BR112017025815B1 - TAXANE PARTICLES, COMPOSITIONS COMPRISING TAXANE PARTICLES, USE OF THE COMPOSITION COMPRISING TAXANE PARTICLES AND METHODS OF MANUFACTURING THE TAXANE PARTICLES - Google Patents

Abstract

TAXANE PARTICLES AND USE THEREOF. Compositions are provided which include having at least 95% by weight of a taxane, or a pharmaceutically acceptable salt thereof, wherein the particles have an average bulk density between about 0.050 g/cm3 and about 0.15 g/cm3, and /or a specific surface area (SSA) of at least 18 m2/g, 20 m2/g, 25 m2/g, 30 m2/g, 32 m2/g, 34 m2/g, or 35 m2/g. Methods for making and using such compositions are also provided.

Description

Cross reference

[001] This application claims priority to United States Provisional Patent Application Serial Numbers 62/171060 filed June 4, 2015, 62/171001 filed June 4, 2015, and 62/171008 filed June 4 2015, each incorporated herein by reference in its entirety.

Fundamentals of Invention

[002] The dissolution rate is a key parameter in determining the rate and extent of absorption and bioavailability of the drug. Poor aqueous solubility and poor in vivo dissolution are limiting factors for the in vivo bioavailability of many drugs. Thus, in vitro dissolution rates are recognized as an important element in drug development, and methods and compositions to increase dissolution rates of poorly soluble drugs are needed.

Summary of the invention

[003] In a first aspect, the invention provides compositions, comprising particles, including at least 95% by weight of a taxane, or a pharmaceutically acceptable salt thereof, wherein the particles have one or both of the following characteristics: (i) an average bulk density of between about 0.050 g/cm3 and about 0.15 g/cm3, and/or; (j) ) have a specific surface area (SSA) of at least 18 m2/g, 20 m2/g, 25 m2/g, 30 m2/g, 32 m2/g, 34 m2/g, or 35 m2/g g.

[004] In one embodiment, the taxane is selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, taxadiene, baccatin III, taxkinin A, brevifoliol, and taxuspin D, or a pharmaceutically acceptable salt thereof. In another embodiment, the taxane is selected from the group consisting of paclitaxel, docetaxel, and cabazitaxel, or a pharmaceutically acceptable salt thereof.

[005] In a further embodiment, the taxane is paclitaxel or a pharmaceutically acceptable salt thereof, and wherein the particles have an average apparent density between about 0.050 g/cm3 and about 0.12 g/cm3, or between about of 0.060 g/cm3 and about 0.11 g/cm3. Paclitaxel particles may have a specific surface area (SSA) of at least 18 m2/g, 20 m2/g, 25 m2/g, 30 m2/g, 32 m2/g, 34 m2/g, or 35 m2/g. Paclitaxel particles can have an SSA of between about 22 m2/g and about 40 m2/g, 25 m2/g and about 40 m2/g, 30 m2/g and about 40 m2/g, or between about 35 m2/g and about 40 m2/g. Paclitaxel particles can have an apparent density of between about 0.060 g/cm3 and about 0.11 g/cm3 and an SSA of between about 22 m2/g and about 40 m2/g. In another embodiment, at least 40% (w/w) of the paclitaxel is dissolved in 30 minutes or less in a 50% methanol/50% water ((v/v)) solution at 37°C and pH 7. .0 on a USP II paddle apparatus operating at 75 RPM.

[006] In one embodiment, the taxane is docetaxel or a pharmaceutically acceptable salt thereof, and wherein the particles have an average apparent density between about 0.050 g/cm3 and about 0.12 g/cm3, or between about 0.06 g/cm3 and about 0.1 g/cm3. Docetaxel particles can have an SSA of at least 18 m2/g, 20 m2/g, 25 m2/g, 30 m2/g, 35 m2/g, 40 m2/g, or 42 m2/g. Docetaxel particles can have an SSA of between about 40 m2/g and about 50 m2/g, or between about 43 m2/g and about 46 m2/g. Docetaxel particles may have an apparent density of between about 0.06 g/cm3 and about 0.1 g/cm3, and an SSA of between about 40 m2/g and about 50 m2/g. In a further embodiment, at least 20% (w/w) of docetaxel is dissolved in 30 minutes or less in a 15% methanol/85% water (v/v) solution at 37°C and pH 7. .0 on a USP II paddle apparatus operating at 75 RPM.

[007] In a further aspect, the invention provides compositions comprising particles comprising at least 95% by weight of paclitaxel, or a pharmaceutically acceptable salt thereof, wherein the particles have a specific surface area (SSA) of at least less, 12 m2/g. Paclitaxel particles may have an SSA of at least 12 m2/g, 15 m2/g, 20 m2/g, 25 m2/g, 30 m2/g, 32 m2/g, 34 m2/g, or 35 m2/g. In one embodiment, at least 40% (w/w) of the paclitaxel dissolves in 30 minutes or less, in a 50% methanol/50% water (v/v) solution at 37°C and pH 7, 0 on a USP II paddle apparatus operating at 75 RPM.

[008] In another aspect, the invention provides compositions comprising particles including at least 95% by weight of paclitaxel, wherein at least 40% (w/w) of the paclitaxel is dissolved in 30 minutes or less, in a solution of 50% methanol/50% water (v/v) in a USP II paddle apparatus operating at 75 RPM. The invention also provides compositions comprising including at least 95% by weight docetaxel, wherein at least 20% (w/w) of the docetaxel is dissolved in 30 minutes or less in a 15% methanol/85% water solution. (v/v) at 37°C and pH 7.0, in a USP II paddle apparatus operating at 75 RPM.

[009] The compositions of the invention may comprise particles that have an average particle size between about 0.4 μm and about 1.2 μm, or between about 0.6 μm and about 1.0 μm. The particles may be uncoated and exclude polymer, protein, polyethoxylated castor oil and polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol. The compositions may further be incorporated into a suspension, which further comprises a pharmaceutically acceptable aqueous carrier. The composition may further comprise one or more components selected from the group consisting of polysorbate, methylcellulose, polyvinylpyrrolidone, mannitol and hydroxypropylmethylcellulose. The compositions may comprise, by weight, at least 96%, 97%, 98%, 99%, or 100% of the compound.

[010] The invention further provides methods for treating a tumor, comprising administering to a subject with a tumor a tumor-treating effective amount of a composition according to any embodiment or a combination of embodiments of the invention. In one embodiment, the tumor may be selected from the group consisting of a breast tumor, an ovarian tumor, a lung tumor, a bladder tumor, a prostate tumor, a bone tumor, a stomach tumor, and a pancreatic tumor. In another embodiment, the composition is administered intraperitoneally, such as by infusion or as a bolus into the peritoneal cavity. In one embodiment, intraperitoneal administration is initiated after removal of ascites fluid from the peritoneal cavity. In another embodiment, the subject is a human subject.

[011] The invention further provides methods for manufacturing composite particles, comprising: (k) introducing (i) a solution comprising at least one solvent and at least one solute comprising a compound of interest into an inlet of the nozzle, and (ii) a fluid compressed in an inlet of a container defining a pressurizable chamber; (l) passing the solution out of a nozzle orifice and into the pressurizable chamber to produce an outflow of atomized droplets, wherein the nozzle orifice is located between 2 mm and 20 mm from a sonic energy source located within the exit stream, wherein the sonic energy source produces sonic energy with an amplitude between 10% and 100% during passage, and wherein the nozzle orifice has a diameter of between 20 μm and 125 μm; and (m) contacting the atomized droplets with the compressed fluid, to cause depletion of the solvent from the atomized droplets, to produce the compound particles, in which steps (a), (b), and (c) are carried out under supercritical temperature and pressure conditions for the compressed fluid.

[012] In one embodiment, the method further comprises: (n) contacting the atomized droplets produced in step (c) with an antisolvent to cause further depletion of the solvent from the compound particles, in which step (d) is carried out under supercritical temperature and pressure for the antisolvent.

[013] In one embodiment, a flow rate of the solution through the nozzle has a range of about 0.5 mL/min to about 30 mL/min. In a further embodiment, the sonic energy source comprises one of a sonic horn, a sonic probe or a sonic plate. In another embodiment, the sonic energy source has a frequency between about 18 kHx and about 22 kHz, or about 20 kHz.

[014] The methods may further comprise: (o) receiving the plurality of particles through the outlet of the pressurizable chamber; and (p) collecting the plurality of particles in a collection device.

[015] In one embodiment, the compound is a taxane. The method of any one of claims 30-35, wherein the compound is a taxane. Exemplary taxanes may include paclitaxel, docetaxel, cabazitaxel, taxadiene, baccatin III, taxkinin A, brevifoliol, and taxuspin D, or a pharmaceutically acceptable salt thereof. In a specific embodiment, the taxane is selected from the group consisting of paclitaxel, docetaxel, and cabazitaxel, or a pharmaceutically acceptable salt thereof. In one embodiment, the solvent is selected from the group consisting of acetone, ethanol, methanol, dichloromethane, ethyl acetate, chloroform, acetonitrile, and suitable combinations thereof. In various embodiments, the compressed fluid and/or antisolvent may be supercritical carbon dioxide. In one embodiment, the compound is paclitaxel and the solvent comprises acetone. In another embodiment, the compound is docetaxel and the solvent comprises ethanol. In a further embodiment, the method is carried out between 31.1°C and about 60°C, and between about 1071 psi and about 1800 psi.

[016] The invention also provides compound particles prepared by the method of any embodiment or a combination of embodiments of the invention.

Brief Description of Figures

[017] Figure 1 is an electron micrograph of paclitaxel particles exemplary of the invention.

