Sorafenib particles and uses thereof

Abstract

A composition comprising at least 95% by weight of particles of sorafenib or a pharmaceutically acceptable salt thereof wherein the particles have a specific surface area of at least 2 m / g and an average particle size in volume distribution of 0.7 [mu] m to 8 [mu] m, comprising: (a) introducing (i) a solution comprising at least one solvent and at least one solute comprising sorafenib into a nozzle inlet, and (ii) introducing a compressed fluid into an inlet of a container defining a pressurizable chamber; (b) discharging the solution from a nozzle orifice and into a pressurizable chamber to produce an output stream of atomized droplets, where the nozzle orifice is located 2 mm to 20 mm from a source of acoustic energy within the output stream, where the source of acoustic energy produces acoustic energy having an amplitude of 10% to 100% during passage, and the nozzle orifice has a diameter of 20 [mu] m to 125 [mu] m, (c) contacting the atomized droplets with a compressed fluid, step (a), (b), and (c) are carried out at a supercritical temperature and pressure of the compressed fluid to deplete the solvent from the atomized droplets to produce compound particles.

Description

[0001] Cross-references

[0002] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 055786, filed on July 23, 2020, and is incorporated herein by reference in its entirety. Background Art

[0003] Dissolution rate is a key parameter that determines the rate and extent of drug absorption and bioavailability. Poor water solubility and poor in vivo solubility are limiting factors for the in vivo bioavailability of many drugs. Therefore, in vitro dissolution rate is considered to be an important factor in drug development, and methods and compositions for increasing the dissolution rate of poorly soluble drugs are needed. Summary of the invention

[0004] In one aspect, the present invention provides a composition comprising particles comprising at least 95% by weight of sorafenib or a pharmaceutically acceptable salt thereof, wherein the particles have at least 2 m 2 / g specific surface area (SSA), and has an average particle size (volume distribution) of about 0.7 μm to about 8 μm. In various embodiments, the particles have at least 5 μm 2 / g or at least 10m 2 In other embodiments, the SSA of the particles is 2 m 2 / g to about 50m 2 / g, about 3m 2 / g to 50m 2 / g, 5m 2 / g to 50m 2 / g, 7m 2 / g to 50m 2 / g or 10m 2 / g to 50m 2 / g. In another embodiment, the particles have an average particle size (volume distribution) of about 1 μm to about 8 μm. In one embodiment, the particles contain at least 96%, 97%, 98%, 99% or 100% sorafenib or a pharmaceutically acceptable salt thereof. In another embodiment, the particles are uncoated and do not include polymers, proteins, polyethoxylated castor oil and polyethylene glycol glycerides, which are composed of monoglycerides, diglycerides and triglycerides and monoesters and diesters of polyethylene glycol. In another embodiment, the composition includes a suspension further comprising a pharmaceutically acceptable liquid carrier. In one embodiment, the composition further comprises one or more components selected from polysorbate, methylcellulose, polyvinyl pyrrolidone, mannitol and hydroxypropyl methylcellulose. In other embodiments, the mean bulk density of the particles is

[0005] (a) About 0.010 g / cm 3 To about 0.200g / cm 3 , about 0.025g / cm 3 To about 0.175g / cm 3 , about 0.050g / cm 3 To about 0.150g / cm 3 , about 0.075g / cm 3 To about 0.125g / cm 3 or about 0.085g / cm 3 About 0.115g / cm 3 , shake solid;

[0006] (b) About 0.010 g / cm 3 To about 0.200g / cm 3 , about 0.020g / cm 3 Up to 0.175g / cm 3 , about 0.040g / cm 3 Up to 0.125g / cm 3 , about 0.050g / cm 3 Up to 0.100g / cm 3 , or about 0.060g / cm 3 Up to 0.090g / cm 3 , not yet vibrated;

[0007] (c) less than about 0.200 g / cm 3 , 0.175g / cm 3 、0.150g / cm 3 or 0.125g / cm 3 , compaction; and / or

[0008] (d) less than about 0.200 g / cm 3 , 0.175g / cm 3 、0.150g / cm 3 or 0.125g / cm 3 , 0.100g / cm 3 or 0.090g / cm 3 , not yet solid.

[0009] In another embodiment, the pharmaceutically acceptable salt of sorafenib comprises sorafenib tosylate.

