizing agent, where the stabilizing agent is sodium pyrophosphate and where the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments of the invention, the composition further includes a biocompatible polymer. In some embodiments of the invention, the biocompatible polymer is a protein carrier (such as albumin, for example, NBZA).

In some embodiments of the invention, the composition includes a poorly water-soluble pharmaceutical agent, albumin, and a stabilizing agent, wherein the mass ratio of albumin to poorly water-soluble pharmaceutical agent in the composition is from about 0.01:1 to about 100:1, and where the stability of the composition is increased by with such a composition without a stabilizing agent. In some embodiments of the invention, the composition includes a poorly water-soluble pharmaceutical agent, albumin, and a stabilizing agent, wherein the mass ratio of albumin to poorly water-soluble pharmaceutical agent in the composition is about 18:11 or less (including, for example, any of: from about 1 :1 to about 18:1, from about 2:1 to about 15:1, from about 3:1 to about 12:11, from about 4:1 to about 10:1, and about 9:1) and where the stability of the composition increases compared to such a composition without a stabilizing agent. In some embodiments of the invention, the composition comprises docetaxel, albumin, and a stabilizing agent, wherein the mass ratio of albumin to docetaxel in the composition is about 18:1 or less (including, for example, any of: from about 1:1 to about 18:21, from about 2:1 to about 15:1, from about 3:1 to about 12:1, from about 4:1 to about 10:1, and about 91) and wherein the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments of the invention, the stabilizing agent is a complexing agent such as any of (and in some embodiments selected from the group consisting of) edetate, citrate, malic acid, pentetate, tromethamine, derivatives thereof, and mixtures thereof . In some embodiments of the invention, the stabilizing agent is citrate or its derivative (such as sodium citrate). In some embodiments of the invention, the composition includes sodium citrate and sodium chloride. In some embodiments of the invention, the stabilizing agent is edetate or a derivative thereof (such as EDTA).

In some embodiments of the invention, the stabilizing agent is sodium gluconate. In some embodiments of the invention, the stabilizing agent is sodium pyrophosphate.

In some embodiments of the invention, the protein/pharmaceutical agent is in particle form(s), which in various embodiments of the invention may be of medium diameter as described herein.

In some embodiments of the invention, the composition includes a protein-associated poorly water-soluble pharmaceutical agent and a stabilizing agent, where the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments of the invention, the composition includes protein-associated docetaxel and a stabilizing agent, where the stability of the composition is increased compared to such a composition without the stabilizing agent. In some embodiments, the stabilizing agent is a complexing agent such as any of (and in some embodiments selected from) edetate, citrate, malic acid, pentetate, tromethamine, derivatives thereof, and mixtures thereof . In some embodiments of the invention, the stabilizing agent is citrate or its derivative (such as sodium citrate). In some embodiments of the invention, the composition includes sodium citrate and sodium chloride. In some embodiments of the invention, the stabilizing agent is edetate or a derivative thereof (such as EDTA). In some embodiments of the invention, the stabilizing agent is sodium gluconate. In some embodiments of the invention, the stabilizing agent is sodium pyrophosphate.

In some embodiments of the invention, the composition includes: 1) particles (such as nanoparticles) comprising (in various embodiments, consisting of or consisting primarily of 3) a poorly water-soluble pharmaceutical agent and a biocompatible polymer (such as a carrier protein , which can be albumin, such as NBZA); and 2) a stabilizing agent, where the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments of the invention, the composition includes particles (such as nanoparticles) comprising (in various embodiments of the invention consisting of or consisting primarily of 3): 1) docetaxel and a biocompatible polymer (such as a carrier protein that can be albumin, such as NBZA); and 2) a stabilizing agent, where the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments of the invention, docetaxel is coated with a biocompatible polymer (such as a protein/carrier). In some embodiments, the stabilizing agent is a complexing agent such as any of (and in some embodiments selected from) edetate, citrate, malic acid, pentetate, tromethamine, derivatives thereof, and mixtures thereof . In some embodiments of the invention, the stabilizing agent is citrate or its derivative (such as sodium citrate). In some embodiments of the invention, the composition includes sodium citrate and sodium chloride. In some embodiments of the invention, the stabilizing agent is edetate or a derivative thereof (such as EDTA). In some embodiments of the invention, the stabilizing agent is malic acid. In some embodiments of the invention, the stabilizing agent is sodium gluconate. In some embodiments of the invention, the stabilizing agent is sodium pyrophosphate.

In some embodiments of the invention, the composition includes: 1) particles (such as nanoparticles) that include (in various embodiments of the invention consisting of or consisting primarily of 3) a poorly water-soluble pharmaceutical agent and albumin; and 2) a stabilizing agent, wherein the mass ratio of albumin to poorly water-soluble pharmaceutical agent in the composition is from about 0.01:1 to about 100:1, and wherein the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments of the invention, the poorly water-soluble pharmaceutical agent is coated with albumin. In some embodiments of the invention, the composition includes: 1) particles (such as nanoparticles),

which include (in various embodiments of the invention, consisting of or consisting mainly of 3) a poorly water-soluble pharmaceutical agent and albumin; and 2) a stabilizing agent, wherein the weight ratio of albumin to poorly water-soluble pharmaceutical agent in the composition is about 18:1 or less (including, for example, any of: from about 1:11 to about 18:1, from about 2: 1 to about 15:1, from about 3:1 to about 12:1, from about 4:1 to about 10:1, and about 9:1) and where the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments of the invention, the poorly water-soluble pharmaceutical agent is coated with albumin.

In some embodiments of the invention, the composition includes: 1) particles (such as nanoparticles) that include (in various embodiments of the invention, consisting of or consisting primarily of 3) docetaxel and albumin; and 2) a stabilizing agent, wherein the mass ratio of albumin to docetaxel in the composition is from about 0.01:1 to about 100:1 and where the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments of the invention, the composition includes: 1) particles (such as nanoparticles) comprising (in various embodiments, consisting of or consisting primarily of) docetaxel and albumin; and 2) a stabilizing agent, wherein the mass ratio of albumin to docetaxel in the composition is about 18:1 or less (including, for example, any of: from about 1:1 to about 18:1, from about 2:1 to about 15 :1, from about 3:1 to about 12:11, from about 4:11 to about 10:11, and about 9:1) and wherein the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments of the invention, docetaxel is coated with albumin. In some embodiments of the invention, the composition is substantially free (such as free) of surfactants. In some embodiments of the invention, the composition comprises a stable aqueous suspension of particles (such as nanoparticles) comprising docetaxel and albumin (such as albumin-coated docetaxel particles), wherein the composition further comprises a stabilizing agent, wherein the mass ratio of albumin to docetaxel in the composition is about 18 :11 or less (including, for example, from about 1:1 to about 18:11, from about 2:1 to about 15:1, from about 3:1 to about 12:1, from about 4:1 to about 10 :11 and about 9:1) and where the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments of the invention, the composition comprises a dry (such as lyophilized) composition that can be reconstituted, resuspended, or rehydrated to form a generally stable aqueous suspension of particles (such as nanoparticles) comprising docetaxel and albumin (such as docetaxel coated albumin), wherein the composition further comprises a stabilizing agent, wherein the mass ratio of albumin to docetaxel in the composition is about 18:1 or less (including, for example, any of: from about 1:1 to about 18:1, from about 2: 1 to about 15:1, from about 3:1 to about 121, from about 4:1 to about 10:1, and about 9:1) and where the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments, the stabilizing agent is a complexing agent such as any of (and in some embodiments selected from) edetate, citrate, malic acid, pentetate, tromethamine, derivatives thereof, and mixtures thereof . In some embodiments of the invention, the stabilizing agent is citrate or its derivative (such as sodium citrate). In some embodiments of the invention, the composition includes sodium citrate and sodium chloride. In some embodiments of the invention, the stabilizing agent is edetate or a derivative thereof (such as EDTA). In some embodiments of the invention, the stabilizing agent is sodium gluconate. In some embodiments of the invention, the stabilizing agent is sodium pyrophosphate.

In some embodiments of the invention, the particles (such as nanoparticles) in the composition have a mean or average diameter of no greater than about any of: 1000, 900, 800, 700, 600, 500, 400, 300, 200, and 100 nm. In some embodiments of the invention, the front or average diameter of the particles is between about 20 and about 400 nm. In some embodiments of the invention, the mean or average diameter of the particles is between about 40 and about 200 nm. In some embodiments of the invention, the particles or droplets are suitable for sterile filtration.

The compositions disclosed herein may be a stable aqueous suspension of a sparingly water-soluble pharmaceutical agent, such as a stable aqueous suspension of a sparingly water-soluble pharmaceutical agent at a concentration of any of: from about 0.1 to about 100 mg/ml, including, e.g. , from about 0.1 to about 50 mg/mL, from about 0.1 to about 20 mg/mL, from about 1 to about mg/mL, from about 1 to about 10 mg/mL, from about 2 to about 8 mg/ml, from about 4 to about b mg/ml and about 5 mg/ml. In some embodiments of the invention, the concentration of the poorly water-soluble pharmaceutical agent is at least about any of: 1 mg/ml, 1.3 mg/ml, 1.5 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg /ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg /ml, 40 mg/ml and 50 mg/ml.

In some embodiments of the invention, the composition is a dry (such as lyophilized) composition that can be reconstituted, resuspended, or rehydrated to form a stable aqueous suspension of a poorly water-soluble pharmaceutical agent. In some embodiments of the invention, the composition is a liquid (such as aqueous) composition obtained by reconstitution or resuspension of a dry composition. In some embodiments of the invention, the composition is an intermediate of a liquid (such as aqueous) composition that can be dried (such as lyophilized).

In some embodiments of the invention, the composition is suitable for parenteral (such as intravenous) administration. In some embodiments of the invention, the composition is suitable for multiple administration. In some embodiments of the invention, the composition is suitable for sterile filtration. In some embodiments of the invention, the composition does not cause significant side effects in an individual (such as a human) when administered to the individual. In some embodiments of the invention, the compositions described herein are substantially free (such as free) of surfactants. Stabilizing agent compositions described herein may further include sugar (including, for example, sucrose, mannitol, fructose, lactose, maltose, and trehalose) or other lyophilization or reconstitution aids.

In some embodiments of the invention, the amount of stabilizing agent in the composition is below a level that induces a toxic effect (ie, above a clinically acceptable level of toxicity) or is at a level where the potential side effect can be controlled or tolerated by the patient when the composition is administered individual

In another aspect, compositions (such as a pharmaceutical composition) comprising docetaxel are provided, wherein the docetaxel used to form the composition is in an anhydrous form (eg, the docetaxel may be anhydrous prior to inclusion in the composition). In some embodiments of the invention, the composition further includes a stabilizing agent (such as the stabilizing agents described herein).

Compositions that include the use of docetaxel anhydrous are further described in the section below.

In some embodiments, the composition includes docetaxel and a biocompatible polymer (such as a carrier protein, for example, albumin), where the docetaxel used to prepare the composition is in an anhydrous form. In some embodiments of the invention, the composition includes particles (such as nanoparticles) comprising docetaxel and a biocompatible polymer (such as a carrier protein, for example, albumin), where the docetaxel used to prepare the composition is in an anhydrous form.

In some embodiments of the invention, the composition includes nanoparticles comprising docetaxel and albumin, where the docetaxel used to prepare the composition is an anhydrous form. In some embodiments of the invention, the weight ratio of albumin to docetaxel in the composition is less than about 18:11, including, for example, any of: from about 1:11 to about 18:1, from about 2:1 to about 15:1 , from about 3:1 to about 12:1, from about 4:1 to about 101, and from about 9:1. In some embodiments of the invention, docetaxel is coated with albumin. In some embodiments of the invention, the nanoparticles in the composition have an average or average particle size of no greater than about 200 nm. In some embodiments of the invention, the particles in the composition are suitable for sterile filtration. In some embodiments of the invention, the nanoparticles in the composition have two or more properties.

In some embodiments of the invention, the composition includes docetaxel and a surfactant, where the docetaxel used to prepare the composition is an anhydrous form. In some embodiments of the invention, the surfactant used to prepare the composition is anhydrous. In some embodiments of the invention, the surfactant is a polysorbate (such as Tmeep 80). In some embodiments of the invention, the surfactant is Stetorpog. In some embodiments of the invention, the composition further includes a stabilizing agent (such as the stabilizing agents described herein).

Compositions obtained with anhydrous docetaxel can be dry (such as lyophilized) compositions.

In some embodiments of the invention, the composition is a liquid (such as an aqueous) composition obtained by reconstitution or resuspension of a dry composition. In some embodiments of the invention, the composition is an intermediate of a liquid (such as aqueous) composition that can be dried (such as lyophilized).

Also offered are compositions of standard dosage forms described herein, articles comprising compositions of the invention or standard dosage forms in acceptable packaging (such as ampoules or tubes (including sealed ampoules or tubes and sterile sealed ampoules or tubes)), and kits, which include compositions. The invention also provides methods of preparing compositions as described herein.

Methods of stabilizing a slightly water-soluble pharmaceutical agent in the composition are also proposed. In some embodiments, the invention provides a method of stabilizing a poorly water-soluble pharmaceutical agent in a composition (such as a nanoparticle composition) that includes combining a composition (such as a nanoparticle composition) that includes a poorly water-soluble pharmaceutical agent with a stabilizing agent, where the resulting composition is stable under the same conditions under which the composition is unstable before the addition of the stabilizing agent. In some embodiments of the invention, the method further includes identifying and selecting a composition that is unstable under one or more conditions. In some embodiments of the invention, the selection composition includes a poorly water-soluble pharmaceutical agent and a carrier protein (such as albumin).

Methods of using the compositions described in this description are also proposed. For example, in some embodiments, the invention provides a method of treating cancer in an individual (such as a human), comprising administering to the individual an effective amount of a composition comprising a poorly water-soluble antiblastoma agent, a carrier protein (such as albumin), and a stabilizing agent, wherein the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments, the invention provides a method of treating cancer in an individual (such as a human) comprising administering to the individual an effective amount of a composition comprising docetaxel, a carrier protein (such as albumin) and a stabilizing agent, wherein the stability of the composition is increased compared to such a composition without stabilizing agent. In some embodiments of the invention, the composition includes particles (such as nanoparticles) comprising docetaxel and a carrier protein. In some embodiments of the invention, the composition includes particles (such as nanoparticles) that include docetaxel and albumin (such as albumin-containing nanoparticle compositions of docetaxel or Mar-docetaxel). In some embodiments of the invention, the composition includes Mar-docetaxel and citrate. In some embodiments of the invention, the composition includes

Mar-docetaxel, citrate and sodium chloride (such as 200 mM sodium chloride and approximately 300 mM sodium citrate).

In some embodiments of the invention, the cancer is any of: prostate cancer, colon cancer, head and neck cancer, breast cancer, pancreatic cancer, lung cancer, and ovarian cancer. In some embodiments of the invention, the cancer is a solid tumor. In some embodiments of the invention, the composition is administered at least about any of the following: once every three weeks, once every two weeks, once a week, twice a week, three times a week, four times a week, five times per week, six times per week or daily. In some embodiments, the composition is administered (with or without interruption) for at least about any of the following intervals: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months (iv). In some embodiments of the invention, the composition is administered by any of the following methods: intravenous, intra-arterial, oral, topical or inhalation methods of application.

A general reference to "compositions" or "composition" includes and applies to the compositions of the invention.

The invention also provides pharmaceutical compositions comprising the components described herein.

Reference to docetaxel in this description applies to docetaxel or its derivatives (or analogues) and, thus, the invention contemplates and includes both of these variants. References to "docetaxel" simplify the description and are illustrative. Derivatives or analogs of docetaxel include, but are not limited to, compounds that are structurally similar to docetaxel or are in the same general chemical class as docetaxel, such as taxanes. In some embodiments of the invention, a derivative or analogue of docetaxel retains a similar biological, pharmacological, chemical and/or physical property (including, for example, functionality) of docetaxel. Examples of docetaxel derivatives or analogs include paclitaxel and ortataxel. The same principle of the description applies to other agents given in this description, such as including, for example, stabilizing agents and poorly water-soluble pharmaceutical agents (such as a taxane (including paclitaxel, ortataxel or other taxanes), geldanamycin, 17-allylaminogeldanamycin, thiocolchicine and its dimers, rapamycin, cyclosporine, epothilone, radicicol, and combretastatin).