[018] Figure 2 is an electron micrograph of raw paclitaxel particles.

[019] Figure 3 illustrates a cross-sectional view of an exemplary nozzle assembly, according to an exemplary embodiment.

[020] Figure 4 illustrates a cross-sectional view of another exemplary nozzle assembly, according to an exemplary embodiment.

[021] Figure 5 illustrates a perspective view of a particle collection device, according to an exemplary embodiment.

[022] Figure 6 illustrates a top view of the particle collection device, according to an exemplary embodiment.

[023] Figure 7 illustrates a cross-sectional view of the particle collection device, according to an exemplary embodiment.

[024] Figure 8 illustrates another cross-sectional view of the particle collection device, according to an exemplary embodiment.

[025] Figure 9 illustrates another cross-sectional view of the particle collection device, according to an exemplary embodiment.

[026] Figure 10 illustrates a perspective view of a support structure, according to an exemplary embodiment.

Detailed Description of the Invention

[027] All references cited are incorporated herein by reference in their entirety. As used herein, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. “And” as used herein is used interchangeably with “or” unless expressly indicated otherwise. All embodiments of any aspect of the invention may be used in combination unless the context clearly dictates otherwise.

[028] As used herein, “about” means +/- 5% of the recited value.

[029] In one aspect, the present invention provides compositions comprising particles including at least 95% by weight of a taxane, or a pharmaceutically acceptable salt thereof, wherein the particles have one or both of the following characteristics: (i) a density apparent average between about 0.050 g/cm3 and about 0.15 g/cm3, and/or (ii) have a specific surface area (SSA) of at least 18 m2/g, 20 m2/g, 25 m2/ g, 30 m2/g, 32 m2/g, 34 m2/g, or 35 m2/g.

[030] The inventors were unexpectedly able to produce compositions comprising the aforementioned taxane particles that have an average apparent density between about 0.050 g/cm3 and about 0.15 g/cm3, and/or a specific surface area (SSA ) of at least 18 m2/g, an SSA using new methods for producing the particles as described herein. As shown in the examples that follow, the increased specific surface area and reduced bulk density of the taxane particles result in significant increases in dissolution rate compared to the raw taxane and the ground taxane products used for comparison. Dissolution only occurs at a solid/liquid interface. Therefore, the increased specific surface area will increase the dissolution rate, due to a greater number of molecules on the particle surface having contact with the dissolution medium. The apparent density takes into account the macrostructure and inter-particle space of a powder. Parameters that contribute to bulk density include particle size distribution, particle shape, and particle affinity for one another (i.e., agglomeration). Lower apparent powder densities yield faster dissolution rates. This is due to the ability of dissolution media to more easily penetrate interstitial or inter-particle spaces and have greater contact with the particle surface. Therefore, each of the increased specific surface area and decreased bulk density results in a significant increase in the dissolution rate for the taxane particles of the invention compared to the unprocessed or raw material, and the milled taxane product used for comparison. This provides a significant improvement for the use of the taxane particles of the invention in, for example, tumor treatment.

[031] As used herein, the “specific surface area” is the total surface area of the paclitaxel particle per unit mass of paclitaxel, as measured by the Brunauer-Emmett-Teller (“BET”) isotherm (i.e. : BET SSA). As will be understood by those skilled in the art, "taxane particles" include both agglomerated taxane particles and non-agglomerated taxane particles; Since SSA is determined on a per gram basis, it takes into account both agglomerated and non-agglomerated taxane particles in the composition. The BET specific surface area test procedure is a compendium method included in both the United States Pharmacopoeia and the European Pharmacopoeia.

[032] As used herein, the apparent density of taxane particles is the mass of all the particles in the composition divided by the total volume they occupy when poured into a graduated cylinder. The total volume includes particle volume, interparticle void volume, and internal pore volume.

[033] Taxanes are a class of diterpenoids containing a taxadiene nucleus that are very poorly soluble in water. The taxane particles of the invention may be any suitable taxane, including, but not limited to, paclitaxel, docetaxel, cabazitaxel, taxadiene, baccatin III, taxkinin A, brevifoliol, and taxuspin D, combinations thereof, or pharmaceutically acceptable salts thereof. . In one embodiment, the taxane is selected from the group consisting of paclitaxel, docetaxel, and cabazitaxel, or a pharmaceutically acceptable salt thereof.

[034] “Taxane particles” refer to taxane particles that do not include an added excipient. Taxane particles are different from “taxane-containing particles,” which are particles that contain taxane and at least one added excipient. The taxane particles of the invention exclude a polymeric excipient, wax or protein and are not incorporated, contained, enclosed or encapsulated within a solid excipient. The taxane particles of the invention may, however, contain impurities and by-products typically encountered during the preparation of taxane. Even so, the taxane particles comprise at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% taxane, which means that the taxane particles consist of or consist of essentially substantially pure taxane. In one embodiment, the taxane particles are uncoated and exclude polymer, protein, polyethoxylated castor oil, and polyethylene glycol glycerides composed of mono-, di-triglycerides, and polyethylene glycol mono- and diesters.

[035] The compositions of the invention have an average particle size in the range of about 0.2 μm to about 5 μm, about 0.4 μm to about 3 μm, or about 0.5 μm to about 1.4 μm. In a further embodiment, the compositions have an average particle size between about 0.4 μm and about 1.2 μm. In another embodiment, the average particle size is between about 0.4 μm and about 1.2 μm, or between about 0.6 μm and about 1.0 μm.

[036] In one embodiment, the taxane is paclitaxel or a pharmaceutically acceptable salt thereof, and the particles have an average apparent density between about 0.050 g/cm3 and about 0.12 g/cm3. In another embodiment, the paclitaxel particles have an average bulk density between about 0.060 g/cm3 and about 0.11 g/cm3.

[037] In a further embodiment, the taxane is paclitaxel or a pharmaceutically acceptable salt thereof, and wherein the paclitaxel particles have a specific surface area (SSA) of at least 18 m2/g. In various other embodiments, the paclitaxel particles have an SSA of at least 20 m2/g, 25 m2/g, 30 m2/g, 32 m2/g, 34 m2/g, or 35 m2/g. In a further embodiment, the paclitaxel particles have an SSA of between about 22 m2/g and about 40 m2/g, between about 25 m2/g and about 40 m2/g, between about 30 m2/g and about 40 m2/g, or between about 35 m2/g and about 40 m2/g.

[038] In a preferred embodiment, the paclitaxel particles have an average apparent density between about 0.050 g/cm3 and about 0.12 g/cm3, and an SSA of at least 30 m2/g. In another preferred embodiment, the paclitaxel particles have an average bulk density between about about 0.050 g/cm3 and about 0.12 g/cm3, and an SSA of at least 35 m2/g. In one, the paclitaxel particles have an average bulk density between about 0.050 g/cm3 and about 0.12 g/cm3, and an SSA between about 30 m2/g and about 40 m2/g. In another preferred embodiment, the paclitaxel particles have an average bulk density of between about 0.060 g/cm3 and about 0.11 g/cm3, and an SSA of between about 30 m2/g and about 40 m2/g. In another preferred embodiment, the paclitaxel particles have an average bulk density of between about 0.060 g/cm3 and about 0.11 g/cm3 and an SSA of at least 30 m2/g. In a further embodiment, the paclitaxel particles have an average bulk density of between about 0.060 g/cm3 and about 0.11 g/cm3 and an SSA of at least 35 m2/g. These various modalities are exemplified in the following examples.

[039] In any of these various embodiments, the paclitaxel particles may include at least 4.16 x 10-13 grams of paclitaxel, or a pharmaceutically acceptable salt thereof per paclitaxel particle.

[040] In another embodiment, at least 40% (w/w) of paclitaxel in the paclitaxel particles of the composition is dissolved in 30 minutes or less, in a solution of 50% methanol/50% water (v/v) on a USP II paddle apparatus operating at 75 RPM. pH 7 was used, and the solubility of taxanes is not effected by pH. In another embodiment, dissolution studies are carried out at 37°C.

[041] In another embodiment, the taxane is docetaxel or a pharmaceutically acceptable salt thereof, and the docetaxel particles have an average bulk density between about 0.050 g/cm3 and about 0.12 g/cm3. In a further embodiment, the average apparent density of docetaxel particles is between about 0.06 g/cm3 and about 0.1 g/cm3.

[042] In another embodiment, the taxane is docetaxel or a pharmaceutically acceptable salt thereof, and in which the docetaxel particles have an SSA of at least 18 m2/g. In various additional embodiments, the docetaxel particles have an SSA of at least 20 m2/g, 25 m2/g, 30 m2/g, 35 m2/g, 40 m2/g, or 42 m2/g. In a further embodiment, docetaxel particles have an SSA of between about 40 m2/g and about 50 m2/g. In another embodiment, the docetaxel particles have an SSA of between about 43 m2/g and about 46 m2/g.

[043] In a preferred embodiment, docetaxel particles have an average apparent density between about 0.050 g/cm3 and about 0.12 g/cm3 and an SSA of at least 30 m2/g. In another preferred embodiment, the docetaxel particles have an average bulk density between about 0.050 g/cm3 and about 0.12 g/cm3, and an SSA of at least 35 m2/g. In a further preferred embodiment, the docetaxel particles have an average bulk density between about 0.050 g/cm3 and about 0.12 g/cm3 and an SSA of at least 40 m2/g. In a preferred embodiment, the docetaxel particles have an average bulk density between about 0.050 g/cm3 and about 0.12 g/cm3, and an SSA of between about 40 m2/g and about 50 m2/g. In another preferred embodiment, the average apparent density of docetaxel particles is between about 0.06 g/cm3 and about 0.1 g/cm3, and the SSA is between about 40 m2/g and about 50 m2/g . These various modalities are exemplified in the following examples.