[0010] In another aspect, the present disclosure provides a method for treating a tumor, comprising administering to a subject with a tumor a composition of any embodiment disclosed herein or a combination of embodiments in an amount effective to treat the tumor. In various embodiments, the tumor is selected from thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, pancreatic tumors, prostate tumors, bladder tumors, lung tumors, and ovarian cancer. In one embodiment, the subject is a human subject. In another embodiment, the composition is administered by intratumoral injection, peritumoral injection, or intraperitoneal injection.

[0011] In another aspect, the present invention provides a method for preparing compound particles, comprising:

[0012] (a) introducing (i) a solution comprising at least one solvent and at least one solute comprising sorafenib or a pharmaceutically acceptable salt thereof into an inlet of a nozzle, and (ii) introducing a compressed fluid into an inlet of a container defining a pressurizable chamber;

[0013] (b) causing the solution to flow out of a nozzle orifice and into the pressurizable chamber to produce an output stream of atomized droplets, wherein the nozzle orifice is located 2 mm to 20 mm from an acoustic energy source located within the output stream, wherein the acoustic energy source generates acoustic energy with an amplitude of between 10% and 100% during the passage, and wherein the nozzle orifice has a diameter of between 20 μm and 125 μm;

[0014] (c) contacting the atomized droplets with a compressed fluid to deplete the solvent from the atomized droplets to produce compound particles comprising at least 95% sorafenib or a pharmaceutically acceptable salt thereof, wherein the particles have a particle size of at least 2 m 2 / g specific surface area (SSA), and having a volume distribution of an average particle size of about 0.7 μm to about 8 μm,

[0015] Steps (a), (b) and (c) are carried out at supercritical temperature and pressure of the compressed fluid.

[0016] In one embodiment, the method further comprises:

[0017] (d) contacting the compound particles produced in step (c) with an anti-solvent to further deplete the solvent from the compound particles, wherein step (d) is performed at a supercritical temperature and pressure of the anti-solvent.

[0018] In one embodiment, the flow rate of the solution through the nozzle ranges from about 0.5 mL / min to about 30 mL / min. In another embodiment, the sonic energy source comprises one of a sonic horn, a sonic probe, or a sonic plate. In another embodiment, the frequency of the sonic energy source is from about 18 kHz to about 22 kHz or about 20 kHz. In one embodiment, the method further comprises:

[0019] (e) receiving the plurality of particles through an outlet of the pressurizable chamber; and

[0020] (f) collecting the plurality of particles in a collection device.

[0021] In another embodiment, the compressed fluid is supercritical carbon dioxide. In another embodiment, the anti-solvent is supercritical carbon dioxide. In various embodiments, the solvent may include, but is not limited to, acetone, ethanol, methanol, or a combination thereof. In one embodiment, the solvent includes acetone. In another embodiment, the method is carried out at 31.1°C to about 60°C and about 1071 psi to about 1800 psi. In another embodiment, the particles have at least 5 m 2 / g, at least 7.5m 2 / g or at least 10m 2 / g of SSA, and / or wherein the particle is a particle in a composition of any embodiment or combination of embodiments of the present disclosure.

[0022] In another embodiment, the present disclosure provides compound particles prepared by the method of any embodiment or combination of embodiments of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 (AD). (A) 1000 times magnification of raw material Sorafenib, (B) 2500 times magnification of raw material Sorafenib, (C) exemplary scanning electron microscope micrograph of Sorafenib particles according to the present invention produced using acetone as solvent; 2500 times magnification, (D) Sorafenib particles according to the present invention produced using acetone as solvent; 10000 times magnification.

[0024] Figure 2 (AD). (AB) Exemplary scanning electron microscope micrographs of Sorafenib particles according to the present invention produced using ethanol as a solvent, (A) 2500 times magnification, (B) 10000 times magnification; or using methanol as a solvent (C) 2500 times magnification, (B) 5000 times magnification.

[0025] Figure 3 . An exemplary X-ray diffraction pattern of the produced Sorafenib according to the present invention compared to the raw material Sorafenib.

[0026] Figure 4 Sorafenib dissolution in 900 mL 0.1N HCl, 1% SDS, 75 rpm, pH = 1, 37 °C

[0027] Figure 5 . Sorafenib was dissolved in 500 mL 50% ethanol water, 50 rpm, pH = 7, 37 ° C DETAILED DESCRIPTION

[0028] All references cited are incorporated herein by reference in their entirety. As used herein, the singular forms "a", "an", and "the" include plural meanings unless the context clearly dictates otherwise. All embodiments of any aspect of the present disclosure may be used in combination unless the context clearly dictates otherwise.