It should be understood that aspects and embodiments of the invention described herein include "consisting of" and/or "consisting primarily of" aspects and embodiments of the invention.

Stabilizing agents

Various compositions described herein include a stabilizing agent. The term "stabilizing agent" as used herein refers to an agent that increases the stability of a composition compared to a composition without the addition of a stabilizing agent. In such embodiments of the invention, the stability of the composition containing the stabilizing agent is at least about 1.5x (including, for example, at least about any of: 2x, 3x, 4x, Bh, bh, 7x, 3x, Ux, 10x, 15x , 20x, 25x, 30x or more) greater compared to such a composition without a stabilizing agent.

As described above, the stability of the composition can be assessed by the ability of the poorly water-soluble pharmaceutical agent to remain unprecipitated or precipitated (eg, based on visual and/or microscopic observation) in a liquid suspension over a period of time.

The stability of a dry (such as lyophilized) composition can be assessed based on the behavior of a liquid suspension obtained after re-reconstitution or re-hydration of the dry composition.

In some embodiments of the invention, the stabilizing agent slows down or prevents the precipitation or precipitation of the poorly water-soluble pharmaceutical agent in the liquid suspension. In some embodiments of the invention, the stabilizing agent slows down or prevents crystallization of the poorly water-soluble pharmaceutical agent in the composition. In some embodiments of the invention, when the composition includes particles of poorly water-soluble agents, the stabilizing agent can prevent or slow down the change in particle size in the composition.

Stabilizing agents, in particular, are used for compositions that would otherwise exhibit significant instability. For example, in some embodiments of the invention, the composition is stable for less than about 24 hours (including, for example, less than about any of 12, 10, 8, 6, 4, or 2 hours) prior to the addition of the stabilizing agent. In some embodiments of the invention, the poorly water-soluble pharmaceutical agent in the liquid suspension is precipitated or precipitated for at least about 24 hours (including, for example, less than about any of: 12, 10, 8, 6, 4, or 2 hours) prior to the addition of the stabilizer ). In some embodiments of the invention, the composition is precipitated or precipitated for at least about 24 hours before the addition of the stabilizing agent, when the concentration of the poorly water-soluble pharmaceutical agent is greater than about 0.1 mg/mL (including, for example, greater than about any of: 0.5 mg/ml, 1 mg/ml, 1.3 mg/ml, 1.5 mg/ml, 2 mg/ml, C mg/ml, 4 mg/ml, 5 mg/ml or 10 mg/ml ).

In some embodiments of the invention, the composition before adding a stabilizing agent is precipitated or precipitated when diluting the composition for parenteral administration. The addition of a stabilizing agent to such compositions allows the compositions to remain stable (eg, not precipitate or settle) under similar conditions. Accordingly, in some embodiments, the invention provides a composition comprising a poorly water-soluble pharmaceutical agent and a stabilizing agent, wherein the composition (such as a nanoparticle composition) is stabilized under the same conditions in which the composition without the stabilizing agent is unstable. In some embodiments of the invention, the stabilizing agent slows down or prevents the precipitation or sedimentation of the poorly water-soluble pharmaceutical agent in the liquid suspension of the composition under conditions where the poorly water-soluble pharmaceutical agent would otherwise precipitate or settle.

Acceptable stabilizing agents include, but are not limited to, sodium citrate (all forms, 0.01-2090% w/v), sodium pyrophosphate (0.1-1095 w/v), EDTA (all forms, 0, 01-2095), pentetate (all forms, 0.01-2095), sodium gluconate (0.1-1095 w/v), and acceptable combinations thereof. Mass percentage (w/w) refers to the percentage of stabilizing agent in the liquid composition or, in the case of a solid composition, the mass percentage (w/w) of the stabilizing agent upon re-reduction or re-hydration. A stabilizing agent should be used in an amount sufficient to increase the stability of the composition. Preferably, the amount of stabilizing agent used will provide a stable composition that shows no signs of sedimentation or sediment formation for at least about 8 hours, more preferably at least about 24 hours after reconstitution or rehydration, more preferably at least about 48 hours, most preferably for at least about 72 hours.

In some embodiments of the invention, the stabilizing agent is a complexing agent. These complexing agents are specific for a particular metal ion (such as calcium, zinc, magnesium, etc.) or show specificity for a wide range of metal ions. In some embodiments of the invention, the complexing agent is a polydentate. In some embodiments of the invention, the complexing agent includes one or more carboxylic acid groups. In some embodiments of the invention, the complexing agent is not deferoxamine. Acceptable complexing agents include, but are not limited to, edetate, citrate, malic acid, pentetate, tromethamine, and derivatives thereof.

One stabilizing agent contemplated herein is edetate, ie ethylenediaminetetraacetic acid (EDTA) and its derivatives. Acceptable edetates include edetate disodium, edetate trisodium, edetate tetrasodium and edetate disodium calcium. In some embodiments of the invention, edetate is present in the compositions at a concentration of from about 0.01 mg/mL to about 200 mg/mL, including, for example, from about 0.05 mg/mL to about 150 mg/mL, from about 0.1 mg /ml to about 100 mg/ml, from about 0.2 mg/ml to about 50 mg/ml, from about 0.5 mg/ml to about 20 mg/ml, from about 1 mg/ml to about 10 mg/ ml and from about 1 mg/ml to about 5 mg/ml. In some embodiments of the invention, the mass ratio of edetate to a poorly water-soluble pharmaceutical agent (such as docetaxel) in the composition is from about 0.002:1 to about 40:1, including, for example, from about 0.01:1 to about 30:1, from from about 0.02:1 to about 20:1, from about 0.041 to about 10:1, from about 0.1:1 to about 41, from about 0.2:1 to about 2:1, from about 0.2 :1 to about 11.

Another stabilizing agent contemplated herein is citrate or its derivative (ie, citric acid or its derivatives), such as sodium citrate. Acceptable citrate concentrations include, for example, from about 0.1 mg/mL to about 200 mg/mL, including, for example, any of: from about 0.2 mg/mL to about 100 mg/mL, from about 0, 3 mg/ml to about 50 mg/ml, from about 0.5 mg/ml to about 10 mg/ml, and from about 1 mg/ml to about 5 mg/ml. In some embodiments of the invention, the citrate concentration is less than about 200 mg/ml, such as less than about any of: 100; 50530; 20:10:59; 8;7;6;5;54;3;2;150,9:50,850,750,6;50,5; 0.4; 0.3 or 0.2 mg/ml. In some embodiments of the invention, the mass ratio of citrate to poorly water-soluble pharmaceutical agent (such as docetaxel) in the composition is from about 0.02:1 to about 40:1, including, for example, any of: from about 0.04: 1 to about 20:1, from about 0.06:1 to about 10:1, from about 0.1:1 to about 2:1, and from about 0.2:1 to about 1:11. In some embodiments of the invention, the mass ratio of citrate and poorly water-soluble pharmaceutical agent in the composition is less than about any of: 20:1; 10:1; 8:1; 5:15 2:1;1:150,8:150,5:1502:110,11.

Any form of citrate is acceptable for use in the present invention and includes, for example, citric acid and sodium citrate. Sodium citrate is particularly preferred. When sodium citrate is used, acceptable concentrations include from about 1 to 600 mM. When citrate and sodium chloride are used, acceptable concentrations include from about 1 to 600 mM and 1-1000 mM, respectively. In some embodiments of the invention, the concentrations of citrate and sodium chloride are from about 50 to about 200 mM and from about 300 to about 500 mM, respectively. In some embodiments of the invention, the composition includes about 50 mM citrate (such as sodium citrate) and about 500 mM sodium chloride. In some embodiments of the invention, the composition comprises about 200 mM citrate (such as sodium citrate) and about 300

MM of sodium chloride. In some embodiments of the invention, the composition is a dry (such as lyophilized) composition where the mass ratio of citrate to docetaxel in the composition is about 17:1 and, when sodium chloride is present, the mass ratio of sodium chloride to docetaxel is about 3.5:1. In other embodiments of the invention, the stabilizing agent is not citrate (ie other than citrate).

The stabilizing agent may also be a pentetate (including calcium trisodium pentetate). In some embodiments of the invention, the amount of pentetate is at a concentration of from about 0.01 mg/mL to about 200 mg/mL, including, for example, any of: from about 0.05 mg/mL to about 150 mg/mL, from from about 0.1 mg/ml to about 100 mg/ml, from about 0.2 mg/ml to about 50 mg/ml, from about 0.5 mg/ml to about 20 mg/ml, from about 1 mg/ml to about 10 mg/ml and from about 1 mg/ml to about 5 mg/ml. In some embodiments of the invention, the mass ratio of pentetate to poorly soluble pharmaceutical agent (such as docetaxel) in the composition is from about 0.002:1 to about 40:11, including, for example, any of: from about 0.01:1 to about 30 :1, from about 0.02:1 to about 20:1, from about 0.04:1 to about 10:1, from about 0.1:1 to about 471, from about 0.211 to about 21, from about 0 ,2:1 to about 1:1.

Another stabilizing agent considered in this description is tromethamine. Tromethamine, as used herein, refers to 2-amino-2-hydroxymethyl-1,3-propanediol, also known as TAI5. In some embodiments of the invention, tromethamine is present at a concentration of from about 0.1 mg/mL to about 100 mg/mL, including, for example, from about 0.5 mg/mL to about 50 mg/mL, from about 1 mg/mL to about 10 mg/ml and from about 2 mg/ml to about 5 mg/ml. In some embodiments of the invention, the mass ratio of tromethamine and poorly water-soluble pharmaceutical agent in the composition is from about 0.02:1 to about 20:1, including, for example, from 0.1:1 to about 10:1, from about 0 .2:1 to about 2:1 and from about 0.4:1 to about 1:1.

Other acceptable metal complexing stabilizing agents and exemplary amounts thereof include, but are not limited to, potassium sorbate (0.5 mg/ml), sodium ascorbate (1 mg/ml), sodium formaldehyde sulfoxylate (0.1 mg/ml), and monothioglycerol (5 mg/ml).

In some embodiments of the invention, the stabilizing agent is sodium pyrophosphate. Acceptable concentrations of sodium pyrophosphate include any of from about 0.1 to about 10905 (w/v), from about 0.5 to about 595, and from about 1 to about 295. In some embodiments of the invention, the mass ratio of pyrophosphate of sodium and the poorly water-soluble pharmaceutical agent in the composition is any of: from about 0.2:1 to about 20:1, from about 1:11 to about 10:1, from about 2:1 to about 4:1.

In some embodiments of the invention, the stabilizing agent is sodium gluconate. An acceptable concentration of sodium gluconate includes any of from about 0.1 to about 1095 (w/v), from about 0.5 to about 595, and from about 1 to about 295. In some embodiments of the invention, the mass ratio of gluconate of sodium and the poorly water-soluble pharmaceutical agent in the composition is any of: from about 0.21 to about 20:1, from about 1:1 to about 10:1, from about 2:1 to about 41.

In some embodiments, the compositions described herein include at least two (including, for example, at least any of: 2, 3, 4, 5, 6, 7, 8, 9, or 10) different stabilizing agents (such as stabilizing agents described in this description).

Poorly water-soluble pharmaceutical agents

The compositions disclosed herein include poorly water-soluble pharmaceutical agents. For example, the aqueous solubility of a poorly water-soluble pharmaceutical agent at 20-25°C may be less than about 10 mg/mL, including, for example, less than about any 3:5;2;150,550,2:50,150,0550, 021 0.01 mg/ml.

Poorly water-soluble pharmaceutical agents contemplated for use in the practice of the present invention include poorly water-soluble pharmaceutically active agents, diagnostic agents, agents having nutritional value, and the like. Poorly water-soluble pharmaceutical agents can be, for example: analgesics/antipyretics; anesthetics; antiasthmatic agents; antibiotics; antidepressants; antidiabetic agents; antifungal agents; antihypertensive agents; anti-inflammatory agents; antiblastoma agents; anxiolytic agents; immunosuppressive agents; anti-migraine agents; sedative agents; antianginal agents; antipsychotic agents; agents for the treatment of manic states; antiarrhythmic agents; antiarthritic agents; anti-gout agents; anticoagulants; thrombolytic agents; antifibrinolytic agents; hemorheological agents; antiplatelet agents; anticonvulsants; agents against Parkinson's disease; antihistaminic/antipruritic agents; agents used to regulate calcium; antibacterial agents; antiviral agents; antimicrobial agents; anti-infective agents; bronchodilators; hormones, hypoglycemic agents; hypolipidemic agents; antiulcer/antireflux agents; anti-nausea/nausea agents; oil-soluble vitamins (for example, vitamins A, B, E, K, etc.).

In some embodiments of the invention, the poorly water-soluble pharmaceutical agent is an antiblastoma agent. In some embodiments of the invention, the poorly water-soluble pharmaceutical agent is a chemotherapeutic agent.

Acceptable poorly water-soluble pharmaceutical agents include, but are not limited to, taxanes (such as paclitaxel, docetaxel, ortataxel, and other taxanes), epothilones, camptothecins, colchicines, geldanamycins, amiodarones, thyroid hormones, amphotericin, corticosteroids, propofol, melatonin, cyclosporine , rapamycin (sirolimus) and derivatives, tacrolimus, mycophenolic acids, ifosfamide, vinorelbine, vancomycin, gemcitabine, 505416, thiotepa, bleomycin, diagnostic radiocontrast agents and their derivatives. Other poorly water-soluble pharmaceutical agents for use in the compositions of the invention are described, for example, in US Patent Nos. 5,916,596, 6,096,331, 6,749,868, and 6,537,539. Additional examples of poorly water-soluble pharmaceutical agents include those compounds that are poorly water-soluble and listed in Tpegaretsiis Sagedogu apa Vioiodisa! Asiimiu Ipdeh" oi Tne Megek Ipdeh (127 Eaiiop, 1996).

In some embodiments of the invention, the poorly water-soluble pharmaceutical agent is any of (and in some embodiments is selected from the group consisting of) paclitaxel, docetaxel, ortataxel, or another taxane or taxane analog, 17-allylaminogeldanamycin (17- AAS), 18-derivative geldanamycin, camptothecin, propofol, amiodarone, cyclosporine, epothilone, radicicol, combretastatin, rapamycin, amphotericin, liothyronine, epothilone, colchicine, thiocolchicine and its dimers, thyroid hormone, vasoactive intestinal peptide, corticosteroids, melatonin, tacrolimus , mycophenolic acids, epothilones, radicicols, combretastatins and their analog or derivative. In some embodiments, the poorly water-soluble pharmaceutical agent is any of (and in some embodiments is selected from) paclitaxel, docetaxel, ortataxel or other taxanes, geldanamycin, 17-allylaminogeldanamycin, thiocolchicine and its dimers, rapamycin, cyclosporine, epothilone, radicicol and combretastatin. In some embodiments of the invention, the poorly water-soluble pharmaceutical agent is rapamycin. In some embodiments of the invention, the poorly water-soluble pharmaceutical agent is 17-ADO. In some embodiments of the invention, the poorly water-soluble pharmaceutical agent is a thiocolchicine dimer (such as IOM5404).

In some embodiments of the invention, the poorly water-soluble pharmaceutical agent is a taxane or a derivative thereof, which includes, but is not limited to, paclitaxel, docetaxel, and IUM5109 (ortataxel) or a derivative thereof. In some embodiments of the invention, the composition includes a non-crystalline mAbo amorphous taxane (such as paclitaxel or a derivative thereof). In some embodiments of the invention, the composition is prepared by using an anhydrous taxane (such as anhydrous docetaxel or a derivative thereof).

In some embodiments of the invention, the poorly water-soluble pharmaceutical agent is docetaxel or its derivative. In some embodiments, the docetaxel in the composition is non-crystalline or amorphous. In some embodiments of the invention, docetaxel is in any one or more of the following forms: anhydrous, hemihydrate, dihydrate, and trihydrate forms. Anhydrous docetaxel has been provided to provide a more stable composition than that prepared with hydrated docetaxel, such as docetaxel trihydrate or docetaxel hemihydrate, and is particularly useful in preparing the docetaxel compositions described herein.

Biocompatible polymers and carrier proteins

The compositions disclosed herein may also include biocompatible polymers, such as carrier proteins, further described herein.