[044] In any of these various embodiments, the docetaxel particles may include at least 4.16 x 1013 grams of docetaxel, or a pharmaceutically acceptable salt thereof per docetaxel particle.

[045] In another embodiment, at least 20% (w/w) of docetaxel is dissolved in 30 minutes or less, in a 15% methanol/85% water (v/v) solution in a USP paddle apparatus II operating at 75 RPM. A neutral pH was used, where the solubility of taxanes is not effected by pH. In another embodiment, dissolution studies are carried out at 37°C.

[046] In a further aspect, the invention provides compositions comprising particles comprising at least 95% by weight of paclitaxel, or a pharmaceutically acceptable salt thereof, wherein the particles have a specific surface area (SSA) of at least 12 m2/g. In various embodiments, the paclitaxel particles have an SSA of at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 m2/g. In various additional embodiments, the paclitaxel particles have an SSA of between about 12 m2/g and about 40 m2/g, about 14 m2/g and about 40 m2/g, about 15 m2/g and about 40 m2 /g, about 16 m2/g and about 40 m2/g, about 17 m2/g and about 40 m2/g, about 18 m2/g and about 40 m2/g, about 19 m2/g and about 40 m2/g, about 20 m2/g and about 40 m2/g, about 22 m2/g and about 40 m2/g, about 26 m2/g and about 40 m2/g, about 30 m2/g and about 40 m2/g, between about 20 m2/g and about 29 m2/g, between about 20 m2/g and about 28 m2/g, between about 20 m2/g and about 26.2 m2/g , between about 22 m2/g and about 29 m2/g, between about 22 m2/g and about 28 m2/g, between about 22 m2/g and about 26.2 m2/g, between about 32 m2 /g and about 39 m2/g, between about 32 m2/g and about 38.5 m2/g, between about 32 m2/g and about 35 m2/g, between about 35 m2/g and about 40 m2 /g, and between about 35 m2/g and about 38.5 m2/g. In other embodiments, the paclitaxel particles have an SSA of: (a) between 16 (b) between 16 (c) between 16 (d) between 17 (e) between 17 (f) between 17 (g) between 16 (h ) between 16 (i) between 16 (j) between 17 (k) between 17 (l) between 17 (m) between 16 m2/g and 31 m2/g, m2/g and 30 m2/g, m2/g and 29 m2/ g, m2/g and 31 m2/g, m2/g and 30 m2/g, m2/g and 29 m2/g, m2/g and 31 m2/g, m2/g and 30 m2/g, m2/g and 29 m2/g, m2/g and 31 m2/g, m2/g and 30 m2/g, m2/g and 29 m2/g, m2/g and 31 m2/g, m2/g and 40 m2/g m2/g and 40 m2/g m2/g and 40 m2/g m2/g and 40 m2/g m2/g and 40 m2/g m2/g and 40 m2/g m2/g and 40 m2/g m2/g and 40 m2/g m2/g and 40 m2/g m2/g and 40 m2 /g m2/g and 40 m2/g and 40 m2/g m2/g and 31 m2/g, m2/g and 30 m2/g, m2/g and 30 m2/g, m2/g and 29 m2/g, m2/g and 29 m2 /g, m2/g and 31 m2/g, m2/g and 31 m2/g, m2/g and 30 m2/g, m2/g and 30 m2/g, m2/g and 29 m2/g, m2/g and 29 m2/g , or > 32 m2/g; or > 32 m2/g; or > 32 m2/g; or > 32 m2/g; or > 32 m2/g; or > 33 m2/g; or > 33 m2/g; or > 33 m2/g; or > 33 m2/g; or > 33 m2/g; or or > 33 m2/g.

[047] In another embodiment, at least 40% (w/w) of the paclitaxel in the paclitaxel particles of the composition are dissolved in 30 minutes or less in a solution of 50% methanol/50% water (v/v) in a USP II paddle apparatus operating at 75 RPM. pH 7 was used, and the solubility of taxanes is not effected by pH. In another embodiment, dissolution studies are carried out at 37°C.

[048] In another aspect, the present invention provides compositions, comprising particles including at least 95% by weight of paclitaxel, in which at least 40% (w/w) of the paclitaxel is dissolved in 30 minutes or less in a solution of 50 % methanol/50% water (v/v) in a USP II paddle apparatus operating at 75 RPM. pH 7 was used, and the solubility of taxanes is not effected by pH. In another embodiment, dissolution studies are carried out at 37°C.

[049] In a further aspect, the present invention provides a composition comprising including at least 95% by weight of docetaxel, wherein at least 20% (w/w) of docetaxel is dissolved in 30 minutes or less, in a solution of 15% methanol/85% water (v/v) in a USP II paddle apparatus operating at 75 RPM. pH 7 was used, and the solubility of taxanes is not effected by pH. In another embodiment, dissolution studies are carried out at 37°C.

[050] In an additional embodiment, the composition comprises a suspension that further comprises a pharmaceutically acceptable aqueous vehicle. The suspension of the present invention comprises taxane particles and a liquid carrier. The liquid carrier may be aqueous. The suspension excludes a solid excipient within which paclitaxel is contained, and excludes GELUCIRE® (polyethylene glycol glycerides composed of mono-, di- and triglycerides, and polyethylene glycol mono- and diesters), and CREMOPHOR® (polyethoxylated castor oil) .

[051] Although paclitaxel particles do not include an added excipient, the liquid carrier of the suspension may comprise water and, optionally, one or more excipients selected from the group consisting of buffer, tonicity adjusting agent, preservative, demulcent, viscosity modifier, osmotic agent, surfactant, antioxidant, alkalizing agent, acidifying agent, antifoaming agent and colorant. For example, the suspension may comprise taxane particles, water, buffer and salt. It also optionally comprises a surfactant. In some embodiments, the suspension essentially consists of or consists of water, taxane particles suspended in the water, and buffer. The suspension may also contain an osmotic salt.

[052] The suspension may comprise one or more surfactants. Suitable surfactants include, by way of example and without limitation, polysorbates, lauryl sulfates, acetylated monoglycerides, diacetylated monoglycerides, and poloxamers.

[053] The suspension may comprise one or more tonicity adjusting agents. Suitable tonicity adjusting agents include, by way of example and without limitation, one or more inorganic salts, electrolytes, sodium chloride, potassium chloride, sodium phosphate, potassium phosphate, sodium phosphate, potassium sulfates, sodium bicarbonates, sodium and potassium and alkaline earth metal salts, such as inorganic alkaline earth metal salts, for example, calcium salts and magnesium salts, mannitol, dextrose, glycerin, propylene glycol, and mixtures thereof.

[054] In a modality especially suitable for intraperitoneal (IP) administration, the suspension can be formulated to be hyperosmolar (hypertonic), hypoosmolar (hypotonic) or isosmolar (isotonic), with respect to the fluids of the IP cavity. In some embodiments, the suspension may be isotonic with respect to the fluid in the IP cavity. In such an embodiment, the osmolality of the suspension may range from about 200 to about 380, about 240 to about 340, about 280 to about 300, or about 290 mOsm/kg.

[055] The suspension may comprise one or more buffering agents. Suitable buffering agents include, by way of example and without limitation, dibasic sodium phosphate, monobasic sodium phosphate, citric acid, hydrochloric acid, sodium citrate, sodium hydroxide, tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)iminotris - (hydroxymethyl)methane, and sodium hydrogen carbonate and others known to technicians specialized in the subject. Buffers are generally used to adjust pH to a desirable range for intraperitoneal use. Typically, a pH of about 5 to 9, 5 to 8, 6 to 7.4, 6.5 to 7.5, or 6.9 to 7.4 is desired.

[056] The suspension may comprise one or more demulcents. A demulcent is an agent that forms a soothing film on a mucous membrane, such as the membranes lining the peritoneum and surrounding organs. A demulcent can relieve minor pain and inflammation, and is sometimes referred to as a mucoprotective agent. Suitable demulcents include cellulose derivatives ranging from about 0.2 to about 2.5%, such as sodium carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, and methylcellulose; gelatin at about 0.01%; polyols at about 0.05 to about 1%, also including about 0.05 to about 1%, such as glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, and propylene glycol; polyvinyl alcohol from about 0.1 to about 4%; povidone from about 0.1 to about 2%; and dextran 70 from about 0.1% when used with another polymeric demulcent described herein.

[057] The suspension may comprise one or more alkalizing agents to adjust the pH. As used herein, the term "alkalizing agent" is intended to mean a compound used to provide an alkaline medium. Such compounds include, by way of example and without limitation, ammonia solution, ammonium carbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium hydroxide and others known to those skilled in the art.

[058] The suspension may comprise one or more acidifying agents to adjust the pH. As used herein, the term "acidifying agent" is intended to mean a compound used to provide an acidic medium. Such compounds include, by way of example and without limitation, acetic acid, amino acid, citric acid, nitric acid, fumaric acid and other alpha-hydroxy acids, hydrochloric acid, ascorbic acid, and nitric acid and others known to those skilled in the art.

[059] The suspension may comprise one or more anti-foam agents. As used herein, the term "antifoam agent" is intended to mean a compound or compounds that prevent or reduce the amount of foam forming on the surface of the filler composition. Suitable anti-foaming agents include, by way of example and without limitation, dimethicone, SIMETHICONE®, octoxynol and others known to those skilled in the art.

[060] The suspension may comprise one or more viscosity modifiers that increase or decrease the viscosity of the suspension. Suitable viscosity modifiers include methylcellulose, hydroxypropyl methylcellulose, mannitol and polyvinylpyrrolidone.