[0029] As used herein, "about" means + / - 5% of the stated value.

[0030] In one aspect, the present invention provides a composition comprising particles comprising at least 95% by weight of sorafenib or a pharmaceutically acceptable salt thereof, wherein the particles have at least 2 m 2 / g of specific surface area (SSA), and having a volume distribution of an average particle size of about 0.7 μm to about 8 μm.

[0031] As used herein, "sorafenib" includes any ionization state of sorafenib, including basic, acidic and neutral states.

[0032] Structure of sorafenib

[0033]

[0034] Sorafenib Chemical name: 4-(4-((((4-chloro-3-(trifluoromethyl)phenyl)amino)carbonyl)amino)phenoxy)-N-methyl-2-pyridinecarboxamide

[0035] "Sorafenib particles" refer to Sorafenib particles that do not contain added excipients. Sorafenib particles are different from "Sorafenib-containing particles", i.e. particles containing Sorafenib and at least one added excipient. The Sorafenib particles of the present disclosure do not include polymers, waxes or protein excipients, and are not embedded, contained, enclosed or encapsulated in solid excipients. However, the Sorafenib particles of the present disclosure may contain impurities and by-products that are typically found in the preparation process of Sorafenib. Even so, the Sorafenib particles contain at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% Sorafenib or a pharmaceutically acceptable salt thereof, which means that the Sorafenib particles are composed of or substantially composed of substantially pure Sorafenib or a pharmaceutically acceptable salt of Sorafenib.

[0036] As used herein, "specific surface area" is the total surface area of ​​the sorafenib particles per unit mass of sorafenib as determined by the Brunauer-Emmett-Teller ("BET") isotherm (i.e., BETSSA). As will be appreciated by those skilled in the art, SSA is determined on a per gram basis and takes into account both agglomerated and non-agglomerated sorafenib particles in the composition. The BET specific surface area test procedure is a pharmacopoeial method in the United States Pharmacopoeia and the European Pharmacopoeia. Sorafenib particles have at least 2 m 2 In various further embodiments, the sorafenib particles have a specific surface area (SSA) of at least 3 m 2 / g5m 2 / g, 6m 2 / g, 7m 2 / g, 8m 2 / g, 9m 2 / g, 10m 2 / g, 11m 2 / g, 12m 2 / g, 13m 2 / g, 15m 2 In another embodiment, the SSA of the sorafenib particles is about 2 m / g or greater. 2 / g to about 50m 2 / g, about 3m 2 / g to about 50m 2 / g, about 5m 2 / g to 50m 2 / g, about 7m 2 / g to 50m 2 / g, or about 10m 2 / g to about 40m 2 / g.

[0037] In various embodiments, the particles have an average bulk density of about 0.010 g / cm 3 To about 0.200g / cm 3 , about 0.025g / cm 3 To about 0.175g / cm 3 , 0.050g / cm 3 To about 0.150g / cm 3 , about 0.075g / cm 3 To about 0.125g / cm 3 , or about 0.085 g / cm 3 About 0.115g / cm 3 As used herein, the tap density of a particle is obtained by mechanically tapping a graduated cylinder containing the sample until little further volume change is observed.

[0038] In other embodiments, the particles have an average bulk density of about 0.010 g / cm 3 To about 0.200g / cm 3 , about 0.025g / cm 3 To about 0.175g / cm 3 , 0.040g / cm 3 To about 0.125g / cm 3 , 0.050g / cm 3 To about 0.100g / cm 3 , or about 0.060 g / cm 3 About 0.090g / cm 3 As used herein, the bulk density (untapped) of a particle is the ratio of the mass to volume (including the void volume between particles) of an untapped powder sample.

[0039] In various other embodiments, the particles have an average bulk density of less than about 0.200 g / cm 3 , 0.175g / cm 3 、0.150g / cm 3 or 0.125g / cm 3 In other embodiments, the average bulk density of the particles is less than about 0.200 g / cm 3 , 0.175g / cm 3 、0.150g / cm 3 or 0.125g / cm 3 , 0.100g / cm 3 or 0.090g / cm 3 , not yet solid.

[0040] The average particle size (by volume distribution) of the sorafenib particles is about 0.7 microns to about 8 microns in diameter. In some embodiments, the average particle size (by volume distribution) of the sorafenib particles is about 1 micron to about 8 microns in diameter, about 1 micron to about 7.5 microns in diameter, about 1.5 microns to about 7 microns in diameter, 0.7 microns to about 6 microns in diameter, 1 micron to about 6 microns in diameter, about 1.5 microns to about 6 microns in diameter, about 0.7 microns to about 5 microns in diameter, about 1 micron to about 5 microns in diameter, or about 1.5 microns to about 5 microns in diameter. The size range of the sorafenib particles is unlikely to be discharged from the tumor through the systemic circulation, but its high specific surface area can enhance the dissolution and release of the drug.