As used herein, the term "biocompatible" describes a substance that does not significantly alter or affect in any harmful way the biological system into which it is administered. A biocompatible polymer includes naturally occurring or synthetic biocompatible materials such as proteins, polynucleotides, polysaccharides (eg, starch, cellulose, dextrans, alginates, chitosan, pectin, hyaluronic acid, and the like), and lipids. Acceptable biocompatible polymers include, for example, naturally occurring or synthetic proteins such as albumin, insulin, hemoglobin, lysozyme, immunoglobulins, ss-2-macroglobulin, fibronectin, vitronectin, fibrinogen, casein, and the like, as well as combinations of the two any of them or more.

Synthetic polymers include, for example, polyalkylene glycols (eg, linear or branched chain), polyvinyl alcohol, polyacrylates, polyhydroxyethyl methacrylate, polyacrylic acid, polyethyloxazoline, polyacrylamides, polyisopropyl acrylamides, polyvinylpyrrolidone, polylactide/glycolide, and the like, and combinations thereof.

The term "proteins" refers to polypeptides or polymers of amino acids of any length (including full length or fragments), which may be linear or branched, including modified amino acids, and/or are interrupted by non-amino acids. The term also covers an amino acid polymer that has been modified by nature or by intervention; for example, disulfide bond formation, glycosylation, lipidization, adacetylation, phosphorylation, or any other manipulation or modification.

Also included in this term are, for example, polypeptides containing one or more amino acid analogues (including, for example, non-natural amino acids and so on), as well as other modifications known in the art. Proteins described herein may be naturally occurring, i.e. obtained from or derived from a natural source (such as blood), or synthesized (such as chemically synthesized or synthesized by recombinant DNA technology).

Examples of acceptable proteins include proteins found under normal conditions in blood or plasma, which include, but are not limited to, albumin, immunoglobulin, including Ida, lipoproteins, apolipoprotein B, o-acid glycoprotein, p-2-macroglobulin, thyroglobulin, transferrin , fibronectin, factor

MI, MI factor, IX factor, X factor and so on. In some embodiments of the invention, the carrier protein is a non-blood protein, such as casein, x-lactalbumin, p-lactoglobulin. Proteins can be natural in origin or synthetically obtained. In some embodiments of the invention, the protein is albumin, such as H5A. H5A is a highly soluble globular protein with M, 65K and consists of 585 amino acids. NBA is the most abundant protein in plasma and accounts for 70-8095 of the colloid osmotic pressure of human plasma. The H5A amino acid sequence contains only 17 disulfide bridges, one free thiol (Suz 34) and a single tryptophan (Tgtr 214). Intravenous use of NA solution for the prevention and treatment of hypovolemic shock has been shown (see, for example, Tyii5, CHAMA, 237, 355-360, 460-463, (1977)) and

Noizeg et al., Zygdegu, Supesoiodu apa ObBzieyigisv, 150, 811-816 (1980)) and in combination with exchange transfusion for the treatment of neonatal hyperbilirubinemia (see, for example, Ripiauzop, Zetipagv ip

Tnpgotroviv apa Netoviav, 6, 85-120, (1980)). Other albumins, such as bovine serum albumin, are being considered. The use of such non-human albumins may be intended, for example, in the context of the use of these compositions for non-human mammals such as livestock (including pets and farm animals).

Human serum albumin (HSA) has numerous hydrophobic binding sites (eight in total for fatty acids, the endogenous ligand NB5ZA) and binds a diverse set of pharmaceutical agents, especially neutral and negatively charged hydrophobic compounds (Ssoodtap et al., Te RPaptasiodisa!

Vavziv oi Tnegareshiisv, 9" ey, MeSgam/-Niyi Mem mok (1996)). Two high-affinity binding sites have been proposed in the IA and SHA NA subdomains, which are highly elongated hydrophobic pockets with charged lysine and arginine residues near the surface, which functions as binding points for polar elements of ligands (see, for example, Renzke et al., Viospet. RNagtasoi., 30, 687-92 (1981), Mogat, Oap. Med. Vii, 46, 379-99 (1999) . 12, 439-46 (1999), Ne et al., Maishge, 358, 209- (1992) and Sapeg et al., Adu. Rgoieip. Spet, 45, 153-203 (1994)).Paclitaxel and propofol have been shown to bind H5BA (see, for example, Raai et al., Eig. U. Viospet, 268(7), 2187-91 (2001),

Rigseyi with employees, Viosnpit. Viorpuz. Asia, 1478(1), 61-8 (2000), AKtaueig with collaborators,

Aggpeitiyenog5spypo, 45, 1053-6 (1995) and Sagido et al., Neu. Ezr. Apezipevio!. Neapit, 41, 308-12 (1994)). In addition, docetaxel has been shown to bind to human plasma proteins (see, for example, Ogyep et al., Ipmezi. Mem Ogydv, 14(2), 147-51 (1996)).

Exemplary carrier proteins are further described below. It should be understood that this description usually applies to biocompatible polymers.

A carrier protein (such as albumin) in the composition usually serves as a carrier for the poorly water-soluble pharmaceutical agent, i.e., the carrier protein in the composition makes the poorly water-soluble pharmaceutical agent more easily suspended in an aqueous medium or helps to maintain suspension compared to compositions that do not include protein -carrier. This helps avoid the use of toxic solvents to solubilize the poorly water-soluble pharmaceutical agent, and therefore may reduce one or more side effects of administering the poorly water-soluble pharmaceutical agent to an individual (such as a human).

Thus, in some embodiments of the invention, the composition described herein is substantially free (such as free) of surfactants (such as Tmeep 20). A composition is "substantially free of surfactant" if the amount of surfactant in the composition is not sufficient to cause one or more adverse effects in an individual when the composition is administered to the individual.

In some embodiments of the invention, the carrier protein is associated with a poorly water-soluble pharmaceutical agent, that is, the composition includes a poorly water-soluble pharmaceutical agent associated with the carrier protein. "Association" or "associated" is used in this description in a general sense and refers to a carrier protein that affects the behavior and/or property of a poorly water-soluble pharmaceutical agent in an aqueous composition. For example, a carrier protein and a poorly water-soluble pharmaceutical agent are considered "associated" if the carrier protein makes the poorly water-soluble pharmaceutical agent more easily suspended in an aqueous medium compared to a composition without the carrier protein. In another example, the carrier protein and the poorly water-soluble pharmaceutical agent are associated if the carrier protein stabilizes the poorly water-soluble pharmaceutical agent in an aqueous suspension. For example, a carrier protein and a poorly water-soluble pharmaceutical agent can be presented in a particle or nanoparticle, which is further described in this description.

A poorly water-soluble pharmaceutical agent is "stabilized" by a carrier protein in an aqueous suspension if it remains suspended in an aqueous medium (such as without apparent precipitation or sedimentation) for an extended period of time, such as for at least about any of: 01;0,2:50,2550,5;51;52;3;54:5;6;7:58;:9; 10; 11; 12; 24; 36; 48; 60 or 72 hours. The suspension is usually, but not necessarily, acceptable for administration to an individual (such as a human). As described above, the stability of the suspension is in some embodiments of the invention increased at room temperature (such as 20-25"C) or under cooling conditions (such as 4"C). Stability can also be evaluated under accelerated testing conditions, such as temperatures that are higher than about 40°C. As described above, suspension stability can be further increased by adding stabilizing agents described herein.

The carrier protein and the poorly water-soluble pharmaceutical agent can be associated in a variety of ways.

For example, in some embodiments of the invention, the carrier protein is mixed with a poorly water-soluble pharmaceutical agent. In some embodiments of the invention, the carrier protein encapsulates or entraps a poorly water-soluble pharmaceutical agent. In some embodiments of the invention, the carrier protein is linked (such as non-covalently linked) to a poorly water-soluble pharmaceutical agent. In some embodiments of the invention, the composition may exhibit one or more of the aforementioned aspects.

In some embodiments of the invention, the composition includes particles (such as nanoparticles) that include (in various embodiments of the invention that are mainly with) a poorly water-soluble pharmaceutical agent and a carrier protein. When the poorly water-soluble pharmaceutical agent is in liquid form, the particles or nanoparticles are also referred to as droplets or nanodroplets. In some embodiments of the invention, a poorly water-soluble pharmaceutical agent is coated with a carrier protein. Particles (such as nanoparticles) of a poorly water-soluble pharmaceutical agent have been disclosed, for example, in U.S. Pat.

MoMe5916596, 6506405 and 6537579, as well as in US Patent Publication Me2005/0004002A1.

In some embodiments, the composition includes particles (such as nanoparticles) having a mean or average diameter of no greater than about 1000 nanometers (nm), such as less than about any of: 900, 800, 700, 600, 500, 400, 300, 200 and 100 nm. In some embodiments of the invention, the average or average diameter of the particles is no more than about 200 nm. In some embodiments of the invention, the mean or average diameter of the particles is between about 20 and about 400 nm.

In some embodiments of the invention, the mean or average diameter of the particles is between about 40 and about 200 nm. In some embodiments of the invention, the nanoparticles in the composition have an average or averaged particle size of no more than 200 nm. In some embodiments of the invention, the particles are suitable for sterile filtration.

The particles (such as nanoparticles) described herein can be presented in a dry composition (such as a lyophilized composition) or suspended in a biocompatible medium. Acceptable biocompatible media include, but are not limited to, water, buffered aqueous media, saline, optionally buffered solutions of amino acids, optionally buffered solutions of proteins, optionally buffered solutions of sugars, optionally buffered solutions of vitamins, optionally buffered solutions of synthetic polymers, lipid-containing emulsions, etc.

The amount of carrier protein in the composition described herein will vary depending on the poorly water-soluble pharmaceutical agent and other components in the composition. In some embodiments of the invention, the composition includes a carrier protein in an amount sufficient to stabilize a poorly water-soluble pharmaceutical agent in an aqueous suspension, for example, in the form of a stable colloidal suspension (such as a stable suspension of nanoparticles). In some embodiments of the invention, the carrier protein is present in an amount that reduces the rate of precipitation of a poorly water-soluble pharmaceutical agent in an aqueous environment. For compositions containing particles, the amount of carrier protein also depends on the size and density of the particles of the poorly water-soluble pharmaceutical agent.

In some embodiments of the invention, the carrier protein is present in an amount that is sufficient to stabilize a poorly water-soluble pharmaceutical agent in an aqueous suspension at a certain concentration.

For example, the concentration of the poorly 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, from about 0.1 to about about 20 mg/ml, from about 1 to about 10 mg/ml, from about 2 to about 8 mg/ml, and from about 4 to about 6 mg/ml. In some embodiments of the invention, the concentration of the poorly water-soluble pharmaceutical agent is at least about any of: 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 of the invention, the carrier protein is present in an amount that avoids the use of surface-active substances (such as Tmeep 80 or

Stethornog), so that the composition is free or substantially free of surfactant (such as

Tmeep 80 or Stetorpog).

In some embodiments, the composition in liquid form comprises from about 0.195 to about 5095 (w/v) (e.g., about 0.595 (w/v), about 595 (w/v), about 1095 (wt /vol), about 1595 (wt/vol), about 2095 (wt/vol), about 3095 (wt/vol), about 4095 (wt/vol), about 5095 (wt /volume)) carrier protein. In some embodiments of the invention, the composition in liquid form includes from about 0.595 to about 595 (w/v) of carrier protein.

In some embodiments of the invention, the mass ratio of the carrier protein, such as 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 weight ratio of carrier protein to pharmaceutical agent will be optimized for various combinations of carrier protein and drug, a typical weight ratio of carrier protein, such as albumin, to pharmaceutical agent (w/w) is from about 0.01:1 to about 100:1, including, for example, any of: from about 0.02:1 to about 50:1, from about 0.05:1 to about 20:1, from about 0.01:1 to about 20: 1, from about 1:1 to about 18:1, from about 2:1 to about 15:1, from about 3:1 to about 12:11, from about 4:1 to about 10:1, from about 5: 11 to about 9:1 and about 9:11. In some embodiments of the invention, the mass ratio of carrier protein to poorly water-soluble pharmaceutical agent is about any of 18:1 or less, such as about any of: 15:1 or less, 14:1 or less, 13: 11 or less, 12:11 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 31 or less.

In some embodiments of the invention, the carrier protein provides a composition for administration to an individual (such as a human) without significant side effects. In some embodiments of the invention, the carrier protein (such as albumin) is present in an amount that is effective in reducing one or more side effects of administering a poorly water-soluble pharmaceutical agent to a human. The term "reducing one or more side effects of administration of a poorly water-soluble pharmaceutical agent" refers to the reduction, alleviation, elimination, or avoidance of one or more undesirable effects caused by a poorly water-soluble pharmaceutical agent, as well as side effects caused by delivery vehicles (such as solvents that make poorly water-soluble pharmaceutical agents acceptable for injection) that are used to deliver a poorly water-soluble pharmaceutical agent. Such adverse 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 merely illustrative and other side effects or combinations of side effects associated with various pharmaceutical agents may be reduced.

In some embodiments of the invention, the composition includes particles (such as nanoparticles) comprising (in various embodiments, consisting of or consisting primarily of 3) a poorly water-soluble pharmaceutical agent and albumin, where the mass ratio of albumin to poorly water-soluble pharmaceutical agent in the composition (w/w) is from about 0.01:1 to about 100:1, including, for example, any of: from about 0.02:1 to about 50:1, from about 0.051 to about 20 :1, from about 0.1:1 to about 20:1, from about 1:11 to about 18:1, from about 2:1 to about 15:1, from about 3:1 to about 12:1, from about 4:1 to about 1071, from about 5:11 to about 9:11, and about 9:1. In some embodiments of the invention, the mass ratio of carrier protein to poorly water-soluble pharmaceutical agent is approximately any of: 18:11 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 of the invention, the poorly water-soluble pharmaceutical agent is coated with albumin. In some embodiments of the invention, particles (such as nanoparticles) comprising a poorly water-soluble pharmaceutical agent and albumin are suspended in an aqueous medium (such as an aqueous medium containing albumin). For example, the composition may be a colloidal suspension of particles of a poorly water-soluble pharmaceutical agent (such as nanoparticles). In some embodiments of the invention, the composition is a dry (such as lyophilized) composition that can be reconstituted or resuspended into a stable particle suspension or described herein. The concentration of the poorly water-soluble pharmaceutical agent in the liquid formulation or reconstituted formulation may be diluted (0.1 mg/mL) or concentrated (100 mg/mL), including, for example, any of: from about 0.1 to about 50 mg /ml, from about 0.1 to about 20 mg/ml, from about 1 to about 10 mg/ml, from about 2 to about 8 mg/ml, from about 4 to about 6 mg/ml, and 5 mg/ml. In some embodiments of the invention, the concentration of the poorly water-soluble pharmaceutical agent (such as docetaxel) is greater than about 0.1 mg/ml. In some embodiments of the invention, the concentration of the poorly water-soluble pharmaceutical agent is greater than about any 3:1,2,3,4,5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 25, 30, 35, 40, 45 or 50 mg/ml. In some embodiments of the invention, the poorly water-soluble pharmaceutical agent is a taxane or a derivative thereof (such as docetaxel or a derivative thereof).

In some embodiments, the composition includes particles (such as nanoparticles) comprising docetaxel, such as nanoparticles with an average or average diameter between about 20 and about 400 nm. In some embodiments of the invention, the particles have an average or average diameter between about 40 and about 200 nm. In some embodiments of the invention, the composition includes particles (such as nanoparticles) that include (in various embodiments of the invention that are mainly 3) docetaxel and albumin. In some embodiments of the invention, docetaxel is coated with albumin. In some embodiments of the invention, the mass ratio of albumin to docetaxel (w/w) in the composition is from about 0.01:1 to about 100:1, including, for example, any of: from about 0.02:1 to about 50 :1, from about 0.05:1 to about 20:1, from about 1:1 to about 18:1, from about 2:1 to about 15:1, from about 3:1 to about 12:1. In some embodiments, the ratio of albumin to docetaxel (w/v) is about any of: 18:1 or less, 15:11 or less, 14:11 or less, 13:11 or less, 12:11 or less, 10:11 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 31 or less.

In some embodiments of the invention, particles (such as nanoparticles) comprising docetaxel and albumin are suspended in an aqueous medium (such as an aqueous medium containing albumin).

For example, the composition may be a colloidal suspension of docetaxel-containing particles (such as nanoparticles).