[061] The suspension may comprise one or more osmotic agents, such as those used for peritoneal dialysis. Suitable osmotic agents include icodextrin (a polymer of glucose), sodium chloride, potassium chloride, and salts that are also used as buffering agents.

[062] As used herein, “pharmaceutically acceptable salts” of taxanes are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable risk/benefit ratio, and effective for their intended use, as well as zwitterionic forms, where possible, of taxanes. The term “salts” refers to the relatively non-toxic organic and inorganic acid addition salts of taxanes. Representative salts include the salts hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate, and the like. These may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. (See, for example, Berge S.M. et al., “Pharmaceutical Salts”, J. Pharm Sci., 1977; 66:1-19 which is incorporated herein by reference).

[063] In one embodiment, the composition comprises a dosage form of taxane in suspension (that is: with a pharmaceutically acceptable carrier and any other components), in a dosage considered appropriate by the attending physician for an intended use. Any suitable dosage form may be used; In various non-limiting embodiments, the dosage form is suitable for providing about 0.01 mg/kg to about 50 mg/kg of body weight per day. In various further embodiments, the dosage form is suitable for providing about 0.01 mg/kg to about 45 mg/kg, about 0.01 mg/kg to about 40 mg/kg, about 0.01 mg/kg to about 35 mg/kg, about 0.01 mg/kg to about 30 mg/kg, about 0.01 mg/kg to about 25 mg/kg, about 0.01 mg/kg kg to about 20 mg/kg, about 0.01 mg/kg to about 15 mg/kg, about 0.01 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 5 mg/kg, or about 0.01 mg/kg to about 1 mg/kg of body weight per day. The suspension may be administered as is, or may be diluted with a diluent, for example, with saline water for injection, optionally including a buffering agent and one or more other excipients, prior to administration. For example, the volume ratio of suspension to diluent may be in the range of 1:1 to 1:100 (v/v) or another suitable ratio.

[064] In another aspect, the invention provides methods for treating a tumor, comprising administering to a subject with a tumor a tumor-effective amount of the composition or suspension of any modality or a combination of modalities of the invention. The inventors have unexpectedly been able to produce compositions comprising the recited taxane particles having an average apparent density between about 0.050 g/cm3 and about 0.15 g/cm3, and/or a specific surface area (SSA) of at least minus 18 m2/g, an SSA using new methods to produce particles as described herein. Each of the increased specific surface area and decreased bulk density results in a significant increase in the dissolution rate for the taxane particles of the invention compared to the unprocessed or raw material, and the milled taxane product used for comparison. This provides a significant improvement for the use of the taxane particles of the invention, for example, in the treatment of tumors.

[065] As used herein, a “tumor” includes benign tumors, pre-malignant tumors, malignant tumors that have not metastasized, and malignant tumors that have metastasized.

[066] The methods of the invention can be used to treat tumor that is susceptible to treatment with taxanes, including, but not limited to breast tumors, ovarian tumors, lung tumors, bladder tumors, prostate tumors, bone tumors , stomach tumors and pancreatic tumors. In a non-limiting embodiment, the tumor is located in whole or in part in the intraperitoneal cavity.

[067] The subject can be any suitable subject with a tumor, including, but not limited to humans, primates, dogs, cats, horses, cattle, etc.

[068] As used herein, “treat” or “treatment” means to accomplish one or more of the following: (a) reduce the severity of the disorder; (b) limit or prevent the development of symptoms characteristic of the disorders being treated; (c) inhibit the worsening of symptoms characteristic of the disorders to be treated; (d) limit or prevent recurrence of the disorders in patients who have previously had the disorders; and (e) limit or prevent recurrence of symptoms in patients who were previously symptomatic for the disorders.

[069] Effective amounts for such uses depend on factors including, but not limited to, the nature of the taxane (specific activity, etc.), the route of administration, the state and severity of the disorder, the weight and general health of the patient. subject, and the judgment of the prescribed doctor. It will be understood that the amount of the suspension composition of the invention actually administered will be determined by a physician in light of the above relevant circumstances. In a non-limiting embodiment, an effective amount is an amount that provides between 0.01 mg/kg to about 50 mg/kg of body weight per day.

[070] The compositions can be administered via any suitable route, including, but not limited to, oral, pulmonary, intraperitoneal, subcutaneous injection, intramuscular injection, or any other form of injection, as deemed most appropriate, through personal medical care. , in light of all factors for a given subject. In one embodiment, the composition or suspension is administered intraperitoneally, for example, when the tumor is located (at least in part) in the peritoneal cavity. In this embodiment, the composition or suspension can be administered, for example, by infusion or as a bolus into the peritoneal cavity. In a further embodiment, administration may be initiated after removal of ascites fluid from the peritoneal cavity.

[071] A dosage period is that period of time during which a dose of taxane particles in the composition or suspension is administered. The period of administration may be a single period of time during which the entire dose is administered, or may be divided into two or more periods of time during each of which a portion of the dose is administered.

[072] A post-dosing period is that period of time that begins after the completion of a previous dosing period, and ends after the beginning of a subsequent dosing period. The length of the post-dosing period may vary depending on a subject's clinical response to paclitaxel. The suspension is not administered during the post-dosing period. A post-dosing period may last at least 7 days, at least 14 days, at least 21 days, at least 28 days, at least 35 days, at least 60 days, or at least 90 days or longer. The post-dosing period can be kept constant for a subject, or two or more different post-dosing periods can be used for a subject.

[073] A dosing cycle comprises a dosing period and a post-dosing period. Therefore, the duration of a dosing cycle will be the sum of the dosing period and the post-dosing period. The dosage cycle may be kept constant for a subject or two or more different dosage cycles may be used for a subject.

[074] In one embodiment, the administration is carried out more than once, and in which each administration is separated in time by at least 21 days.

[075] In another aspect, the invention provides methods for manufacturing composite particles, comprising: (a) introducing (i) a solution comprising at least one solvent and at least one solute comprising a compound of interest into an inlet of the nozzle, and (ii) a compressed fluid to an inlet of a container defining a pressurizable chamber; (b) passing the solution from a nozzle orifice and into the pressurizable chamber to produce an outflow of atomized droplets, wherein the nozzle orifice is between 2 mm and 20 mm from a source of sonic energy located within the exit stream, wherein the sonic energy source produces sonic energy with an amplitude between 10% and 100% of the total energy that can be generated using the sonic energy source during the passage, and wherein the nozzle orifice has a diameter of between 20 μm and 125 μm; (c) contacting the atomized droplets with the compressed fluid to cause depletion of the solvent from the atomized droplets to produce the compound particles; wherein steps (a), (b), and (c) are carried out under supercritical temperature and pressure conditions for the compressed fluid.

[076] The methods of the invention involve contacting a solution, including a solvent, with at least one compound of interest (including, but not limited to, an active pharmaceutical ingredient, such as taxane) dispersed in the solvent, with a compressed fluid under supercritical conditions for the compressed fluid, so as to cause the compressed fluid to exhaust the solvent and precipitate the compound as extremely small particles.

[077] The methods of the present invention provide a significant improvement over methods such as those described in US Patent Nos. 5,833,891; 5,874,029; 6,113,795; and 8,778,181 (incorporated herein by reference in their entirety) using a compressed fluid in combination with appropriate solvents to reproductively precipitate the compounds as fine particles having a narrow size distribution. The methods of the present invention are capable of producing the particles of the invention with significantly improved bulk density, SSA and dissolution properties and, thus, significantly improved therapeutic benefits. The methods provide this significant improvement, at least in part, through the use of the sonic energy source external to the nozzle and the cited distance from the nozzle orifice to provide significantly increased sonic energy and improved disruption of the solvent-solute stream as it exits. of the nozzle compared to the methods described in US Patent Nos. 5,833,891 and 5,874,029 which use a convergent divergent nozzle to create sonic energy.

[078] In one embodiment, the methods further comprise: (d) contacting the atomized droplets produced in step (c) with an antisolvent to cause further depletion of the solvent from the compound particles, wherein step (d) is carried out under supercritical temperature and pressure for the antisolvent.

[079] The methods of the invention use a sonic energy source located directly in the outlet stream of the solute dissolved in the solvent. Any suitable source of sonic energy may be utilized that is compatible with the methods of the invention, including, but not limited to, a sonic horn, a sonic probe, or a sonic plate. In various embodiments, the nozzle orifice is located between about 2 mm and about 20 mm, about 2 mm and about 18 mm, about 2 mm and about 16 mm, about 2 mm and about 14 mm. , about 2mm and about 12mm, about 2mm and about 10mm, about 2mm and about 8mm, about 2mm and about 6mm, about 2mm and about 4mm , about 4mm and about 20mm, about 4mm and about 18mm, about 4mm and about 16mm, about 4mm and about 14mm, about 4mm and about 12mm , about 4mm and about 10mm, about 4mm and about 8mm, about 4mm and about 6mm, about 6mm and about 20mm, about 6mm and about 18mm , about 6mm and about 16mm, about 6mm and about 14mm, about 6mm and about 12mm, about 6mm and about 10mm, about 6mm and about 8mm , about 8mm and about 20mm, about 8mm and about 18mm, about 8mm and about 16mm, about 8mm and about 14mm, about 8mm and about 12mm , about 8mm and about 10mm, about 10mm and about 20mm, about 10mm and about 18mm, about 10mm and about 16mm, about 10mm and about 14mm , about 10mm and about 12mm, about 12mm and about 20mm, about 12mm and about 18mm, about 12mm and about 16mm, about 12mm and about 14mm , about 14mm and about 20mm, about 14mm and about 18mm, about 14mm and about 16mm, about 16mm and about 20mm, about 16mm and about 18mm , and about 18 mm and about 20 mm, from the sonic energy source.