In some embodiments of the invention, the composition is dry (such as a lyophilized composition) that can be reconstituted into an aqueous suspension of docetaxel-containing particles. In some embodiments of the invention, the concentration of docetaxel in the composition is between about 0.1 mg/mL and about 100 mg/mL, including, for example, any of: from about 0.1 to about 50 mg/mL, from about 0.1 to about mg/ml, about 1 to about 10 mg/ml, about 2 to about 8 mg/ml, about 4 to about 6 mg/ml, and about 5 mg/ml. In some embodiments, the docetaxel concentration is at least about any of: 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

Docetaxel anhydrous

In addition to the use of stabilizing agents disclosed herein (such as sodium citrate and sodium citrate/sodium chloride), it has been found that the use of anhydrous docetaxel results in a more stable formulation than that which could be obtained with hydrated docetaxel, such as the trihydrate or docetaxel hemihydrate. Compositions of anhydrous docetaxel according to the present invention further improve the stability of aqueous suspensions of nanoparticles so that the stability of the suspensions before or after lyophilization exceeds 1 day. In addition, the advantage of the acquired stability of anhydrous docetaxel also extends to standard compositions, such as compositions with Tmeep 80, Stethornpog or other known surfactants.

Thus, in accordance with this invention, docetaxel can be dissolved in a pharmaceutically acceptable solvent or solvents at a final concentration in the range of about 1-9995 v/v, more preferably in the range of about 5-2595 v/v. Solvents include, for example, chlorinated solvents, ethyl acetate, ethanol, tetrahydrofuran, dioxane, acetonitrile, acetone, dimethylsulfoxide, dimethylformamide, methylpyrrolidinone, oils such as soybean oil, safflower oil, and other injectable oils, and the like.

In some embodiments of the invention, the composition includes docetaxel, where the docetaxel used to prepare the composition is in anhydrous form. In some embodiments, the invention provides a composition comprising docetaxel, wherein at least some of the docetaxel in the composition is in anhydrous form. For example, in some embodiments of the invention, at least about 1095 (such as at least about any of: 2095, 30905, 4090, and 5095) of docetaxel in the composition is in anhydrous form. In some embodiments of the invention, the composition further includes a stabilizing agent (such as a stabilizing agent described herein).

In some embodiments of the invention, the composition includes docetaxel and a biocompatible polymer (such as a carrier protein described herein, for example, albumin), where the docetaxel used to prepare the composition is in anhydrous form. In some embodiments of the invention, the composition includes docetaxel, a biocompatible polymer (such as a carrier protein described herein, e.g., albumin) and a stabilizing agent (such as a stabilizing agent described herein), wherein the docetaxel used to prepare the composition , is in anhydrous form. In some embodiments of the invention, the composition is substantially free (such as free) of surfactants. In some embodiments of the invention, the composition includes a surfactant.

In some embodiments of the invention, the composition includes docetaxel and a biocompatible polymer (such as a carrier protein, for example, albumin), where at least some amount of docetaxel in the composition is in anhydrous form. For example, in some embodiments of the invention, at least about 1095 (such as at least about any of: 2095, 3090, 4095, and 5095) of docetaxel in the composition is in anhydrous form. In some embodiments of the invention, the composition further includes a stabilizing agent (such as a stabilizing agent described herein).

In some embodiments of the invention, the composition includes docetaxel and a surfactant (such as an anhydrous surfactant), where the docetaxel used to prepare the composition is in anhydrous form. In some embodiments of the invention, the surfactant used to prepare the composition is in anhydrous form. Acceptable surfactants include, for example, polysorbate (such as Tjmeep) and Stethorpog. In some embodiments of the invention, the composition may further include a stabilizing agent described herein.

In some embodiments, the invention provides a composition comprising docetaxel and a surfactant, wherein at least some of the docetaxel in the composition is in anhydrous form.

For example, in some embodiments of the invention, at least about 1095 (such as at least about any of: 2095, 3090, 40905 and 5095) of docetaxel in the composition is in anhydrous form.

In some embodiments of the invention, the composition disclosed herein is a dry (such as lyophilized) composition that can be reconstituted, resuspended, or rehydrated, typically to form a stable aqueous suspension of docetaxel. In some embodiments of the invention, the composition is a liquid (such as aqueous) composition obtained by reconstitution or resuspension of a dry composition. In some embodiments of the invention, the composition is an intermediate of a liquid (such as aqueous) composition that can be dried (such as lyophilized).

In some embodiments, the invention provides a method of preparing compositions including docetaxel and a surfactant, where the method includes combining anhydrous docetaxel with a surfactant. In some embodiments of the invention, the surfactant used to prepare the composition is anhydrous. In some embodiments of the invention, a method of preparing a composition including docetaxel and a biocompatible polymer (such as a carrier protein, for example, albumin) is provided, where the method includes combining anhydrous docetaxel with a biocompatible polymer (such as a carrier protein, for example, albumin). Compositions obtained by the methods described herein are also provided.

Other components in compositions

The compositions disclosed in this description may include other agents, excipients or stabilizers to improve the properties of the composition. Examples of acceptable excipients and solvents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline , molasses, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate and mineral oil. The compositions may additionally include lubricating agents, wetting agents,

emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. Examples of emulsifying agents include tocopherol esters such as tocopherol polyethylene glycol succinate and the like, Opluronic® (block copolymer of polyoxyethylene and polyoxypropylene), emulsifiers based on polyoxyethylene compounds, Zrap 80 and related compounds, and other emulsifiers known in the art and approved for use of medicinal forms in animals and humans.

The compositions may be formulated to provide rapid, sustained, or sustained release of the active ingredient after administration to the patient using procedures well known in the art.

Preferred compositions for administration by injection include those that contain a poorly water-soluble pharmaceutical agent as the active ingredient in association with a surfactant (either a wetting agent or a surfactant) or in emulsion form (e.g., water-in-water emulsions oil or oil in water). Other ingredients may be added, such as mannitol or other pharmaceutically acceptable carriers, if necessary.

In some embodiments of the invention, the composition is suitable for human administration. In some embodiments of the invention, the composition is suitable for administration to a mammal, such as in a veterinary context, including livestock and farm animals. There are a wide variety of acceptable compositions of the invention (see, for example, US MoMo Patents 5,916,596 and 6,096,331). The following compositions and methods are merely typical and are in no way limited. Compositions suitable for oral administration may consist of: a) liquid solutions such as an effective amount of the compound dissolved in diluents such as water, saline or orange juice; b) capsules, sachets or tablets, each of which contains a predetermined amount of the active ingredient as a solid or granules; c) suspensions in the corresponding liquid; d) acceptable emulsions; and e) powders. Tableted forms may include one or more of: lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, gum, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid and other excipients, dyes, diluents, buffering agents , wetting agents, preservatives, flavoring agents and pharmacologically compatible excipients. Forms for absorption may include the active ingredient in a flavoring, usually sucrose and gum or tragacanth, as well as lozenges that include the active ingredient in an inert base such as gelatin and glycerin or sucrose and gum, emulsions, gels, and the like containing in addition to the active ingredient such excipients as are known in this field.

Compositions suitable for parenteral administration include aqueous and anhydrous, isotonic sterile injectable solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the composition compatible with the blood of the intended recipient, and aqueous and anhydrous sterile suspensions which may include suspending agents, solubilizers, thickeners, stabilizers and preservatives. The compositions may be presented in sealed containers containing the medicinal product in single or multi-dose doses, such as ampoules and tubes, and may be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid excipient, e.g. of water, for injections, immediately before use. Extemporaneous injection solutions and suspensions can be obtained from sterile powders, granules and tablets of the type described earlier. Injectable compositions are preferred.

Compositions suitable for aerosol administration include compositions of the invention comprising aqueous and anhydrous isotonic sterile solutions that may contain antioxidants, buffers, bacteriostats, and solutes, as well as aqueous and anhydrous sterile suspensions that may include suspending agents, solubilizers, thickeners , stabilizers and preservatives individually or in combination with other acceptable components, which can be obtained in aerosol compositions for administration by inhalation. These aerosol compositions can be contained in those under pressure with acceptable propellants such as dichlorodifluoromethane, propane, nitrogen and the like. They may also be formulated as pharmaceutical products for non-pressurized devices such as an inhaler or nebulizer.

In some embodiments of the invention, the composition is formulated with a pH in the range of from about 4.5 to about 9.0, including, for example, a pH in the range of any of: from about 5.0 to about 8.0; from about 6.5 to about 7.5 and from about 6.5 to about 7.0. In some embodiments of the invention, the pH of the composition is not less than about 6, including, for example, not less than about any of: 6.5; 7 or 8 (such as about 7.5 or about 8). The composition can also be made isotonic with blood by adding a suitable tonicity modifier, such as glycerin.

Also provided are articles incorporating the compositions disclosed herein in acceptable packaging.

Acceptable packaging for the compositions described herein are known in the art and include, for example, tubes (such as sealed tubes), vessels (such as sealed vessels), ampoules, jars, flexible packages (such as sealed polyester Mylar film or plastic containers) and so on. These products can then be sterilized and/or hermetically sealed. Standard dosage forms incorporating the compositions disclosed herein are also provided. These standard dosage forms can be stored in an acceptable package in a single-use standard dosage form or in a reusable standard dosage form and can also be further sterilized and/or hermetically sealed.

The present invention also provides kits that include the compositions (or standard dosage forms and/or articles) described in this description, and may further include instruction(s) for methods of application of the composition, such as used hereinafter in this description. In some embodiments of the invention, the kit of the invention includes the package described above. In another embodiment of the invention, the kit according to the invention includes the package described above and a second package including a buffer. It may further include other materials desired by the industry and the user, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for performing any of the methods described herein.

Kits may also be provided that contain sufficient doses of a poorly water-soluble pharmaceutical agent (such as docetaxel) as described herein to provide effective treatment of an individual for an extended period of time, such as any of: a week, 2 weeks, 3 weeks , 4 weeks, 6 weeks, 8 weeks, From months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or more. Kits may also include multiple standard doses of a poorly water-soluble pharmaceutical agent and pharmaceutical compositions and instructions for use and packaged in quantities sufficient for storage and use in pharmacies, such as hospital pharmacies and compounding pharmacies.

Method of preparation and application of compositions

Methods of preparation and use of the compositions disclosed in this description are also provided. For example, a method of preparing a composition comprising a poorly water-soluble pharmaceutical agent (such as a taxane, e.g., paclitaxel, docetaxel, or ortataxel), an optionally biocompatible polymer (such as a carrier protein, e.g., albumin) and a stabilizing agent, where the stability of the composition is proposed is increased compared to such a composition without a stabilizing agent, which involves combining (such as mixing) a composition containing a poorly water-soluble pharmaceutical agent and optionally a biocompatible polymer (such as a carrier protein) with a stabilizing agent.

Methods of formation of docetaxel nanoparticles obtained under conditions of intense shear forces (for example, destruction by ultrasound, homogenization at high pressure or etc.) are also proposed. Nanoparticle preparations of biocompatible polymers (eg, albumin) are disclosed, for example, in US Patent Nos. 5,916,596, 6,506,405, and 6,537,579, and also in US Patent Publication 2005/0004002 A1, incorporated herein by reference.

Briefly, a poorly water-soluble pharmaceutical agent (such as docetaxel) is diluted in an organic solvent and the solution can be added to an aqueous solution of albumin. The mixture is homogenized under high pressure. The organic solvent can then be removed by evaporation. The resulting dispersion can be further lyophilized. Acceptable organic solvents include, for example, ketone, ether, simple ether, chlorinated solvents, and other solvents known in the art. For example, the organic solvent may be methylene chloride or chloroform/ethanol (eg, 1:29, 1:8, 1:7, 176, 1:5, 1:4, 1:3,1:2,1:1, 2:1,3:1,4:1, 5:1,6:1, 71, 81 or 91).

It was surprising to find that docetaxel formulations such as those obtained in the above-cited references have a stability of less than 1 day. Indeed, when tested, many compositions were stable for only 4-8 hours. The present invention provides an increase in liquid stability and stability after repeated recovery by adding certain stabilizers before the formation of nanoparticles or after the nanoparticles are formed.

Therefore, methods of stabilizing a composition comprising a poorly water-soluble pharmaceutical agent are proposed, which include combining the composition with a stabilizing agent, where the resulting composition is stable under the same conditions under which the composition is unstable before the addition of the stabilizing agent. In some embodiments of the invention, the method further includes identifying and selecting a composition that is unstable under certain conditions. In some embodiments of the invention, the selection composition includes a poorly water-soluble pharmaceutical agent and a carrier protein (such as albumin). In some embodiments of the invention, the selection composition includes particles (such as nanoparticles) comprising a poorly water-soluble pharmaceutical agent and a carrier protein (such as albumin).

Pharmaceutically acceptable excipients may also be added to the composition. Pharmaceutically acceptable excipients can be a solution, emulsion or suspension. For example, an emulsion of propofol in oil and stabilized with lecithin is well known in the art. It is also possible to obtain other emulsion or nanoparticulate compositions according to the invention. The emulsion is formed by homogenization under high pressure and intense shear forces. Such homogenization is conveniently performed in a high-pressure homogenizer, usually operating at a pressure in the range of approximately 3,000 to 30,000 psi. Preferably, such methods are performed at a pressure in the range from approximately 6000 to 25000 rvzi. The resulting emulsion includes very small nanodroplets of an anhydrous solvent containing a dissolved pharmacologically active agent and very small nanodroplets of a protein-stabilizing agent. Acceptable homogenization methods include high shear and cavitation methods such as, for example, high pressure homogenization, high shear mixers, sonication, high shear impellers, and the like.

The colloidal systems obtained according to this invention can be further converted into a powder form by removing water, for example, by lyophilization at an acceptable temperature/time profile.

The protein (e.g., H5A) itself acts as a cryoprotectant and the powder is easily reconstituted by adding water, saline, or buffer without the need for standard cryoprotectants such as mannitol, sucrose, glycine, and the like. While this is not required, it should of course be understood that standard cryoprotectants can be added to pharmaceutical compositions at will.

The stabilizing agent can be mixed with a poorly water-soluble pharmaceutical agent and/or carrier protein during the preparation of the poorly water-soluble pharmaceutical agent/protein-carrier composition or added after the preparation of the poorly water-soluble pharmaceutical agent/protein-carrier composition. For example, a stabilizing agent can be presented in a protein solution before the formation of a slightly water-soluble pharmaceutical agent/carrier protein composition. A stabilizing agent may also be added together with the aqueous medium used to reconstitute/suspend the poorly water-soluble pharmaceutical agent/carrier protein composition, or added to an aqueous suspension of a poorly water-soluble pharmaceutical agent associated with the carrier protein. In some embodiments of the invention, the stabilizing agent is mixed with the poorly water-soluble pharmaceutical agent/carrier protein composition prior to lyophilization. In some embodiments of the invention, a stabilizing agent is added as a dry component to a lyophilized composition of a poorly water-soluble pharmaceutical agent/carrier protein. In some embodiments of the invention, when the composition includes particles (such as nanoparticles), a stabilizing agent can be added before or after the formation of the particles.

In some embodiments of the invention, when the addition of a stabilizing agent changes the pH of the composition, the pH of the composition is usually (but not necessarily) adjusted to the desired pH. Exemplary pH values of the compositions include, for example, from about 5 to about 8.5. In some embodiments of the invention, the pH of the composition is adjusted to not less than about 6, including, for example, not less than about any of: 6.5; 7 or 8 (such as about 7.5 or 8).

Also provided are methods of preparing pharmaceutical compositions comprising combining any of the compositions described herein (including the above) with a pharmaceutically acceptable excipient.

Methods of using the compositions according to the present invention are also proposed in this description. In some embodiments, the invention provides a method of treating a disease or condition responsive to a poorly water-soluble pharmaceutical agent, comprising administering a composition that includes an effective amount of a poorly water-soluble pharmaceutical agent, optionally a biocompatible polymer (such as a carrier protein), and a stabilizing agent, where the stability of the composition is increased compared to such a composition without a stabilizing agent. For example, in some embodiments, the invention provides a method of treating cancer in an individual (such as a human), comprising administering to the individual a composition that includes an effective amount of a poorly water-soluble antiblastoma agent (such as docetaxel), optionally a carrier protein, and a stabilizing agent, where the stability of the composition is increased compared to such a composition without a stabilizing agent. In some embodiments of the invention, the amount of stabilizing agent in the composition does not cause any toxic effects when the composition is administered to an individual (such as a human). In some embodiments, the invention provides a method of treating cancer in an individual (such as a human) comprising administering to the individual an effective amount of docetaxel, wherein the docetaxel used in the formulation is in anhydrous form. For example, docetaxel may be anhydrous prior to incorporation into the composition.