[080] According to other embodiments, with reference to the Figures, as shown in Figure 3, the nozzle assembly 100 includes a container 102 that defines a pressurizable chamber 104. The container 102 includes a distal end 106 and a proximal end 108. The nozzle assembly 100 further includes an inlet 110 of the pressurizable chamber 104 at the proximal end 108 of the container 102. The nozzle assembly 100 further includes a nozzle 112 positioned within the pressurizable chamber 104. As shown in Figure 3, the nozzle 112 includes an inlet tube 114 in fluid communication with the inlet 110 of the pressurizable chamber 104. Additionally, the nozzle 112 includes an outlet opening 116. Furthermore, as shown in Figure 3, the nozzle 112 is adjustable to change a distance 118 between the proximal end 108 of the container 102 and the outlet 116 of the nozzle opening 112. As shown in Figure 3, the nozzle 112 is further adjustable to change an angle 120 between a longitudinal axis of the container 122 and a longitudinal axis of the nozzle 124. In addition Furthermore, the nozzle assembly 100 includes an outlet 126 from the pressurizable chamber 104 at the distal end 106 of the container 102.

[081] The nozzle assembly 100 may further include a first reservoir 128 and a second reservoir 130. The first reservoir 128 may include a solvent supply, while the second reservoir 130 may include an antisolvent supply. The inlet 110 of the pressurizable chamber 104 may be in fluid communication with the first reservoir 128, and a second inlet 132 of the pressurizable chamber 104 may be in fluid communication with the second reservoir 130. In one example, the first reservoir 128 is in fluid communication with the inlet tube 114 of the nozzle 112, such that the solvent enters the pressurizable chamber 104 through the nozzle 112. Other examples are also possible.

[082] The outlet opening 116 of the nozzle 112 may include a plurality of grooves to create a vortex within the nozzle 112 such that the solvent exits the nozzle 112 through turbulent flow. In another example, the nozzle 112 may include a porous frit interior for the nozzle 112 such that the solvent exits the nozzle 112 through turbulent flow. In yet another example, the outlet opening 116 of the nozzle 112 may have a small diameter (as discussed in further detail below) so that the solvent exits the nozzle 112 through turbulent flow. These various embodiments that cause turbulent flow may assist in mixing the solvent with the antisolvent within the pressurizable chamber 104. Furthermore, the inlet tube 114 of the nozzle 112 may have an interior diameter with a range of about 1.5875 mm. at about 6.35 mm.

[083] In one example, both the angle of the nozzle 112 and the vertical position of the nozzle 112 can be manually adjusted by a user. For example, the nozzle 112 can be positioned on a vertical support that can be adjusted to change the distance 118 between the proximal end 108 of the container 102 and the exit opening 116 of the nozzle 112. Additionally, the nozzle 112 can be rotated manually to adjust the angle 120 between the longitudinal axis of the container 122 and the longitudinal axis of the nozzle 124.

[084] In another example, the nozzle assembly 100 may include a motor coupled to the nozzle 112. In various examples, the motor may be configured to change the distance 118 between the proximal end 108 of the container 102 and the outlet opening 116 of the nozzle 112 and/or change the angle 120 between the longitudinal axis of the container 122 and the longitudinal axis of the nozzle 124. Such a motor may be an electric motor powered by electrical energy, or may be powered by a number of different energy sources, such as a gas-based fuel or solar energy. The motor may be coupled directly or indirectly to the nozzle 112, such that when the motor is turned on the distance 118 between the proximal end 108 of the container 102 and the outlet opening 116 of the nozzle 112 increases or decreases depending on the direction in which the engine rotates. The motor may be coupled to a series of gears that adjust the distance 118 between the proximal end 108 of the container 102 and the outlet opening 116 of the nozzle 112, and/or adjust the angle 120 between the longitudinal axis of the container 122 and the axis longitudinal axis of the nozzle 124, or the motor may be coupled to a pulley system that adjusts the distance 118 between the proximal end 108 of the container 102 and the outlet opening 116 of the nozzle 112, and/or adjusts the angle 120 between the longitudinal axis of the container 122 and the longitudinal axis of the nozzle 124. Other configurations are also possible.

[085] In another example, the nozzle assembly 112 may include an actuator coupled with the nozzle 112, when the actuator changes the distance 118 between the proximal end 108 of the container 120 and the outlet opening 116 of the nozzle 112, and/or changes the angle 120 between the longitudinal axis of the container 122 and the longitudinal axis of the nozzle 124. Such an actuator may be an electromechanical actuator, which includes an electric motor, which converts a rotational movement of the electric motor to a linear displacement by means of a connection system. Other potential actuators are also possible, such as hydraulic actuators, pneumatic actuators, piezoelectric actuators, linear motors or telescopic linear actuators, as examples.

[086] In one example, as shown in Figures 3 and 4, the mounting nozzle further includes a sonic energy source 134 positioned adjacent to the exit opening 116 of the nozzle 112. In one example, the sonic energy source 134 may include a sonic probe that extends into the pressurizable chamber 104. In another example, the sonic energy source 134 may include a sonic surface positioned in the pressurizable chamber 104. Sound waves from the sonic energy source 134 carry the liquids in the pressurizable chamber 104 to break down, thereby increasing the mixing of the solvent and antisolvent solutions to create particles within the pressurizable chamber 104. In one example, the sonic energy source 134 is positioned at a 45 degree angle to the longitudinal axis of nozzle 124. Other angles are also possible. In one example, the sonic energy source 134 may be adjustable to change a distance between the exit opening 116 of the nozzle 112 and the sonic energy source 134. Additionally, the sonic energy source 134 may be adjustable to change an angle between the sonic energy source 134 and the longitudinal axis of the nozzle 124.

[087] Any suitable source of sonic energy can be used that is compatible with the methods of the invention, including, but not limited to, a sonic horn, a sonic probe, or a sonic plate. In various other embodiments, the sonic energy source produces sonic energy with an amplitude between about 1% and about 100% of the total energy that can be generated using the sonic energy source. In light of the precepts explained here, any person skilled in the art can determine a suitable source of sonic energy having a specific total output power to be used. In one embodiment, the sonic energy source has a total power of between about 500 and about 900 watts; in various other embodiments, between about 600 and about 800 watts, about 650-750 watts, or about 700 watts.

[088] In various other embodiments, the sonic energy source produces sonic energy with a power output between about 5% and about 100%, about 10% and about 100%, 20% and about 100%, about 30% and about 100%, about 40% and about 100%, about 50% and about 100%, about 60% and about 100%, about 70% and about 100%, about 80% and about 100%, about 90% and about 100%, about 1% and about 90%, about 5% and about 90%, about 10% and about 90%, about 20% and about 90%, about 30% and about 90%, about 40% and about 90%, about 50% and about 90%, about 60% and about 90%, about 70% and about 90%, about 80% and about 90%, about 1% and about 80%, about 5% and about 80%, about 10% and about 80%, about 20% and about 80%, about 30% and about 80%, about 40% and about 80%, about 50% and about 80%, about 60% and about 80%, about 70% and about 80%, about 1% and about 70%, about 5% and about 70%, about 10% and about 70%, about 20% and about 70%, about 30% and about 70%, about 40% and about 70%, about 50% and about 70%, about 60% and about 70%, about 1% and about 60%, about 5% and about 60%, about 10% and about 60%, about 20% and about 60%, about 30% and about 60%, about 40% and about 60%, about 50% and about 60%, about 1% and about 50%, about 5% and about 50%, about 10% and about 50%, about 20% and about 50%, about 30% and about 50%, about 40% and about 50%, about 1% and about 40%, about 5% and about 40%, about 10% and about 40%, about 20% and about 40%, about 30% and about 40%, about 1% and about 30%, about 5% and about 30%, about 10% and about 30%, about 20% and about 30%, about 1% and about 20%, about 5% and about 20%, about 10% and about 20%, about 1%, 5%, 10% , 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 100% of the total energy that can be generated using the sonic energy source. In various embodiments, the sonic energy source produces sonic energy with a power of about 1% to 80%, 20 to 80%, 30 to 70%, 40 to 60%, or about 60% of the total energy that can be be generated using sonic energy source. In light of the teachings described herein, a person skilled in the art can determine an appropriate frequency to be used in the sonic energy source. In one embodiment, a frequency of between about 18 and about 22 kHz in the sonic energy source is used. In various other embodiments, a frequency of between about 19 and about 21 kHz, about 19.5 and about 20.5, or, a frequency of about 20 kHz in the sonic energy source is used.