As used herein, the term "effective amount" refers to an amount of a compound or composition sufficient to treat a specific disorder, condition or disease, such as ameliorating, temporarily alleviating the symptoms of the disease, reducing and/or delaying the development of one or more of its symptoms. With respect to cancer or other unwanted cell proliferation, an effective amount includes an amount sufficient to cause a reduction in tumor volume and/or a reduction in the rate of tumor growth (such as inhibition of tumor growth). In some embodiments of the invention, an effective amount is an amount sufficient to slow tumor growth. In some embodiments of the invention, an effective amount is an amount sufficient to prevent the occurrence and/or recurrence of a tumor.

An effective amount may be administered by one or more routes of administration.

Cancers for treatment with the compositions described herein (such as a composition comprising a poorly water-soluble pharmaceutical agent such as docetaxel, rapamycin, and 17AAS) include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia . Examples of cancers that can be treated with the compositions disclosed herein include, but are not limited to, squamous cell carcinoma, lung cancer (including small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous cell carcinoma of the lung), abdominal cancer, hepatocellular carcinoma, stomach cancer 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, salivary gland carcinoma, kidney or renal cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, head and neck cancer, colon and rectal cancer, rectal cancer, sarcoma m of any tissue, Kaposi's sarcoma, B-cell lymphoma (including low-grade/follicular non-Hodgkin's lymphoma (NHL), small-cell lymphocytic in (51) MNI., intermediate stage of malignancy/follicular MNI., intermediate stage of malignancy/diffuse MNI,, highly malignant immunoblastic

MNI,, highly malignant lymphoblastic MNI,, highly malignant with uncleaved nuclei MNI, MNI with a massive lesion, mantle cell lymphoma, AIDS-related lymphoma and macroglobulinemia

Waldenström), chronic lymphocytic leukemia (CI), acute lymphoblastic leukemia (A!I), myeloma, hairy cell leukemia, chronic myeloblastic leukemia and post-transplant lymphoproliferative disorder (RTI 0), as well as abnormal vascular proliferation associated with phakomatosis, edema (such as associated with brain tumors), and Meigs syndrome. In some embodiments, the invention provides a method of treating metastatic cancer (such as cancer that metastasizes from a primary tumor). In some variants of implementation of the invention, a method of reducing the level of cell proliferation and/or cell migration is proposed. In some embodiments, the invention provides a method of treating hyperplasia.

In some embodiments, the invention provides a method of treating cancer in an advanced stage(s). In some embodiments of the invention, methods of treating breast cancer (which may be

HENV2-positive or HENg-negative), including, for example, advanced breast cancer, stage IM breast cancer, locally advanced breast cancer and metastatic breast cancer.

In some embodiments of the invention, the cancer is lung cancer, including, for example, non-small cell lung cancer (M5CI C, such as progressive MLS C), small cell lung cancer (5CI1C, such as progressive 5CI C), and progressive solid malignant tumor in the lung. In some embodiments, the cancer is ovarian cancer, head and neck cancer, gastric malignancy, melanoma (including metastatic melanoma), colon and rectal cancer, pancreatic cancer, and solid tumors (such as advanced solid tumors). In some embodiments of the invention, the cancer is any of (and in some embodiments is selected from the group consisting of) breast cancer, colon and rectal cancer, rectal cancer, non-small cell lung cancer, non-Hodgkin lymphoma (NSCLC ), renal cell carcinoma, prostate cancer, liver cancer, pancreatic cancer, soft tissue sarcoma, Kaposi's sarcoma, carcinoid sarcoma, head and neck cancer, melanoma, ovarian cancer, mesothelioma, glioma, glioblastoma, neuroblastoma, and multiple myeloma. In some embodiments of the invention, the cancer is a solid tumor. In some embodiments, the cancer is any of: (and in some embodiments is selected from the group consisting of) prostate cancer, colon cancer,

breast cancer, head and neck cancer, pancreatic cancer, lung cancer and ovarian cancer.

Individuals eligible for these compositions depending on the nature of the poorly water-soluble pharmaceutical agent and the disease/condition/disorder receive treatment and/or prevention.

Accordingly, the term "individual" includes any of vertebrates, mammals, and humans depending on the intended use. In some embodiments of the invention, the individual is a mammal. In some embodiments of the invention, the individual is any one or more humans, cattle, horses, cats, dogs, rodents, or primates. In some embodiments of the invention, the individual is a human.

In another aspect, a method of treating carcinoma (such as colon carcinoma) in an individual is provided, wherein the method comprises administering to the individual a composition comprising an effective amount of docetaxel

Its carrier protein (such as albumin). In some embodiments of the invention, the composition further includes a stabilizing agent described herein, such as citrate. In some embodiments of the invention, the docetaxel used to prepare the composition to be administered to an individual is in anhydrous form. Docetaxel and the carrier protein can be presented in the form of nanoparticles (such as the nanoparticles described herein).

The compositions disclosed herein may be administered individually or in combination with other pharmaceutical agents, including poorly water-soluble pharmaceutical agents. For example, when the composition includes a taxane (such as docetaxel), it may be co-administered with one or more other chemotherapeutic agents including, but not limited to, carboplatin, navelbinF (vinorelbine), anthracycline (Oohii), lapatinib ((2UU57016) , Herceptin, Gemcitabine (Sbetlagb), Capecitabine (Heyudaf), Alimta, Cisplatin, 5-Fluorouracil, Epirubicin, Cyclophosphamide, Avastin, VelkadfF, etc. In some embodiments, the taxane composition is co-administered with a chemotherapeutic agent selected from the group consisting of consists of antimetabolites (including nucleoside analogs), platinum-based agents, alkylating agents, tyrosine kinase inhibitors, anthracycline antibiotics, periwinkle alkaloids, proteasome inhibitors, macrolides, and topoisomerase inhibitors. These other pharmaceutical agents may be present in the same formulation as the drug (such as a taxane), or in a separate composition that is administered simultaneously or sequentially with the drug om (such as taxane)-containing composition. Methods of combined therapy using nanoparticulate taxane compositions with other agents (or therapeutic methods) were described in International Patent Application Me PCT/O52006/006167.

The dose of the composition according to the invention administered to an individual (such as a person) will vary depending on the specific composition, the method of administration and the specific disease being treated. The dose should be sufficient to provide the desired response, such as a therapeutic or prophylactic response against a particular disease or condition. For example, the dose of docetaxel administered can be from about 1 to about 300 mg/m, including, for example, from about 10 to about 300 mg/m?, from about 30 to about 200 mg/m? and from about 70 to about 150 mg/m2. Typically, the dosage of docetaxel in the composition can range from about 50 to about 200 mg/m when given on a 3-week schedule, or from about 10 to about 100 mg/m when given on a weekly schedule. Alternatively, if given on a metronomic schedule (eg, daily or several times a week) the dosage may be in the range of approximately 1-50 mg/m."

The dosing frequency for the composition includes, but is not limited to, at least about any of: once every three weeks, once every two weeks, once a week, twice a week, three times a week, four times a week , five times a week, six times a week or every day. In some embodiments of the invention, the interval between each administration is less than about a week, such as less than about any of: 6, 5, 4, 3, 2, or 1 day. In some embodiments of the invention, the interval between each input is constant. For example, the administration can be performed daily, every two days, every three days, every four days, every five days, or every week. In some embodiments of the invention, the administration may be twice daily, three times daily, or more often.

Administration of the composition may be continued for a long period of time, such as from about one month to about three years. For example, the dosing schedule can be extended for a period of any of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, and 36 months. In some embodiments of the invention, there is no break in the dose administration scheme. In some embodiments of the invention, the interval between each administration is no more than about a week.

The compositions disclosed herein may be administered to an individual (such as a human) by various routes, including, for example, intravenous, intraarterial, intraperitoneal, oral, inhalation, intravesical, intramuscular, intratracheal, subcutaneous, intraocular, intramucosal, transmucosal, and transdermal For example, the composition of the invention can be administered by inhalation to treat respiratory conditions. The composition can be used to treat respiratory conditions such as pulmonary fibrosis, bronchiolitis obliterans, lung cancer, bronchoalveolar carcinoma, and the like. In one embodiment of the invention, nanoparticles (such as albumin nanoparticles) of the compounds of the invention may be administered by any acceptable route, including, but not limited to, oral, intramuscular, transdermal, intravenous, inhaler, or other airborne delivery systems and so on.

When preparing the composition for injection, especially for intravenous delivery, the continuous phase preferably includes an aqueous solution of tonicity modifiers buffered at a pH in the range of about 5 to about 8.5. The pH may also be lower than 7 or lower than 6. In some embodiments of the invention, the pH of the composition is at least about 6, including, for example, not less than about any of: 6.5; 7 or 8 (such as 7.5 or 8).

The nanoparticles of the present invention may be encapsulated in a hard or soft capsule, may be compressed into tablets, or may be incorporated into beverages or foods, or otherwise incorporated into the diet. Capsules can be formulated by mixing the nanoparticles with an inert pharmaceutical diluent and inserting the mixture into a hard gelatin capsule of the desired size. If soft capsules are desired, a thick suspension of the nanoparticles with an acceptable vegetable oil, light petroleum ether, or other inert oil can be incorporated by machine into the gelatin capsule.

Also provided herein are methods of reducing side effects associated with administration of a poorly water-soluble pharmaceutical agent to a human, comprising administering to a human a pharmaceutical composition that includes a poorly water-soluble pharmaceutical agent, a biocompatible polymer (such as a carrier protein), and a stabilizing agent, wherein the stability of the composition increases in comparison with such a composition without a stabilizing agent. For example, the invention provides methods of reducing various side effects associated with administration of a poorly water-soluble pharmaceutical agent, including, but not limited to, myelosuppression, neurotoxicity, hypersensitivity, inflammation, venous irritation, phlebitis, pain, skin irritation, peripheral neuropathy, neutropenic fever , anaphylactic reaction, hematological toxicity and cerebral or neurological toxicity and their combinations. In some embodiments, the invention provides a method of reducing hypersensitivity reactions associated with the administration of a poorly water-soluble pharmaceutical agent, including, for example, severe skin rashes, urticaria, facial flushing, shortness of breath, tachycardia, and others.

In addition, a method of increasing stabilization of a composition comprising a poorly water-soluble pharmaceutical agent and optionally a biocompatible polymer (such as a carrier protein) is provided, comprising adding to the composition a stabilizing agent in an amount effective to increase the stability of the composition. In some embodiments, the invention provides a method for preparing a composition that includes a poorly water-soluble pharmaceutical agent (such as docetaxel), a biocompatible polymer (such as a protein carrier, for example, albumin) and a stabilizing agent that includes combining (such as mixing) a poorly water-soluble a pharmaceutical agent and a biocompatible polymer with a stabilizing agent. In some embodiments of the invention, the composition is a liquid composition. In some embodiments of the invention, the composition is a reconstituted composition.

The stabilizing agent can be mixed with a poorly water-soluble pharmaceutical agent and/or protein carrier during the preparation of the poorly water-soluble pharmaceutical agent/protein-carrier composition or added individually to the aqueous medium used for reconstitution of the poorly water-soluble pharmaceutical agent/protein-carrier composition. carrier.

In a further aspect of the invention, it is proposed to use the compositions described in this description for the manufacture of a medicinal product. In particular, the manufacture of a medicinal product for use in the treatment of the conditions described in this description. Further, the pharmaceutical composition of such, variously described herein, is also intended for use in the manufacture of a medicinal product used to treat conditions and according to the methods described herein, unless otherwise specified.

Those skilled in the art will recognize that some variations are possible in the scope and spirit of the present invention. The invention will therefore not be described in more detail by reference to the following non-limiting examples. Unless otherwise indicated, the stability of the compositions in the examples below is evaluated at 25"C or 426.

Example 1

This example demonstrates the instability of the preparation of pharmaceutical compositions comprising docetaxel and albumin prepared as described in US Patent Publication 2005/0004002 A1. mg of docetaxel was dissolved in 2 ml of chloroform/ethanol. The solution was then added to 27.0 ml of NBA solution (395 wt/vol). The mixture was homogenized for 5 minutes at low rpm (Mini homogenizer model

Grouse 1.0.) to form a crude emulsion and then transferred to a high-pressure homogenizer (Ameviip). Emulsification was performed at 9000-40000 rvz. The resulting system was transferred to Nkoiamar and the solvent was quickly removed under reduced pressure. The resulting dispersion was translucent and the typical average diameter of the resulting particles was in the range of 50-220 nm (27-mean,

Maimet 2 eiavigeg). The dispersion was further lyophilized for 48 hours. The resulting sediment on the filter was easily reconstituted into the original dispersion by adding sterile water or physiological saline. The particle size after reconstitution was the same as before lyophilization. When the liquid suspension was stored prior to lyophilization, it was found that while the suspension was stable at approximately 4-8 hours after preparation, some sediment formation was observed at 24 hours, indicating instability.

Similarly, for the lyophilized reconstituted suspension, we were surprised to find that while the suspension was stable at approximately 4-8 hours after preparation, at 24 hours some precipitation was observed, indicating instability. This instability at 24 hours, which was not previously observed by the inventors, as the monitored period after the initial reception of the composition and repeated recovery was usually only 4-8 hours.

Example 2

This example demonstrates the instability of sonicated docetaxel nanoparticles. 25.9 mg of docetaxel was added to a 20 ml scintillation tube and dissolved in 0.3 ml of chloroform. 4.7 ml of NBA (3.095, w/v) was added to the mixture with dissolved docetaxel. The composition was treated with ultrasound (Zopis Yuivtetrgayu", model 550, Rizpeg Zsiepiis Sotrapu, Ryibrygo, RA 155275) at 5090 power for 1 min. The mixture was transferred to a rotary evaporator and chloroform-ethanol was quickly removed at 45"C under reduced pressure. The diameter of the docetaxel particles obtained as a result was 250-300 nm (2- average, MayImet 7 eiavzieg). The suspension settled in less than 1 day.

Example C

This example demonstrates the instability of docetaxel nanoparticles prepared by sonication with soybean oil tested as a stabilizer. 18.0 mg of docetaxel was added to a 20 ml scintillation tube and dissolved in 0.1 ml of a chloroform-ethanol mixture. 0.05 ml soybean oil and 2.35 ml NBZA (5.095, mass/volume) were added to the above organic solvent. The sample was treated with ultrasound (description YuOivtetrgay!, model 550, Rizpeg Zsiepiys

Sotrapu, Rikberigo, RA 155275) within 2 minutes. The mixture was transferred to a rotary evaporator and the chloroform-ethanol was rapidly removed at 45 °C under reduced pressure. The diameter of the resulting docetaxel particles was approximately 270 nm (2-mean, Maimegp 7eiavi2eg). The suspension precipitated in less than 1 day.

Example 4

This example demonstrates the instability of docetaxel nanoparticles produced by sonication using an ethyl acetate-n-butyl acetate mixture. 22.7 mg of docetaxel was added to a 20 ml scintillation tube and dissolved in 1.0 ml of a mixture of ethyl acetate-n-butyl acetate. 2.4 ml of NBZA (5.095, mass/volume) was added to docetaxel dissolved in an organic solvent.

The sample was treated with ultrasound (bopis Juivitetrgai"!, model 550, Rizpeg Zsiepiis Sotrapu, Riiberigo, RA 155275) at 5095 power for 1 min. The mixture was transferred to a rotary evaporator and ethyl acetate and n-butyl acetate were removed at 45"C under reduced pressure. The composition precipitated within an hour.

Example 5

This example demonstrates the instability of docetaxel nanoparticles obtained by homogenization at high pressure. 49.0 mg of docetaxel was dissolved in 0.56 ml of chloroform. The solution was added to 9.6 mL of NBA (5.095, w/v).

The mixture was pre-homogenized to form a crude emulsion and then transferred to a high-pressure homogenizer (Ameviip). Emulsification was performed at 18,000-20,000 rpm. The resulting system was transferred to a rotary evaporator and chloroform and tert-butyl alcohol were removed under reduced pressure. The diameter of the docetaxel particles obtained as a result was 160-175 nm (2-average, MaYmet 7 eavihg). Deposition was observed for "1 day. Crystal deposits were observed during microscopic examination.