[089] In various additional embodiments, the nozzle orifice has a diameter of about 20 μm and about 125 μm, about 20 μm and about 115 μm, about 20 μm and about 100 μm, about 20 μm and about 90 μm, about 20 μm and about 80 μm, about 20 μm and about 70 μm, about 20 μm and about 60 μm, about 20 μm and about 50 μm, about 20 μm and about 40 μm, about 20 μm and about 30 μm, between about 30 μm and about 125 μm, about 30 μm and about 115 μm, about 30 μm and about 100 μm, about 30 µm and about 90 µm, about 30 µm and about 80 µm, about 30 µm and about 70 µm, about 30 µm and about 60 µm, about 30 µm and about 50 µm, about 30 µm and about 40 µm, between about 40 µm and about 125 µm, about 40 µm and about 115 µm, about 40 µm and about 100 µm, about 40 µm and about 90 µm, about 40 μm and about 80 μm, about 40 μm and about 70 μm, about 40 μm and about 60 μm, about 40 μm and about 50 μm, between about 50 μm and about 125 μm, about of 50 μm and about 115 μm, about 50 μm and about 100 μm, about 50 μm and about 90 μm, about 50 μm and about 80 μm, about 50 μm and about 70 μm, about from 50 μm to about 60 μm, from about 60 μm to about 125 μm, from about 60 μm to about 115 μm, from about 60 μm to about 100 μm, from about 60 μm to about 90 μm, about 60 μm and about 80 μm, about 60 μm and about 70 μm, between about 70 μm and about 125 μm, about 70 μm and about 115 μm, about 70 μm and about 100 μm , about 70 μm and about 90 μm, about 70 μm and about 80 μm, between about 80 μm and about 125 μm, about 80 μm and about 115 μm, about 80 μm and about 100 µm, about 80 µm and about 90 µm, between about 90 µm and about 125 µm, about 90 µm and about 115 µm, about 90 µm and about 100 µm, between about 100 µm and about from 125 μm, about 100 μm and about 115 μm, between about 115 μm and about 125 μm, about 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm , 100 μm, 115 μm, or about 120 μm. The nozzle is inert to both the solvent and the compressed fluid used in the methods.

[090] In further examples, the system may include a plurality of nozzles, wherein each nozzle is positioned at a different angle between a longitudinal axis of the container and a longitudinal axis of the nozzle and/or a different distance between the nozzle orifice and the sonic energy source. A given nozzle from the plurality of nozzles may be chosen for a given production run, when producing a given type of particle having a given SSA.

[091] Any suitable solvent and solute can be used; Examples of such solutes and solvents are disclosed in U.S. Patent Nos. 5,833,891 and 5,874,029. In a non-limiting embodiment, the solute/compound comprises a taxane, including those discussed herein. In various other non-limiting embodiments, the solvent may comprise acetone, ethanol, methanol, dichloromethane, ethyl acetate, chloroform, acetonitrile, and suitable combinations thereof. In one embodiment, the solute/compound is paclitaxel and the solvent is acetone. In another embodiment, the solute/compound is docetaxel and the solvent is ethanol. The solvents should comprise at least about 80%, 85%, or 90% by weight of the total solution.

[092] The compressed fluid is capable of forming a supercritical fluid under the conditions used, and the solute that forms the particles is poorly soluble or insoluble in the compressed fluid. As experts in the field know, a supercritical fluid is any substance at a temperature and pressure above its critical point, where there are no distinct liquid and gaseous phases. Steps (a), (b), and (c) of the methods of the invention are carried out under supercritical temperature and pressure conditions for the compressed fluid, such that the compressed fluid is present as a supercritical fluid during these processing steps. .

[093] The compressed fluid can serve as a solvent for and can be used to remove unwanted components in the particles. Any suitable compressed fluid may be used in the methods of the invention; such exemplary compressed fluids are disclosed in US Patent Nos. 5,833,891 and 5,874,029. In a non-limiting embodiment, compressed fluids and/or suitable supercritical antisolvents forming supercritical fluid may comprise carbon dioxide, ethane, propane, butane, isobutane, nitrous oxide, xenon, sulfur hexafluoride and trifluoromethane. The antisolvent referred to in step (d) for causing depletion of another solvent, is a compressed fluid as defined above, and may be the same compressed fluid used in steps (a-c), or may be different. In one embodiment, the antisolvent used in step (d) is the same as the compressed fluid used in steps (a-c). In a preferred embodiment, the compressed fluid and the antisolvent are both supercritical carbon dioxide.

[094] In all cases, the compressed fluid and antisolvent must be substantially miscible with the solvent while the compound to be precipitated must be substantially insoluble in the compressed fluid, that is, the compound, in which the selected solvent/compressed fluid contacting under the conditions, it should be no more than about 5% by weight soluble in the compressed fluid or antisolvent, and preferably is essentially completely insoluble.

[095] The supercritical conditions used in the methods of the invention are typically in the range from 1X to about 1.4X, or 1X to about 1.2X of the critical temperature of the supercritical fluid, and from 1X to about 7X , or 1X to about 2X, of supercritical pressure for the compressed fluid.

[096] It is well within the level of those skilled in the art to determine the critical temperature and pressure for a given compressed fluid or anti-solvent. In one embodiment, the compressed fluid and antisolvent are both supercritical carbon dioxide, and the critical temperature is at least 31.1°C and up to about 60°C, and the critical pressure is at least 1071 psi and up to about 1800 psi. In another embodiment, the compressed fluid and antisolvent are both supercritical carbon dioxide, and the critical temperature is at least 35°C and up to about 55°C, and the critical pressure is at least 1070 psi and up to about 1500 psi. It will be understood by those skilled in the art that the temperature and specific critical pressure may be different at different stages during processing.

[097] Any suitable pressurizable chamber can be used, including, but not limited to, those disclosed in US Patent Nos. 5,833,891 and 5,874,029. Likewise, the steps of contacting the atomized droplets with the compressed fluid to cause depletion of the solvent from the droplets; and contacting the droplets with an antisolvent to cause further depletion of the solvent from the droplets, to produce particles of the compound may be carried out under any appropriate conditions, including, but not limited to, those disclosed in U.S. Patent Nos. 5,833,891 and 5,874,029.

[098] The flow rate can be adjusted as high as possible to improve output, but below the pressure limits for the equipment, including the nozzle orifice. In one embodiment, the flow rate of the solution through the nozzle has a range of about 0.5 mL/min to about 30 mL/min. In various other embodiments, the flow rate is between about 0.5 mL/min to about 25 mL/min, 0.5 mL/min to about 20 mL/min, 0.5 mL/min to about 15 mL/min, 0.5 mL/min to about 10 mL/min, 0.5 mL/min to about 4 mL/min, about 1 mL/min to about 30 mL/min, about 1 mL/min to about 25 mL/min, about 1 mL/min to about 20 mL/min, 1 mL/min to about 15 mL/min, about 1 mL/min to about 10 mL/min , about 2 mL/min to about 30 mL/min, about 2 mL/min to about 25 mL/min, about 2 mL/min to about 20 mL/min, about 2 mL/min to about from 15 mL/min, or about 2 mL/min to about 10 mL/min. The drug solution subjected to the flow rate can be any suitable concentration, such as between about 1 mg/ml and about 80 mg/ml.

[099] In one embodiment, the methods further comprise receiving the plurality of particles through the outlet of the pressurizable chamber; and collecting a plurality of particles in a collection device.

[0100] In such an embodiment, with reference to the Figures, as shown in Figure 5, the invention comprises a collection device 200 including a container 202 defining a chamber 204. The container 202 includes a distal end 206 and a proximal end 208. outer diameter of container 202 may vary from about 152.4 mm to about 914.4 mm. The collection device 200 further includes an inlet port 210 extending from the proximal end 208 of the container 202. The inlet port 210 is in fluid communication with the chamber 204. The inlet port 210 may have an outer diameter that varies. from about 12.7 mm to about 101.6 mm. Furthermore, the collection device 200 includes an exit port 212 extending from the proximal end 208 of the container 202. As shown in Figures 7 and 8, the exit port 212 is in fluid communication with the chamber 204, and the exit port 212 includes a porous material 214 positioned between the chamber 204 and the exit port 212. The outer diameter of the exit port can vary from about 12.7 mm to about 50.8 mm.

[0101] As shown in Figures 5-9, the collection device 200 may further include a sampling tube 216 that has a distal end 218 and a proximal end 220. The outer diameter of the sampling tube 216 may vary from about 6 .35mm to about 25.4mm. As shown in Figures 7 and 8, the proximal end 220 of the sampling tube 216 extends from the proximal end 208 of the container 202, and the distal end 218 of the sampling tube 216 extends into the chamber 204. The sampling tube 216 extends into the chamber 204. Sampling 216 may be configured to remove a small sample of particles from chamber 204 during a particle production cycle in which additional particles are being formed. In particular, the sampling tube 216 may include a sample thief that allows an operator to remove a small particle sample without opening the chamber 204 or removing the sampling tube 216 from the rest of the collection device 200 during processing. . This allows an operator to test a small sample of particles to ensure the product is within specifications as the process continues to run. For example, particle size or residual solvent analysis can be performed on the sample. If the measured specifications do not match the desired specifications, the operating parameters of the particle formation process can be adjusted appropriately to correct the situation before an entire batch of product with undesirable characteristics is created.

[0102] The porous material 214 positioned between the chamber 204 and the exit port 212 can take a variety of shapes. In one example, the porous material 214 is selected from the group consisting of a porous filter, a mesh, a fabric. As a specific example, the porous material 214 may comprise a high efficiency particulate fraction (HEPA) filter. An example of a HEPA filter may include a mat of randomly arranged fibers, the fibers composed of fiberglass and having diameters between about 0.5 micrometers and about 2.0 micrometers. In another example, the porous material 214 comprises a sintered filter having a distal end 222 and a proximal end 224. In such an example, the proximal end 224 of the sintered filter extends from the proximal end 208 of the container 202 and is coupled to the port outlet 212, and the distal end 222 of the sintered filter extends into the chamber 204. Such a sintered filter may include a porous stainless steel filter cartridge, as an example. Other porous materials are also possible.

[0103] The inlet port 210 may include a coupling mechanism that connects an outlet of a particulate filtration system to the inlet port 210. In one example, the coupling mechanism comprises one or more sanitary fittings. In another example, the coupling mechanism comprises a threaded connection between the outlet of the particle filtration system to the inlet port 210. In yet another example, the coupling mechanism comprises one or more compression fittings. Other exemplary coupling mechanisms are possible as well.