Example 6

This example demonstrates the instability of docetaxel nanoparticles prepared by homogenization at high pressure using lecithin. 55.3 mg of docetaxel and 48.8 mg of egg lecithin were dissolved in 0.56 ml of a mixture of chloroform and tert-butyl alcohol. The solution was added to 9.6 ml of HA5 (5.095, mass/volume). The mixture was pre-homogenized to form a crude emulsion and transferred to a high-pressure homogenizer (Ameviip). Emulsification was performed at 18,000-20,000 r.g. The resulting system was transferred to a rotary evaporator and chloroform and tert-butyl alcohol were removed under reduced pressure. The diameter of the docetaxel particles obtained as a result was 190-220 nm (2-mean, Maimet 2 eiazigeg). Deposition was observed for 24 hours.

Example 7

This example demonstrates the instability of docetaxel nanoparticles prepared by high-pressure homogenization with polylactic acid (PCA) testing. 56.3 mg of docetaxel and 40.8 mg of RI CA (50:50) were dissolved in 0.56 ml of chloroform. The solution was added to 9.6 ml

NZA (5.095, mass/volume). The mixture was pre-homogenized to form a crude emulsion and transferred to a high-pressure homogenizer (Ameziip). Emulsification was performed at 18,000-20,000 rpm. The resulting system was transferred to a rotary evaporator and chloroform and tert-butyl alcohol were removed under reduced pressure.

The diameter of the docetaxel particles obtained as a result was 575 nm (27-average, Maimet 7eiavige!g).

Deposition was observed for 24 hours.

Example 8

This example demonstrates the instability of docetaxel nanoparticles prepared by high-pressure homogenization with benzoic acid testing. 50.3 mg of docetaxel and 3.0 mg of benzoic acid were dissolved in 0.56 ml of a mixture of chloroform and tert-butyl alcohol. The solution was added to 10.0 ml of H5BA (5.095, mass/volume). The mixture was pre-homogenized to form a crude emulsion and transferred to a high-pressure homogenizer (Ameviip). Emulsification was performed at 18,000-20,000 rpm. The resulting emulsion was transferred to a rotary evaporator and chloroform and tert-butyl alcohol were removed under reduced pressure. The diameter of the docetaxel particles obtained as a result was 160 nm (2-average, Maimet 7 eiavziheg). The composition precipitated within 24 hours.

Example 9

This example demonstrates the instability of docetaxel nanoparticles prepared by high-pressure homogenization with cholesterol testing. 51.0 mg of docetaxel and 16.5 mg of cholesterol were dissolved in 0.56 ml of a mixture of chloroform and tert-butyl alcohol. The solution was added to 10.0 ml of H5BA (5.095, mass/volume). The mixture was pre-homogenized to form a crude emulsion and transferred to a high-pressure homogenizer (Ameviip). Emulsification was performed at 18,000-20,000 rpm. The resulting emulsion was transferred to a rotary evaporator and chloroform and tert-butyl alcohol were removed under reduced pressure. Deposition took place within 24 hours.

Example 10

This example demonstrates the stability of docetaxel nanoparticles prepared by high pressure homogenization with sodium citrate testing. 50.0 mg of docetaxel was dissolved in 0.56 ml of a mixture of chloroform and tert-butyl alcohol (10.21 (vol/vol)). The solution was added to 9.6 mL of NBZA (5.095, w/v) containing 100 mM (2.9495 w/v) trisodium citrate. The mixture was pre-homogenized to form a crude emulsion and transferred to a high-pressure homogenizer (Ameziip). Emulsification was performed at 18,000-20,000 rpm. The resulting emulsion was transferred to a rotary evaporator and chloroform and tert-butyl alcohol were removed under reduced pressure. The diameter of the docetaxel particles obtained as a result was 150-225 nm (27-average, Maimet 7 eigavigheg). The composition was surprisingly stable for 24 hours with no visible sediment.

Example 11

This example demonstrates the stability of a docetaxel nanoparticle formulation with citrate (3.990, 133 mM) and sodium chloride (1.7595, 300 mM). The aqueous phase was prepared by adding H5A (595 by weight), sodium citrate (3.995 by weight) and sodium chloride (1.7595 by weight) to water for injection and mixed until dissolved.

The organic phase was prepared by dissolving docetaxel (790 by weight) in a solvent mixture (690 by volume) containing chloroform and ethanol and stirring until dissolved. The organic phase was slowly fed into the aqueous phase and mixed on a rotor-stator mixer. The volume of the series was 20 ml. The crude emulsion was homogenized at a high pressure of 20,000 bar. Chloroform and ethanol in the emulsion were then removed using a rotary evaporator under reduced pressure. The suspension was filtered by serial filtration (1.2 µm, 0.8 µm and 0.45 µm) and then lyophilized (ET5 Tgau Egeyege Oguei).

The liquid suspension is homogeneous and creamy. Particle size analysis was performed using a Mimegp 7eyavigeg. The particles had an average size of 165.6 nm. The sample was also examined under a microscope and most of the particles were “0.5 µm. The suspension was stored at 4"C and 2570. Surprisingly, the suspension was stable up to 3 days at 47C and 1 day at 25"C. The suspension did not exhibit any delamination or sedimentation and did not change color or consistency. In addition, the lyophilized product was a solid deposit on the filter.

Repeated recovery of the lyophilized sediment on the filter took "5 min. After repeated recovery, the particles had an average size of 164.6 nm. The reconstituted suspension was stored at 4°C and surprisingly remained stable for 21 days.

Example 12

This example demonstrates the stability of a docetaxel nanoparticle formulation with citrate (2.995, 100 mM) and sodium chloride (1.75905, 300 mM).

The aqueous phase was prepared by adding H5A (595 by weight), sodium citrate (2.995 by weight) and sodium chloride (1.7595 by weight) to water for injection and mixed until dissolved. The organic phase was prepared by dissolving docetaxel (795 by weight) in a solvent mixture (695 by volume) containing chloroform and ethanol and stirring until dissolved. The organic phase was added to the aqueous phase and mixed using a rotor-stator mixer. The crude emulsion was homogenized at a high pressure of 20,000 bar. Chloroform and ethanol in the emulsion were removed using a rotary evaporator under reduced pressure. The suspension was filtered by serial filtration (1.2 µm, 0.8 µm and 0.45 µm) and lyophilized (ET5 Tgau Egeege Ogueye!).

The liquid suspension was homogeneous and creamy. Particle size analysis was performed using

Maimet 7eiavzigeg. The particles had an average size of 157.1 nm. The sample was also examined with a microscope and most of the particles were “0.5 µm. The suspension was stored at 4°C and 2570. Surprisingly, the suspension was stable for up to 3 days at 4°C and 1 day at 25°C. The suspension did not show any sedimentation or delamination and did not change color or consistency.

The lyophilized product was a solid precipitate on the filter. Repeated recovery of the lyophilized sediment on the filter took "5 min. After reconstitution, the particles had an average particle size of 150.9 nm. The reconstituted suspension was stored at 4" and remained stable for "1 day.

Example 13

This example demonstrates the stability of a nanoparticle formulation of docetaxel with citrate (3.995, 133 mM).

The aqueous phase was prepared by adding H5A (595 by weight) and sodium citrate (3.995 by weight) to water for injection and stirring until dissolved. The organic phase was prepared by dissolving docetaxel (590 by weight) in a solvent mixture (6950 by volume) containing chloroform and ethanol and stirring until dissolved. The organic phase was slowly added to the aqueous phase and mixed using a rotor-stator mixer. The volume of the series was 20 ml. The crude emulsion was homogenized under high pressure at 20,000 psi.

Chloroform and ethanol in the emulsion were removed using a rotary evaporator under reduced pressure.

The suspension was filtered by serial filtration (1.2 μm, 0.8 μm, 0.45 μm and 0.22 μm) and lyophilized (ET5 Tgau

Egeee Ogueeg).

The liquid suspension was homogeneous and creamy. Particle size analysis was performed using

Maimet 2eiavzigegm. The particles had an average size of 131 nm. The sample was also examined under a microscope and most of the particles were “0.5 µm. Surprisingly, the nanoparticle suspension remained stable for 21 days.

Example 14

This example demonstrates the stability of a nanoparticle formulation of docetaxel with citrate (11.795, 400 mM).

The aqueous phase was prepared by adding NB5BA (595 by weight) and sodium citrate (11.795 by weight) to water for injection and stirring until dissolved. The organic phase was prepared by dissolving docetaxel (595 by weight) in a solvent mixture (690 by volume) containing chloroform and ethanol and stirring until dissolved. The organic phase was slowly added to the aqueous phase and mixed using a rotor-stator mixer. The volume of the series was 20 ml. The crude emulsion was homogenized under high pressure at 20,000 psi.

Chloroform and ethanol in the emulsion were then removed using a rotary evaporator under reduced pressure.

The suspension was filtered by serial filtration (1.2 μm, 0.8 μm, 0.45 μm and 0.22 μm) and lyophilized (ET5 Tgau

Egeee Ogueeg).

The liquid suspension was homogeneous and creamy. Particle size analysis was performed using

Maimet 7eiavzigeg. The particles had an average size of 143.5 nm. The sample was also examined under a microscope and most of the particles were “0.5 µm. The suspension was stored at 4"C and 2570. Surprisingly, the suspension was stable up to 3 days at 47C and "1 day at 25"C. The suspension did not show any sedimentation or delamination and did not change color or consistency.

The lyophilized product was a solid precipitate on the filter. Repeated recovery of the lyophilized sediment on the filter took "5 min. After reconstitution, the particles had an average particle size of 151.8 nm. Surprisingly, the reconstituted suspension was stored at 4°C and remained stable for 21 days.

Example 15

This example demonstrates the stability of a nanoparticle formulation of docetaxel with citrate (7.795, 200 mM).

The aqueous phase was prepared by adding H5A (595 by weight) and sodium citrate (7.795 by weight) to water for injection and mixing until dissolved. The organic phase was prepared by dissolving docetaxel (595 by weight) in a solvent mixture (690 by volume) containing chloroform and ethanol and stirring until dissolved. The organic phase was slowly added to the aqueous phase and mixed using a rotor-stator mixer. The volume of the series was 20 ml. The crude emulsion was homogenized under high pressure at 20,000 psi.

Chloroform and ethanol in the emulsion were removed using a rotary evaporator under reduced pressure.

The suspension was filtered by serial filtration (1.2 µm, 0.8 µm, 0.45 µm and 0.22 µm) and then lyophilized (ET5

Tgau Egee;e Ogueyeg).

The liquid suspension was homogeneous and creamy. Particle size analysis was performed using

Maimet 7eiavzigeg. The particles had an average size of 226.4 nm. The sample was also examined under a microscope and most of the particles were “0.5 µm. The suspension was stored at 4"C and 2570. Surprisingly, the suspension was stable up to 3 days at 4C and 1 day at 25"C. The suspension did not show any sedimentation or delamination and did not change color or consistency.

The lyophilized product was a solid precipitate on the filter. Repeated recovery of the lyophilized sediment on the filter took "5 min. After reconstitution, the particles had an average particle size of 211.4 nm. The reconstituted suspension was stored at 4°C and remained stable for 21 days.

Example 16

This example demonstrates the stability of the docetaxel citrate/Masi nanoparticle formulation.

The aqueous phase was prepared by adding H5A (595 by weight) and sodium citrate (5.8895, 200 mM) and Mass (1.7595, 300 mM) to water for injection and mixed until dissolved. The organic phase was prepared by dissolving docetaxel (595 by weight) in a solvent mixture (695 by volume) containing chloroform and ethanol and stirring until dissolved. The organic phase was slowly added to the aqueous phase and mixed using a rotor-stator mixer. The volume of the series was 20 ml. The crude emulsion was homogenized at a high pressure of 20,000 rpm. Solvents in the emulsion were removed using a rotary evaporator under reduced pressure.

The suspension was filtered by serial filtration and then lyophilized (ET5 Tgau Egeege Ogueg).

The liquid suspension was homogeneous and creamy. Particle size analysis was performed using

Maimet 2eiavigeg. The particles had an average size of 200 nm. The sample was also examined under a microscope and most of the particles were “0.5 µm. The suspension was stored and surprisingly the suspension was stable without sediment or settling for 21 days.

The lyophilized product was a solid precipitate on the filter. Repeated recovery of the lyophilized sediment on the filter took "5 min. The reconstituted suspension was stored and surprisingly remained stable for 1 day.

Example 17

This example demonstrates the stability of the docetaxel citrate/Masi nanoparticle formulation.

The aqueous phase was prepared by adding H5BA (595 by weight) and sodium citrate (2.9495, 100 mM) and Mass (2.995, 500 mM) to water for injection and mixed until dissolved. The organic phase was prepared by dissolving docetaxel (595 by weight) in a solvent mixture (6905 by volume) containing chloroform and ethanol and stirring until dissolved. The organic phase was slowly added to the aqueous phase and mixed using a rotor-stator mixer. The volume of the series was 20 ml. The crude emulsion was homogenized under high pressure at 20,000 g. Solvents in the emulsion were removed using a rotary evaporator under reduced pressure.

The suspension was filtered by serial filtration and then lyophilized (ET5 Tgau Egeege Ogueg).

The liquid suspension was homogeneous and creamy. Particle size analysis was performed using

Maimet 2eiavigeg. The particles had an average size of 200 nm. The sample was also examined under a microscope and most of the particles were “0.5 µm. The suspension was stored and surprisingly the suspension was stable without sediment or settling for 21 days.

The lyophilized product was a solid precipitate on the filter. Repeated recovery of the lyophilized sediment on the filter took "5 min. The reconstituted suspension was stored and remained surprisingly stable for 1 day.

Example 18

This example demonstrates the stability of the docetaxel citrate/Masi nanoparticle formulation.

The aqueous phase was prepared by adding H5BA (595 by weight) and sodium citrate (2.9495, 100 mM) and Mass (3.595, 600 mM) to water for injection and mixed until dissolved. The organic phase was prepared by dissolving docetaxel (595 by weight) in a solvent mixture (695 by volume) containing chloroform and ethanol and stirring until dissolved. The organic phase was slowly added to the aqueous phase and mixed using a rotor-stator mixer. The volume of the series was 20 ml. The crude emulsion was homogenized under high pressure at 20,000 g. Solvents in the emulsion were removed using a rotary evaporator under reduced pressure.

The suspension was filtered by serial filtration and then lyophilized (ET5 Tgau Egeege Ogueeg).

The liquid suspension was homogeneous and creamy. Particle size analysis was performed using

Maimet 2eiavigeg. The particles had an average size of 200 nm. The sample was also examined under a microscope and most of the particles were “0.5 µm. The suspension was stored and surprisingly the suspension was stable without sediment or settling for 21 days.

The lyophilized product was a solid precipitate on the filter. Repeated recovery of the lyophilized sediment on the filter took "5 min. The reconstituted suspension was stored and surprisingly remained stable for 1 day.

Example 19

This example demonstrates the stability of the docetaxel citrate/Masi nanoparticle formulation.

The aqueous phase was prepared by adding H5BA (595 by weight) and sodium citrate (1.4795, 50 mM) and Mass (2.995, 500 mM) to water for injection and mixed until dissolved. The organic phase was prepared by dissolving docetaxel (595 by weight) in a solvent mixture (695 by volume) containing chloroform and ethanol and stirring until dissolved. The organic phase was slowly added to the aqueous phase and mixed using a rotor-stator mixer. The volume of the series was 20 ml. The crude emulsion was homogenized under high pressure at 20,000 g. Solvents in the emulsion were removed using a rotary evaporator under reduced pressure.

The suspension was filtered by serial filtration and then lyophilized (ET5 Tgau Egeege Ogueg).

The liquid suspension was homogeneous and creamy. Particle size analysis was performed using

Maimet 2eiavigeg. The particles had an average size of 200 nm. The sample was also examined under a microscope and most of the particles were “0.5 µm. The suspension was stored and surprisingly the suspension was stable without sediment or settling for 21 days.

The lyophilized product was a solid precipitate on the filter. Repeated recovery of the lyophilized sediment on the filter took "5 min. The reconstituted suspension was stored and surprisingly remained stable for 1 day.

Example 20

This example demonstrates the effect of a nanoparticulate formulation of anhydrous versus hydrated docetaxel with citrate/Masi.