[0104] Furthermore, as shown in Figure 9, the collection device 200 may further include a collection insert 226 positioned within the chamber 204 of the container 202, and a support structure 228 positioned between an interior wall 230 of the chamber 204 and the collection insert 226. The collection insert 226 may be a plastic bag, as an example. As shown in Figure 10, the support structure 228 may include a distal ring 232, a proximal ring 234, one or more support legs 236 connecting the distal ring 232 to the proximal ring 234, and a gasket 238 positioned adjacently. to the proximal ring 234. In one example, the gasket 238 may comprise a neoprene gasket. The container 202 may include a removable lid 240 that may be removed to access the collection insert 226 once particle collection is complete. In one such example, the collection insert 226 may be positioned within the chamber 204 of the container 202 such that the upper edge of the collection insert 226 folds over the top of the support structure 228 and is sealed between the gasket 238 and the removable lid 240 when the lid is in the closed position. Other arrangements are possible as well.

[0105] In a particular exemplary method, a solution of 65 mg/ml of paclitaxel is prepared in acetone. The nozzle and a sonic probe are positioned in the pressurizable chamber approximately 8 millimeters away. A stainless steel mesh filter with approximately 100nm holes is attached to the pressurizable chamber to collect the precipitated paclitaxel nanoparticles. Supercritical carbon dioxide is placed in the pressurizable chamber of the manufacturing equipment and brought to about 1200 psi at about 37°C and a flow rate of 18 kg per hour. The sonic probe is adjusted to an amplitude of 60% of maximum power with a frequency of 20 kHz. The acetone solution containing the paclitaxel is pumped through the nozzle at a flow rate of 2 mL/minute for approximately 60 minutes. The precipitated paclitaxel clumps and particles are then collected from the supercritical carbon dioxide as the mixture is pumped through the stainless steel mesh filter. The filter containing the paclitaxel nanoparticles is opened, and the resulting product is collected from the filter.

[0106] In a particular exemplary method, a solution of 79.32 mg/ml of docetaxel is prepared in ethanol. The nozzle and a sonic probe are positioned in the pressurizable chamber about 9 millimeters apart. A stainless steel mesh filter with approximately 100nm holes is attached to the pressurizable chamber to collect the precipitated docetaxel nanoparticles. Supercritical carbon dioxide is placed in the pressurizable chamber of the manufacturing equipment and brought to about 1200 psi at about 38°C, and a flow rate of 63 slpm (standard liters per minute). The sonic probe is adjusted to 60% of the total output power at a frequency of 20 kHz. The ethanol solution containing docetaxel is pumped through the nozzle at a flow rate of 2 mL/minute for approximately 95 minutes, until the drug solution is consumed. The precipitated docetaxel clumps and particles are then collected from the supercritical carbon dioxide as the mixture is pumped through the stainless steel mesh filter. The filter containing the docetaxel nanoparticles is opened, and the resulting product is collected from the filter.

[0107] Furthermore, the system described above can be a component of a larger particle production system. Such a particle production system may include one or more sets of nozzles such as those described above, a sonic energy source positioned adjacent the orifice of each nozzle, one or more particle filtration systems in communication with one or more nozzle assemblies, and one or more particle collection devices in communication with the one or more particle filtration systems. In one example, the one or more particulate filtration systems comprises a tandem particulate filtration system including at least one high pressure collection filter system and at least one tandem low pressure collection filter system. and downstream to the collection filter. In such an example, the particle production system may include at least two particle collection filters, two particle collection filters, and two collection devices.

[0108] In another aspect, the invention provides particles of a compound prepared by the method of any embodiment or a combination of embodiments of the invention.

Examples Materials and methods

[0109] Raw paclitaxel and docetaxel were purchased from Phyton Biotech (British Columbia, Canada), lot numbers FP2-15004 and DT7-14025, respectively. Both were characterized in their raw form. Grinding of both drugs was carried out using a Deco-PBM-V-0.41 mill (Deco). The grinding conditions for both compounds were as follows: Ball size = 5 mm RPM = 600 Processing time = 60 min Room temperature.

Preparation of paclitaxel particles

[0110] A solution of 65 mg/ml of paclitaxel was prepared in acetone. A BETE MicroWhirl® mirror nozzle (BETE Fog Nozzle, Inc) and sonic probe (Qsonica, model number Q700) were positioned in the approximately 8 mm crystallization chamber. A stainless steel mesh filter with approximately 100 nm holes was attached to the crystallization chamber to collect the precipitated paclitaxel nanoparticles. Supercritical carbon dioxide was placed in the crystallization chamber of the manufacturing equipment and brought to approximately 1200 psi at about 38°C and a flow rate of 24 kg/hour. The sonic probe was set to 60% of the total output power at a frequency of 20 kHz. The acetone solution containing paclitaxel was pumped through the nozzle at a flow rate of 4.5 mL/minute for approximately 36 hours. The paclitaxel nanoparticles produced had a mean number-weighted average size of 0.81 μm with an average standard deviation of 0.74 μm over three separate runs. Preparation of docetaxel particles

[0111] A solution of 79.32 mg/ml of docetaxel was prepared in ethanol. The nozzle and a sonic probe were positioned in the pressurizable chamber approximately 9 mm (apart). A stainless steel mesh filter with approximately 100 nm holes was attached to the pressurizable chamber to collect the precipitated docetaxel nanoparticles. Supercritical carbon dioxide was placed in the pressurizable chamber of the manufacturing equipment and brought to approximately 1200 psi at about 38°C, and a flow rate of 68 slpm. The sonic probe was set to 60% of the total output power at a frequency of 20 kHz. The ethanol solution containing docetaxel was pumped through the nozzle at a flow rate of 2 ml/minutes for approximately 95 minutes. The precipitated docetaxel clumps and particles were then collected from the supercritical carbon dioxide as the mixture is pumped through the stainless steel mesh filter. The filter containing the docetaxel nanoparticles was opened, and the resulting product was collected from the filter.

[0112] The docetaxel nanoparticles produced had an average weighted average size of 0.82 μm with an average standard deviation of 0.66 μm over three separate ethanol runs.

Particle Size Analysis

[0113] Particle size was analyzed by both light obscuration and laser diffraction methods. A Particle Sizing Systems AccuSizer 780 SIS system was used for the light obscuration method and Shimadzu SALD- 7101 was used for the laser diffraction method. Paclitaxel nanoparticles were analyzed using 0.10% (w/v) sodium dodecyl sulfate (SDS) in water as a dispersant. Docetaxel nanoparticles were analyzed using Isopar G as the dispersant.

[0114] Paclitaxel suspensions were prepared by adding approximately 7 mL of filtered dispersant to a glass vial containing approximately 4 mg of paclitaxel particles. The vials were shaken for approximately 10 seconds and then sonicated in a sonic bath for approximately 1 minute. If the sample was already suspended, a 1:1 solution of paclitaxel suspension to 0.1% SDS solution was made, vortexed for 10 seconds, and sonicated in the sonic bath for 1 minute.

[0115] Docetaxel suspensions were prepared by adding approximately 7 mL of filtered dispersant to a plastic bottle containing approximately 4 mg of docetaxel particles. The vials were vortexed for approximately 10 seconds and then sonicated in a sonic bath for approximately 2 minutes. This suspension was used for laser diffraction analysis. The unused suspension was poured into a 125 ml particle-free plastic bottle, which was then filled to approximately 100 ml with filtered dispersant. The suspension was vortexed for approximately 10 seconds and then sonicated in the sonic bath for approximately 2 minutes. This diluted suspension was used for light obscuration analysis.

[0116] A background test was first performed before analyzing the particles on the AccuSizer 780 SIS. A new particle-free plastic container was filled with the blank suspension solution by pumping from a reservoir, through a peristaltic pump, through a 0.22 μm Millipore filter and into the container. A background analysis was performed to ensure the particle count/mL was below 100 particles/mL. A small amount of paclitaxel suspension, 5-100 μL depending on the concentration of the solution, was pipetted into the plastic container at the bottom test site, and was filled with ~100 mL of dispersant and analysis was started. Counts were monitored, and paclitaxel solution added to achieve and/or maintain 6000-8000 particle counts/mL throughout the analysis. Once the analysis was completed, background data was removed and any measurements with fewer than four counts were removed.

[0117] To analyze the particles in SALD-7101 using a batch cell, the analysis was initiated by choosing Manual Measurement. The refractive index was defined as 1.5 to 1.7. The batch cell was filled with filtered dispersant just after the recorded line. Blank measurement was performed. A small amount of API suspension (paclitaxel or docetaxel) was pipetted, generally < 1 mL, depending on solution concentration as low as 100 μL, into the batch cell as needed to obtain an acceptable absorbance between 0.15 and 0 .2 absorbance units. The measurements were performed, and the resulting graph with the highest level of confidence was selected; the fund was automatically accounted for.

BET Analysis

[0118] A known mass of between 200 and 300 mg of the analyte was added to a 30 mL sample tube. The loaded tube was then mounted on a Porous Materials Inc. SORPTOMETER®, model BET-202A. Automated testing was then performed using the BETWIN® software package and the surface area of each sample was subsequently calculated.

Bulk density analyte

[0119] The paclitaxel or docetaxel particle preparations were added to a 10 mL tared graduated cylinder through a plastic weighing funnel at room temperature. The mass of the drug was measured to the nearest 0.1 mg, the volume was determined to the nearest 0.1 ml, and the density calculated.