The aqueous phase was prepared by adding H5A (595 wt) and sodium citrate (200 mM) and wt (300 mM) to water for injection and mixed until dissolved. The organic phase for the three different formulations was prepared by dissolving docetaxel anhydrous, docetaxel trihydrate, or docetaxel hemihydrate (partially hydrated) (595 by weight) in a solvent mixture (695 by volume) containing chloroform and ethanol and stirred until dissolved. The organic phase was slowly added to the aqueous phase and mixed using a rotor-stator mixer. The crude emulsion was homogenized under high pressure at 20,000 g. Solvents in the emulsion were removed using a rotary evaporator under reduced pressure. The suspension was filtered by serial filtration and then lyophilized (ET5 Tgau Egeege Ogue!g).

The liquid suspension was homogeneous and creamy. Particle size analysis was performed using

Maimet 2 eiavzigeg. The particles had an average size of 200 nm. The three suspensions were stored and surprisingly, the suspension containing anhydrous docetaxel was more stable with no precipitation or settling for 21 days. Both preparations of hydrated docetaxel showed a precipitate or precipitate within "1 day. The same phenomenon was observed for the lyophilized suspension upon repeated reconstitution. Thus, it was determined that the anhydrous form of docetaxel was the most suitable for the preparation of docetaxel nanoparticles.

Example 20A

This example offers a comparison of docetaxel anhydrous, docetaxel trihydrate, and docetaxel hemihydrate using differential scanning calorimetry (0550).

Three different types of docetaxel were subjected to Y5C using a standard technique. All showed a melting endotherm at approximately 162-1667C. However, only 2 hydrated materials showed a water dehydration endotherm between about 74-8070.

Example 208

This example offers a comparison of docetaxel anhydrous, docetaxel trihydrate and docetaxel hemihydrate using X-ray powder diffractometry (XPR).

Three different types of docetaxel were subjected to XO using a standard technique. All three materials showed a variety of sharp peaks indicating crystallinity. However, the anhydrous material showed a spectrum that differed from the two hydrated materials. In particular, there was a peak occurring in 2-theta 7-8 for the anhydrous sample that was absent in the hydrated material. This indicates a different crystal structure of anhydrous docetaxel compared to hydrated docetaxels.

Example 21

This example demonstrates that the degree of hydration affects the solubility of docetaxel and offers a comparison of the solubility of docetaxel anhydrous, docetaxel trihydrate, and docetaxel hemihydrate.

To compare whether different types of docetaxel material had different solubility profiles due to their different structures, their dissolution rates were compared in acetonitrile solvent. Acetonitrile was added to a fixed amount of docetaxel from different sources to give a concentration of 5 mg/ml (anhydrous base).

The rate at which the dissolution of various docetaxels occurred was noted. It was noted that anhydrous docetaxel (from two different sources) dissolved completely in less than 1 minute. On the other hand, hydrated materials (trihydrate and partial hydrate from two different sources) did not dissolve easily and additional solvent was added to a final concentration of 2.5 mg/ml. Under these other dissolution conditions, the dissolution time was between 5 and 10 minutes for the hydrated materials. A similar observation was made when using the chloroform solvent. Thus, it was surprisingly discovered that the degree of hydration or anhydrous state can significantly affect the solubility of docetaxel.

Example 22

This example demonstrates that the degree of hydration of docetaxel affects stability and offers a comparison of docetaxel trihydrate, docetaxel hemihydrate and docetaxel anhydrous compositions in Tmeep 80.

It is well known that Docetaxel is prepared from Tsheep 80 as a solubilizer or emulsifier for the commercial product Tahoege. Different docetaxels were dissolved in Tmeep 80 at a concentration of 40 mg/ml (on an anhydrous basis). The stability of 2 ml of these solutions over time was noted. We were surprised to find that after several days a precipitate or sediment was observed for hydrated docetaxel, but no precipitation was observed for anhydrous docetaxel. Thus, anhydrous docetaxel is preferred in the composition of Tmeep. Additionally, the use of Tjeep 80 or an equivalent surfactant that is anhydrous or has a very low water content may be beneficial, as the anhydrous form of docetaxel may absorb water to form a hydrated form that could lead to precipitation.

Example 23

This example demonstrates the stability of a docetaxel nanoparticle formulation with anhydrous docetaxel without added stabilizers.

The aqueous phase was obtained by adding HA (595 by weight) to water for injection. The organic phase was prepared by dissolving anhydrous docetaxel (5905 by weight) in a solvent mixture (695 by volume) containing chloroform and ethanol and stirred until dissolved. The organic phase was slowly added to the aqueous phase and mixed using a rotor-stator mixer. The crude emulsion was homogenized at a high pressure of 20,000 bar. Solvents in the emulsion were removed using a rotary evaporator under reduced pressure. The suspension was filtered by serial filtration and then lyophilized (ET5 Tgau Egeege Oguyeg).

The liquid suspension was homogeneous and creamy. Particle size analysis was performed using

Maimet 2eiavigeg. The particles had an average size of 200 nm. The sample was also examined under a microscope and most of the particles were “0.5 µm. The suspension was stored and surprisingly the suspension was stable without sediment or settling for about 1 day. Thus, in the absence of stabilizers, Mar-docetaxel obtained with anhydrous docetaxel is more stable than when obtained with the hydrated form of docetaxel, for which the stability is significantly less than 1 day, usually only a few hours.

Example 24

This example demonstrates the preparation of anhydrous docetaxel citrate/Masi nanoparticles.

The aqueous phase was obtained by adding H5A (8.595 by mass) and sodium citrate (200 mM) and Mass (300

MM) in water for injection and stirred until dissolved. The organic phase was prepared by dissolving anhydrous docetaxel (133 mg/ml) in a solvent mixture containing chloroform and ethanol (1:21) and stirring until dissolved. Slowly the organic phase (695 by volume) was added to the aqueous phase and mixed using a rotor-stator mixer. The volume of the series was 200 ml. The crude emulsion was subjected to homogenization at a high pressure of 20,000 bar. Solvents in the emulsion were removed using a rotary evaporator under reduced pressure. The suspension was filtered by serial filtration and then lyophilized (ET5 Tgau

Egeee Ogueeg).

The liquid suspension was homogeneous and creamy. Particle size analysis was performed using

Maimet 2 eiavigeg. The particles had an average size of 200 nm. The suspension was stored and, surprisingly, no sediment or sediment was found for 1 day. The same phenomenon was observed for the lyophilized suspension upon repeated reconstitution.

Example 25

This example demonstrates the preparation of anhydrous docetaxel citrate/Masi nanoparticles.

The aqueous phase was prepared by adding H5A (595 wt) and sodium citrate (200 mM) and wt (300 mM) to water for injection and mixed until dissolved. The organic phase was prepared by dissolving anhydrous docetaxel (160 mg/ml) in a solvent mixture containing chloroform and ethanol (1:1) and stirring until dissolved. Slowly the organic phase (895 by volume) was added to the aqueous phase and mixed using a rotor-stator mixer. The volume of the series was 200 ml. The crude emulsion was subjected to homogenization at a high pressure of 20,000 bar. Solvents in the emulsion were removed using a rotary evaporator under reduced pressure. The suspension was filtered by serial filtration and then lyophilized (ET5 Tgau Egeege Oguyeg).

The liquid suspension was homogeneous and creamy. Particle size analysis was performed using

Maimet 7eiavigeg. The particles had an average size of less than 200 nm. The suspension was stored and surprisingly no sedimentation or sedimentation was observed for more than one day. The same phenomenon was observed for the lyophilized suspension upon repeated reconstitution.

Example 26

This example demonstrates the preparation of anhydrous docetaxel citrate/Masi nanoparticles.

The aqueous phase was prepared by adding H5A (595 wt) and sodium citrate (200 mM) and wt (300 mM) to water for injection and mixed until dissolved. The organic phase was obtained by dissolving anhydrous docetaxel (160 mg/ml) in a solvent mixture containing chloroform and ethanol (1:11) and stirring until dissolved. Slowly the organic phase (895 by volume) was added to the aqueous phase and mixed using a rotor-stator mixer. The volume of the series was 200 ml. The crude emulsion was subjected to homogenization at a high pressure of 20,000 bar. Solvents in the emulsion were removed using a rotary evaporator under reduced pressure. Additionally, albumin was added to the evaporated suspension, increasing the albumin:drug ratio to 8:1 by weight. The suspension was filtered by serial filtration and then lyophilized (ET5 Tgau Egeege

Ogue!y).

The liquid suspension was homogeneous and creamy. Particle size analysis was performed using

Maimegtt 2eiavigeg. The particles had an average size of less than 200 nm. The suspension was stored and surprisingly no sediment or sediment was found for more than one day. The same phenomenon was observed for the lyophilized suspension upon repeated reconstitution.

Example 27

This example demonstrates the effect of pH on the stability of a nanoparticle suspension, as well as on the chemical degradation of docetaxel.

Docetaxel nanoparticle compositions were prepared as described in the above examples. The effect of pH on these compositions was tested at a pH between pH 4 and pH 9. It was found that an increase in pH above pH 6 increases the physical stability, measured in terms of nanoparticle size and precipitation of the composition, while at the same time the degradation rate of docetaxel increases in 7 -epidocetaxel at room temperature. The optimal pH range, at which physical stability and chemical stability are acceptable, was thus between 6-8.5. The preferred pH range was 6.5-8 and the most preferred pH range was found to be 7.25-7.75.

Example 28

This example compares the stability of Marb-docetaxel prepared with hydrated forms of docetaxel or with anhydrous docetaxel in the presence or absence of acceptable stabilizers.

The stability of these preparations was examined visually before lyophilization and also during repeated reconstitution of lyophilized preparations. In addition, the stability of lyophilized preparations (containing stabilizers) during repeated reconstitution was evaluated at different concentrations of docetaxel in the reconstituted suspension. The results are shown in Tables 1 - C below.

Table 1

Evaluation of the stability of Mar-docetaxel nanoparticle suspension before lyophilization of docetaxel stability stability

Mar-docetaxel without Mar-docetaxel with stabilizers with a stabilizer (citrate 200 mm/Masi 300 mm)

Intermediate formation of sediment ("15 min)

Hemihydrate (Volume I) suspension of nanoparticles, Data are not available once formed - Precipitation of the suspension. ' Precipitation of the suspension

Trihydrate (Volume I) of nanoparticles for about 1 hour of nanoparticles for about 1 day at

Precipitation of filtrate Absence of formation of sediment

Anhydrous (Volume Y) of nanoparticles for about 1 day with the filtrate of nanoparticles for 2 more) days at 4"C

Precipitation of filtrate Absence of formation of sediment

Anhydrous (Volume II) of nanoparticles for about 1 day with filtrate of nanoparticles for 2 more) days at 4"С

As shown in Table 1, the stability of Mar-docetaxel obtained using anhydrous docetaxel was significantly better than Mar-docetaxel obtained using hydrated forms of docetaxel with or without stabilizers in the composition.

The addition of stabilizers (200 mM citrate/300 mM Mass) significantly improves the stability of Mardocetaxel preparations that do not contain a stabilizer.

The addition of stabilizers improves the stability of Mar-docetaxel preparations obtained from docetaxel trihydrate.

Table 2

Reconstituted stability of lyophilized powder, Mar-docetaxel containing stabilizer (200 mM citrate/ 300 mM Masi) reconstituted in 5 mg/ml docetaxel in water for injection

Docetaxel type: trihydrate/anhydrous 15 min 1 hr 2 hr 4 hr b hr 24 hr

Trihydrate (252)

Anhydrous (252) ny I PNYA PNYA PO POL KOH

Trihydrate (407C

Anhydrous (407C)

Code: 1 - no sediment formation 2 - weak sediment formation

C - more sediment formation 4 - abundant sediment formation - complete sedimentation

Table C

Reconstituted Stability of Mab Docetaxel Lyophilized Powder Containing a Stabilizer (200 mM Citrate/ 300 mM Masi) Reconstituted in 1 mg/mL Docetaxel in Water for Injection

Trihydrate/Anhydrous of them I n МНЯ ПО ПО ПО

Trihydrate (42C)

Waterless (47) nyin I I POYA POLOYA POLYA PO

Trihydrate (2520

Anhydrous (25"C) we I I I POYA POLOYA POLO PO

Trihydrate (402C)

Anhydrous (407C

Code: 1 - no sediment formation 2 - weak sediment formation

C - more sediment formation 4 - abundant sediment formation 5 - complete sedimentation

As shown in Tables 2 and 3, the stability of reconstituted Mar-docetaxel containing stabilizers is significantly improved at a higher concentration of 5 mg/ml docetaxel compared to a lower concentration of approximately 1 mg/ml docetaxel. The stability of the reconstituted composition of Mardocetaxel containing stabilizers obtained with anhydrous docetaxel is significantly better than that of Mardocetaxel obtained with docetaxel trihydrate.

Example 29

This example demonstrates the toxicity profiles of a nanoparticulate albumin formulation of docetaxel (Mardocetaxel) compared to Tahoeige.

The maximum acceptable dose (MTO) for Mar-docetaxel and Tahoiegeb (Gueep 80-docetaxel) was determined during a dose-escalation study in pide mice (athymic mice with a mutation in the pide gene). Piae mice, group size 10 per group, were treated with increasing doses of Tahoeige (0 mg/kg, 7 mg/kg, 15 mg/kg, 22 mg/kg, 33 mg/kg, and 50 mg/kg) using the d4x3 schedule. Piae mice, group size 6 per group, were treated with increasing doses

Mar-docetaxel (0 mg/kg, 15 mg/kg, 22 mg/kg, 33 mg/kg, 50 mg/kg and 75 mg/kg) using the d4akh3 scheme. Animals were weighed every other day. Maximum body weight loss was plotted against dose and approximated using the Hill equation. MTO, defined as a mass loss equal to 2095, was calculated using approximate data. MTO was 2.3 times higher for Mar-docetaxel compared to Tahoeige (Tmeep 80-docetaxel). The MTO was 47.2 mg/kg and 20.6 mg/kg for Mardocetaxel and Tahoege, respectively.

Example 30

This example demonstrates the antitumor efficacy of the docetaxel nanoparticle according to the invention (Mardocetaxel) with a stabilizer in comparison with Tahoiege.

The effectiveness of Mar-docetaxel (prepared from 200 mM citrate and 300 mM Masi) was compared with Tahoiege in a mouse tumor model with a xenograft derived from HST-116 human colon tumor cells. 10 mice per group were used for the study. Tahoeige was used in a dose of 15 mg/kg and Mardocetaxel was used in a dose of 22 mg/kg, both according to the d4akh3 scheme. Mar-docetaxel (22 mg/kg) was more effective in tumor suppression than Tahoiege (15 mg/kg, MTO) with r«e0.0001. In addition, Mar-docetaxel showed a greater therapeutic index than Tahoeige, as the maximum weight loss in the Tahoeige group was 2095, while that of Mab-docetaxel was approximately 1795 despite the 5095 maximum dose.

Example 31

This example demonstrates an infusion study of Mab-docetaxel (200 mM citrate/300 mM Masi).

Studies on rats were performed with a 5-min infusion of Mar-docetaxel with increasing infusion rates of a composition of Mar-docetaxel containing approximately 200 mM citrate/300 mM Masi. A 5 min infusion in rats can be considered equivalent to a 30 min infusion in humans.

The maximum safe infusion rate was approximately 0.5 ml/min. It is equivalent to 0.23 mmol/kg/min or 68 mg/kg/min of docetaxel over a 5-min infusion in rats. Translated into a human dose, it is equivalent to approximately 170 mg of docetaxel/m:2 at a 30-minute infusion.

Example 32

This example demonstrates the biocompatibility of blood with 5 mg/ml Mardocetaxel (200 mM citrate/300 mM wt).

IP migo study of hemolysis of rat blood was carried out using a placebo composition (all components except docetaxel) and a Mar-docetaxel composition. Placebo did not cause hemolysis even at the highest rat blood:placebo ratio of 1:1. The composition of Mar-docetaxel interfered with absorption readings due to the characteristic light scattering by nanoparticles, but when the relevant background/control determinations were performed, the absence of hemolysis was recorded at the highest blood pgura:Mar-docetaxel ratio of 1:11. This demonstrates that Mar-docetaxel with stabilizer has been shown to be compatible with rat blood.

Example 33

This example offers a preliminary study of multiple dose escalation in rats. All compositions

Mar-docetaxel, described in this description, contain 200 mM citrate and 300 mM mass.

To compare the safety of the composition of Mar-docetaxel with the composition of Tahoege, rats were given doses of Tmeeep 80 docetaxel (the same composition as Tahoege) or Mab-docetaxel 5.0; 10.0; 15.0; 30.0 IU and 50 mg/kg using a 10-min infusion through indwelling jugular vein catheters on days 0, 4, and 8 for all three treatment courses. Physiological solution (1 ml/kg/min) was used as a control.