Dissolution studies Paclitaxel

[0120] Approximately 50 mg of material (i.e.: crude paclitaxel, ground paclitaxel, or paclitaxel particles) was coated onto approximately 1.5 grams of 1 mm glass beads by dropping the material and beads into a vial during approximately 1 hour. The granules were transferred to a stainless steel mesh container, and placed in the dissolution bath containing a 50/50 (v/v) methanol/water medium at 37°C, pH 7, and a USP II apparatus (Paddle), operating at 75 rpm. At 10, 20, 30, 60, and 90 minutes, a 5 ml aliquot was removed, filtered through a 0.22 μm filter, and analyzed on a U(V/V) spectrophotometer at 227 nm. The absorbance values of the samples were compared with those of standard solutions prepared in the dissolution medium to determine the amount of dissolved material.

Docetaxel

[0121] Approximately 50 mg of material (i.e., crude docetaxel, ground docetaxel or docetaxel particles) was placed directly into the dissolution bath containing 15/85 (v/v) methanol/water medium at 37°C, pH 7 and a USP II Device (Paddle), operating at 75 RPM. At 5, 15, 30, 60, 120, and 225 minutes, a 5 mL aliquot was removed, filtered through a 0.22 μm filter, and analyzed on a UV/VIS spectrophotometer at 232 nm. The absorbance values of the samples were compared with those of standard solutions prepared in dissolution media to determine the amount of dissolved material.

Results

[0122] The BET surface area of particles produced using the above protocol and variations thereof (i.e.: modification nozzles, filters, sonic energy sources, flow rates, etc.) ranged between 22 and 39 m2/g. Figure 1 shows exemplary particles produced using the methods of the invention. By comparison, the BET surface area of raw paclitaxel was measured at 7.25 m2/g (Figure 2), while paclitaxel particles made according to the methods of US Patents 5,833,891 and 5,874,029 varied 11 .3 to 15.58 m2/g. Examples of particle sizes produced using the methods of the invention are shown in Table 1.

[0123] Comparative studies on bulk density, SSA and dissolution rates (performed as noted above) for crude drug, ground drug particles and drug particles produced by the methods of the present invention are provided in Tables 2 and 3 below. The total dissolution time course for paclitaxel and docetaxel materials is provided in Tables 4 and 5, respectively.

Claims (32)

1. Composition characterized by the fact that it comprises particles including a minimum of 95% by weight of a taxane, or a pharmaceutically acceptable salt thereof, wherein the particles have a minimum specific surface area (SSA) of 18 m2/g. 2. Composition according to claim 1, characterized by the fact that the taxane is selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, or a pharmaceutically acceptable salt thereof. 3. Composition according to claim 2, characterized by the fact that the taxane is paclitaxel, or a pharmaceutically acceptable salt thereof. 4. Composition according to claim 3, characterized by the fact that the paclitaxel particles have an average apparent density between 0.050 g/cm3 and 0.12 g/cm3. 5. Composition, according to claim 3, characterized by the fact that the paclitaxel particles have a minimum specific surface area (SSA) of 20 m2/g. 6. Composition according to claim 3, characterized by the fact that the paclitaxel particles have an SSA between 18 m2/g and 40 m2/g. 7. Composition according to claim 3, characterized by the fact that the paclitaxel particles have an SSA of between 20 m2/g and 40 m2/g. 8. Composition according to claim 2, characterized by the fact that the taxane is docetaxel or a pharmaceutically acceptable salt thereof. 9. Composition according to claim 8, characterized by the fact that the docetaxel particles have an apparent density of between 0.050 g/cm3 and 0.12 g/cm3. 10. Composition according to claim 8, characterized by the fact that docetaxel particles have a minimum SSA of 20 m2/g. 11. Composition according to claim 8, characterized by the fact that the docetaxel particles have an SSA of between 18 m2/g and 50 m2/g. 12. Composition according to claim 8, characterized by the fact that the docetaxel particles have an SSA of between 20 m2/g and 50 m2/g 13. Composition according to any one of claims 1, 3 and 8, characterized by the fact that the particles have an average particle size between 0.4 μm and 3 μm. 14. Composition according to any one of claims 1, 3 and 8, characterized by the fact that the particles have an average particle size between 0.4 μm and 1.2 μm. 15. Composition according to claim 1, characterized in that it comprises particles including a minimum of 95% by weight of a taxane selected from the group consisting of paclitaxel and docetaxel, or a pharmaceutically acceptable salt thereof, wherein the paclitaxel particles have a specific surface area (SSA) determined by BET analysis of 18 to 40 m2/g, and an average apparent density between 0.050 g/cm3 and 0.12 g/cm3 and docetaxel particles have an SSA determined by BET analysis from 18 to 50 m2/g, and an average apparent density between 0.050 g/cm3 and 0.12 g/cm3; where the average apparent density is the mass of all the particles divided by the total volume they occupy when spilled. 16. Composition according to claim 15, characterized by the fact that the taxane is paclitaxel or a pharmaceutically acceptable salt thereof, and in which the particles have an average apparent density between 0.060 g/cm3 and 0.11 g/cm3 . 17. Composition according to claim 15 or 16, characterized by the fact that the taxane is paclitaxel or a pharmaceutically acceptable salt thereof, and in which the paclitaxel particles have an SSA between 25 m2/g and 40 m2/g, 30 m2/g and 40 m2/g, or between 35 m2/g and 40 m2/g. 18. Composition according to any one of claims 15 to 17, characterized by the fact that a minimum of 40% (w/w) of paclitaxel is dissolved in 30 minutes or less in a 50% methanol/50% solution of water (v/v) at 37 °C and pH 7.0 on a USP II rowing machine operating at 75 RPM. 19. Composition according to claim 15, characterized by the fact that the taxane is docetaxel or a pharmaceutically acceptable salt thereof, and wherein the docetaxel particles have an SSA of 43 m2/g to 46 m2/g, and/ or wherein the docetaxel particles have an average bulk density between 0.06 g/cm3 and 0.1 g/cm3, and/or wherein a minimum of 20% (w/w) of the docetaxel is dissolved within 30 minutes or least in a 15% methanol/85% water (v/v) solution at 37°C and pH 7.0 on a USP II rowing machine operating at 75 RPM. 20. Composition according to any one of claims 15 to 19, characterized by the fact that the particles have an average particle size between 0.4 μm and 1.2 μm, or between 0.6 μm and 1.0 μm . 21. Composition according to any one of claims 15 to 20, characterized by the fact that (i) the particles are not coated and exclude polymers, proteins, polyethoxylated castor oil and polyethylene glycol glycerides composed of mono, di and triglycerides and polyethylene glycol mono- and diesters, and/or (ii) the composition comprises a suspension further comprising a pharmaceutically acceptable aqueous carrier, and/or (iii) the composition comprises one or more components selected from the group consisting of polysorbate, methylcellulose, polyvinylpyrrolidone, mannitol and hydroxypropylmethylcellulose. 22. Composition according to any one of claims 15 to 21, characterized in that the particles comprise a minimum of 98%, 99% or 100% of the compound. 23. Use of a composition as defined in any one of claims 1 to 22 characterized by the fact that it is in the preparation of a medicament for treating a tumor. 24. Use according to claim 23, characterized in that the tumor is selected from the group consisting of breast tumor, ovarian tumor, lung tumor, bladder tumor, prostate tumor, bone tumor, tumor stomach and pancreatic tumor. 25. Method for manufacturing particles including a minimum of 95% by weight of paclitaxel or docetaxel as described in any one of claims 11 to 24, characterized by the fact that it comprises: (a) introducing (i) a solution comprising a minimum of a solvent and a minimum of a solute comprising paclitaxel or docetaxel into an inlet of the nozzle, and (ii) a compressed fluid into an inlet of a container defining a pressurizable chamber; (b) passing the solution from a nozzle orifice and into the pressurizable chamber to produce an outflow of atomized droplets, wherein the nozzle orifice is situated between 4 mm and 20 mm from a power source sonic located within the exit stream, wherein the sonic energy source produces sonic energy with an amplitude between 10% and 60% during passage, and wherein the nozzle orifice has a diameter of between 20 µm and 125 µm; and (c) contacting the atomized droplets with the compressed fluid, to cause depletion of the solvent from the atomized droplets, to produce particles including a minimum of 95% by weight of paclitaxel or docetaxel, wherein steps (a), (b), and (c) are carried out under supercritical temperature and pressure conditions for the compressed fluid. 26. The method of claim 25, further comprising: (d) contacting the particles produced in step (c) with an antisolvent to cause further depletion of the solvent from the paclitaxel or docetaxel particles, wherein step (d) is carried out under supercritical temperature and pressure for the antisolvent. 27. Method according to any one of claims 25 or 26, characterized by the fact that (i) a flow rate of the solution through the nozzle has a range of 0.5 mL/min to 30 mL/min; and/or (ii) the sonic energy source comprises one of a sonic horn, a sonic probe or a sonic plate; and/or (iii) the sonic energy source has a frequency between 18 kHz and 22 kHz, or 20 kHz. 28. Method according to any one of claims 25 to 27, characterized by the fact that it further comprises: (e) receiving the plurality of particles through the outlet of the pressurizable chamber; and (f) collecting the plurality of particles in a collection device. 29. Method according to any one of claims 25 to 28, characterized in that the compressed fluid is supercritical carbon dioxide and/or in which the antisolvent is supercritical carbon dioxide. 30. Method according to any one of claims 25 to 29, characterized in that the compound is paclitaxel and the solvent comprises acetone. 31. Method according to any one of claims 25 to 29, characterized in that the compound is docetaxel and the solvent comprises ethanol. 32. Paclitaxel or docetaxel particles characterized by the fact that they are prepared by the method as defined in any one of claims 25 to 31.