Each animal was observed and weighed daily during days 0-25. Body weight was recorded daily for each treated animal. Symptoms of clinical dysthesis were recorded daily. Blood was collected on days 13, 16 and 25

EDTA-treated tubes and subjected to differential analysis. An autopsy was performed on day 25.

The results of the study are shown in Table 4. As shown in the table, animals in all dose groups tolerated the first treatment with no acute or infusion-associated toxicity even at the maximum dose of 50 mg/kg. However, only with the introduction of the lowest dose level of 5 mg/kg and the control physiological solution, the animals survived until the end of the experiment (all three treatments). All animals receiving the highest doses died between the second and third doses or after the third dose.

Table 4

Weight loss and mortality in the dose escalation study

Tmzheep 80-docetaxel 50 mg/kg M/A 3/3 died between 2 and 3 doses

ZO mg/kg M/A 3/3 died between 2 and Z dose of 15 mg/kg M/A 3/3 died between 2 and Z dose of 10 mg/kg M/A 2/3 died between 2 and Z dose; 1/3 mg/kg after the third dose

1111іраюь11111111111111110 (О/Ззапынули.і/:3//ССССССССС–СсСсС vrgdocetakoel M/A 3/3 died between 2 and Z dose of mg/kg and and 30 mg/kg M/A 3/3 died between 2 and Z dose of 15 MG/KG M/A 3/3 died between 2 and C dose mg/kg M/A 2I3 died between 2 and C dose; 1/3

B mg/kg after C dose 1595 0/3 died

The weight loss of treated animals is shown in fig. 1. Comparison of neutropenia at a dose of 5 mg/kg docetaxel for

Mar-docetaxel and Gueep 80-docetaxel are shown in Fig.2. Weight loss for 5 mg/kg Mar-docetaxel in the survivor group was significantly less than that for 5 mg/kg Tmeep-docetaxel group (p-0.02-, AMOMA). It was parallel with significantly more severe neutropenia for the Gmeep-docetaxel (5 mg/kg) group versus the Mardocetaxel (5 mg/kg) group, (re0.0001, AMOMA, Fig. 2) on day 13. Autopsy at the end of the experiment ( day 25) of the groups that survived at 5 mg/kg revealed abnormalities in 2/3 of the animals in the Gmeep-docetaxel group (one case of accumulation of chylous fluid in the chest cavity and one case of abnormal attachment of the spleen to the abdominal wall, stomach and pancreas). Animals administered Mar-docetaxel (5 mg/kg) and saline were normal.

This preliminary study showed a significant improvement in the safety of Marb-docetaxel in terms of total body weight loss. Neutropenia was significantly higher with Tmeep-docetaxel.

Example 34

This example demonstrates the blood kinetics of Marb-docetaxel. All Mar-docetaxel compositions described in this description contain 200 mM citrate and 300 mM mass.

Rats were divided into six groups (Z per group). On day 1, each animal was weighed and administered intravenously with an individual dose of the corresponding item below:

Group A: Tahoeige, 10 mg/kg

Group B: Tahoeige, 20 mg/kg

Group C: Tahoeige, 30 mg/kg

Group 0: Mab-docetaxel, 10 mg/kg

Group E: Mar-docetaxel, 20 mg/kg

Group E: Mar-docetaxel, 30 mg/kg

Test items were administered over a period of 10 -/- 1 minute. Blood samples (200 μl) were collected from the tail vein of each rat at the following intervals: before infusion (baseline); during infusion (5 minutes of infusion, Her - -5 minutes); and at the end of the infusion (ii - 0). Blood was also collected at the following time points after completion of the infusion: 5, 10 and 20 minutes; 40 minutes; 2 hours « 5 minutes; From an hour to 2-10 minutes; 4 hours x 10 minutes; 8 hours 10 minutes; 24 5 1 hour; 48 5 1 hour; and 120 5 2 hours. Blood samples were collected in green-capped tubes (heparin sodium) and processed to collect plasma by centrifugation at approximately 2000 rpm for approximately 10 minutes. Plasma samples were kept frozen until immersion in dry ice

AI TA Apa/muisai (ie! Sogado Nijiz, SA) for I C/M5 analysis of docetaxel levels.

The results of the experiments are shown in Fig. 3 and in Table 5. No significant differences were found between the PK profiles of Mar-docetaxel versus Tahoege at 10 mg/kg. However, the differences between Mar-docetaxel and Tahoeige were significant at 20 mg/kg with Stach and AOS, 5395 and 70905 Tahoeige, respectively, and M and Me5 were 17795 and 24395

Tahoeiege respectively. At 30 mg/kg, the differences were again significant with Stach and AOC for Mar-docetaxel, 4695 and 4795 Tahoege, respectively, and M7 and M55 were 22595 and 37590 Tahoege, respectively.

Table 5

RK parameters of Mar-docetaxel and Tahoege p-

DOSE: 10 mg/kg body weight

NO (h) 8.3 -0.3 9.0 5.2 pe

Ttach (h) 0.11-0.05 0.14 - 0.05 pe

Stakh (ng/ml) 4330 - 358 4953-1014 pe

ACS poured. (hr"/ng/ml) 1588 4-77 2069 - 615 pe

M: (l/kg) 76-6 63-14 pe

SI (l/h/kg) 6.3 -0.3 511.5 pe

M88 (l/kg) 28-1 26 -9

DOSE: 20 mg/kg body weight

NO (h) 6.3 1.8 5.1--0.31

Ttah (h) 0.11-0.05 0.14 4 0.05 rpm

Level (ng/ml) 8546-1545 16167 - 2804 0 01

ACS poured. (h"/ng/ml) 3953 - 419 5664 - 500 002

M: (l/kg) 46-10 26-1 0 01

SI (l/h/kg) 5.1-0.5 3.5-0.3 0 01

M88 (l/kg 17 4 7-1 "

NO (h) 0.17 -0.00 0.14 - 0.05 pe

Hours (hours) 15800 - 5408 34467-14221 01

Stach (ng/ml) 7049 - 896 14881 -- 1169 0.008

ACS poured. (hr"/ng/ml) 45-10 20-8 0.03

Ma (l/kg) 4.3 0.5 20-02 0.002

SI (l/h/kg) 15-4 4-1 0.01

Me (l/kg)

When AC was plotted against dose, non-inferiority to Tahoeige was evident, with Mab-docetaxel AC being linear with respect to dose (Figure 3B). This can be explained by the micelle-forming properties of Tmeep 80, the high solubility of docetaxel in the hydrophobic core of micelles and the corresponding sequestration of docetaxel in plasma (6). In addition, the rapid tissue distribution of Mar-docetaxel may also be explained by the utilization of albumin/caveolae-mediated transcytosis by endothelial cells, a process previously described for Abgahape (Mar-paclitaxel).

The LC data lead to the conclusion that Tmeep 80 in Tahoege exhibits docetaxel sequestration in plasma similar to that observed with Stetorgog EI. in the case of Taxol. This results in higher Sths and AOCs and lower volumes of distribution for Tahoeige than for Mar-docetaxel. The LC of Mar-docetaxel is linear, whereas for

The Tmzeep of 80-docetaxel (Tahoegye) is non-linear with respect to dose. The dosages described herein, i.e., 10 mg/kg, 20 mg/kg, and 30 mg/kg, are equivalent to human dosages of about 60 mg/m?, about 120 mg/m: and about 180 mg/m. Of course. the linear LC range of Mar-docetaxel is approximately 10-180 mg/m".

Example 35

This example demonstrates the inhibition of the drug-albumin interaction using a surfactant such as Tueep 80. The experiment was performed using fluorescently labeled paclitaxel (RiIx) as a paclitaxel/docetaxel surrogate. Risakh has been shown to have similar binding to albumin as paclitaxel.

H5ZA was immobilized on a 9b-well plastic microplate. The immobilized albumin reacted for 1 hour at a constant concentration of Risakh and an increased concentration of solvents (Stetornog EI / EYN,

Tmeep 80 and TROB). Unbound ligands were washed with buffer. Bound ligands were quantified using a fluorometer. ISvo was determined using the exponential decay equation.

The results of the experiment are shown in Fig.4. As shown in Fig. 4, the albumin-paclitaxel interaction was inhibited by a solvent commonly used in the composition of water-insoluble medicinal products, such as Stetorpog EG/EUN, Tmeep 80, and TROB (ISvo 0.009905, 0.00395, and 0.00895, respectively ). Complete inhibition occurred at 0.0295 or 0.2 µl of Pmueep 80. It is clinically relevant in Tahoege-treated patients showing 0.07-0.41 µl of blood Tmeeep 80 at the end of drug infusion.

This experiment demonstrates that Tmeep 80 in the composition of Tahoiege can inhibit the binding of docetaxel to albumin and prevent its endothelial transcytosis using the 5rboO/caveolar mechanism. Data

The results of the above-mentioned studies also support this observation.

Example 36

This example provides an evaluation of the antitumor activity of Mar-docetaxel against an H2g9 colon carcinoma xenograft in athymic Pide mice. Mice were divided into a control group and a Mar-docetaxel group (M - 4 per group, each with bilateral tumors). All Mar-docetaxel compositions described in this description contain 200 mM citrate and 300 mM mass.

Briefly, H2g9 tumors were implanted subcutaneously into athymic Pide mice to achieve 100 mm growth and then treated with control (no drug) or Mar-docetaxel (15 mg/kg, D4ax3, IV bolus).

Measurements of tumor size and body weight were carried out three times a week and plotted in Fig. 5.

As shown in fig. 5, there was a significant inhibition of the tumor of HT29 ip mimo, p«e0.0001 compared to the control,

AMOMA. At a dose of 15 mg/kg Mar-docetaxel, mean weight loss between 10-2095 suggested that this dose may be close to the MTO for Mar-docetaxel. The MRL for Tahoeige was reported to be mg/kg for this regimen.

Example 37

This example compares the antitumor activity of Mar-docetaxel and Tahoege using HCT116 colon carcinoma xenografts in athymic mice with a 5095 higher dose of Mar-docetaxel compared to Tahoege. The mice were divided into a control group, a Mar-docetaxel group and a group

Tahoiege (M - 10 mice per group). All Mar-docetaxel compositions described in this description contain 200 mM citrate and 300 mM mass.

Briefly, the antitumor activity of Mar-docetaxel and Tahoiege was compared at a dose of 22 mg/kg d4x3 and 15 mg/kg a4x3, respectively, in the HST116 colon carcinoma xenograft. The results of the experiments are shown in Fig.6.

As shown in Fig.b, Mardocetaxel and Tahoege showed tumor inhibition relative to the respective control. As shown below, tumor inhibition improved with Mab-docetaxel versus Tahoeiege (p-0.03,

AMOMA) and a small decrease in total mass loss was smaller but statistically significant (p-p5, AMOMA) between the two groups.

In this preliminary study, the antitumor activity of Mar-docetaxel was superior to that

Tahoeiege Mice tolerated a 5095 higher dose of docetaxel for Mar-docetaxel with a small reduction in total body weight loss compared to Tahoeiege.

Example 38

This example compares the toxicity of Mar-docetaxel with a stabilizer (citrate/Mas) vs.

Tahoeige (Tmeep-docetaxel) in rats receiving an individual dose of each drug.

Male Zrgadoe-OSamieu rats (160-180 g, p«Z/group) were infused with Tahoiege or Mar-docetaxel (citrate/Masi).

The infusion time was 10 minutes and the following dose levels of docetaxel were used: 25, 50, 75, 100 and 125 mg/kg.

Animals were weighed and monitored daily for signs of toxicity/mortality. The percentage of mortality (905) within 7 days after treatment is shown in Table 6.

Table 6

The percentage of mortality in rats treated with Tahoiege and Mar-docetaxel pn" ННнИШШШШЙИЯЯВВВВВВВВОНИ Dose (mg/kg) 11111115 | lo | 75 | 50 | 25 10096 10096 | 10096 10096 10096

Mar-docetaxel (citrate) 10096

As shown in Table 6, the Mar-docetaxel formulation was significantly less toxic than Tahoiege (Tmeep-docetaxel). This effect is partially expressed in doses of 25 and 50 mg/kg. The calculated IO5o is 63 mg/kg for

Mar-docetaxel versus approximately 12.5 mg/kg for Tmeep-docetaxel.

Example 39

This example shows the effectiveness of Mar-docetaxel in the treatment of prostate cancer in a tumor model of the ROZ xenograft of prostate cancer.

ROZ tumors were implanted subcutaneously in athymic mice with a growth factor of 100 mm3 and then treated d4x3 with i.v. saline or Mar-docetaxel (10, 15, 20 or 30 mg/kg) or Tzhmeep-docetaxel (10 mg/kg). Six mice in each group were evaluated.

The results of the study are shown in Fig. 7. All six mice treated with Tmeep-docetaxel died during the study. On the other hand, Mar-docetaxel was well tolerated at all dose levels. There was only one death at 15 mg/kg and no deaths were observed at the higher dose levels of 20 mg/kg and 30 mg/kg.

Tumor suppression was observed at all dose levels of Mar-docetaxel. In particular, six out of six complete regressions were observed at 30 mg/kg.

Although the above invention has been described in sufficient detail by way of illustration and example for clarity of understanding, it will be apparent to those skilled in the art that certain minor changes and modifications will be made in practice. Therefore, the description and examples should not be construed as limiting the scope of the invention.

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Claims (31)

1. A composition containing docetaxel and citrate, wherein the stability of the composition is increased compared to the composition without citrate. 2. The composition of claim 1, wherein the composition is physically stable and shows no signs of sedimentation or sedimentation for at least about 8 hours after reconstitution or rehydration. 3. The composition according to claim 1 or 2, where the composition is a pharmaceutical composition. 4. The composition according to any of claims 1-3, where the composition is sterilized by filtration. 5. The composition according to any one of claims 1-4, where the composition is sterile. b. The composition according to any one of claims 1-5, wherein the composition is suitable for parenteral administration. 7. The composition according to any one of claims 1-6, where the composition includes nanoparticles. 8. The composition according to any one of claims 1-7, where the composition additionally includes a biocompatible polymer. 9. The composition according to claim 8, where the biocompatible polymer is a carrier protein. 10. Composition according to claim 9, where the carrier protein is albumin. 11. The composition according to claim 10, where the albumin is human serum albumin. 12. The composition according to any one of claims 8-11, wherein the nanoparticles comprising docetaxel are coated with a biocompatible polymer. 13. The composition of any one of claims 10-12, wherein the mass ratio of docetaxel 1 albumin in the composition is about 18:1 or less. 14. The composition of any one of claims 7-13, wherein the nanoparticles have an average diameter of no more than about 200 nm. 15. The composition according to any one of claims 1-14, wherein the composition is a lyophilized composition. 16. The composition of any one of claims 1-15, wherein the composition is a dry composition that can be reconstituted into a liquid suspension with a docetaxel concentration of at least about 1 mg/ml. 17. The composition according to any one of claims 1-14, where the composition is a liquid suspension of docetaxel. 18. The composition of claim 17, wherein the composition is a liquid suspension of docetaxel at a concentration of at least about 1 mg/ml. 19. The composition of claim 185, wherein the composition is a liquid suspension of docetaxel at a concentration of at least about 15 mg/ml. 20. The composition according to any one of claims 1-19, wherein the citrate is citric acid. 21. The composition according to any one of claims 1-19, wherein the citrate is sodium citrate. 22. The composition of any of claims 1-21, wherein the pH of the composition is at least about 7. 23. The composition according to any one of claims 1-22, wherein the composition additionally includes sodium chloride. 24. The composition of claim 23, wherein the composition contains about 200 mM sodium citrate and about 300 mM sodium chloride. 25. The composition according to any of claims 1-24, which additionally contains sugar. 26. The composition according to claim 25, where the sugar is sucrose. 27. Hermetic ampoule containing the composition according to any of claims 1-26. 28. A kit comprising a composition according to any one of claims 1-26 for use in the treatment of cancer, further comprising instructions. 29. Use of the composition according to any one of claims 1-26 for the preparation of a medicinal product for the treatment of cancer. 30. Use of the composition of claim 29, wherein the cancer is any of prostate cancer, colon cancer, breast cancer, head and neck cancer, pancreatic cancer, lung cancer, and ovarian cancer. 31 A method of stabilizing docetaxel in a composition, which includes combining a composition containing docetaxel with citrate.