[0041] In any of these various embodiments, the sorafenib particles may include, for example, at least about 2.8×10 -15 Sorafenib or a pharmaceutically acceptable salt thereof, or each sorafenib particle is at least about 2.8×10-15 About 3.40×10 -9 Cosorafenib or a pharmaceutically acceptable salt thereof.

[0042] In one embodiment, the particles are uncoated and do not include polymers, proteins, polyethoxylated castor oil, and polyethylene glycol glycerides consisting of mono-, di-, and triglycerides and mono- and diesters of polyethylene glycol.

[0043] In another embodiment, the composition comprises a suspension further comprising a pharmaceutically acceptable liquid carrier. The suspension of the present invention comprises Sorafenib particles and a liquid carrier. The liquid carrier can be aqueous or non-aqueous. Even if the Sorafenib particles do not include an added excipient, the liquid carrier of the suspension can also include water and optionally one or more excipients. For example, the suspension may comprise Sorafenib particles, water, a buffer and a salt. It optionally further comprises a surfactant. In some embodiments, the suspension consists essentially of or consists of water, Sorafenib particles suspended in water and a buffer. The suspension may also contain an osmotic salt.

[0044] In one embodiment, the composition further comprises one or more components selected from the group consisting of polysorbate, methylcellulose, polyvinylpyrrolidone, mannitol and hydroxypropylmethylcellulose.

[0045] The suspension may contain one or more surfactants. Suitable surfactants include, but are not limited to, polysorbates, lauryl sulfate, acetylated monoglycerides, diacetylated monoglycerides, and poloxamers.

[0046] The suspension may include one or more tonicity adjusters. Suitable tonicity adjusters include, but are not limited to, one or more inorganic salts, electrolytes, sodium chloride, potassium chloride, sodium phosphate, potassium phosphate, sodium sulfate, potassium sulfate, sodium bicarbonate and potassium bicarbonate, and alkaline earth metal salts, such as alkaline earth metal inorganic salts, such as calcium and magnesium salts, mannitol, dextran, glycerol, propylene glycol, and mixtures thereof.

[0047] In an embodiment particularly suitable for intraperitoneal (IP) administration, the suspension can be formulated to be hypertonic (high tension), hypotonic (low tension) or isotonic (isotonic) relative to the fluid in the IP cavity. In some embodiments, the suspension can be isotonic relative to the fluid in the IP cavity. In such embodiments, the osmotic pressure concentration of the suspension can be in the range of about 200mOsm / kg to about 380mOsm / kg, about 240mOsm / kg to about 340mOsm / kg, about 280mOsm / kg to about 300mOsm / kg, or about 290mOsm / kg.

[0048] The suspension may include one or more buffers. Suitable buffers include, for example, but not limited to, disodium hydrogen phosphate, sodium dihydrogen phosphate, citric acid, sodium citrate, hydrochloric acid, sodium hydroxide, tris (hydroxymethyl) aminomethane, bis (2-hydroxyethyl) iminotris (hydroxymethyl) methane and sodium bicarbonate and other buffers known to those of ordinary skill in the art. Buffers are typically used to adjust the pH value to the desired range for intraperitoneal use. Typically, a pH value of about 5 to 9, 5 to 8, 6 to 7.4, 6.5 to 7.5 or 6.9 to 7.4 is desirable.

[0049] The suspension may include one or more analgesics. An analgesic is a drug that forms a soothing film on mucous membranes, such as the peritoneum and organs within the peritoneum. Analgesics can relieve minor pain and inflammation and are sometimes referred to as mucosal protectants. Suitable analgesics include cellulose derivatives ranging from about 0.2% to about 2.5%, such as sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, and methylcellulose; about 0.01% gelatin; about 0.05% to about 1% polyols, and also about 0.05 to about 1% of, for example, glycerol, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, and propylene glycol; about 0.1 to about 4% polyvinyl alcohol; about 0.1 to about 2% povidone; when used with another polymer analgesic described herein, dextran 70 is about 0.1%.

[0050] The suspension may contain one or more alkalizing agents to adjust the pH. As used herein, the term "alkalizing agent" refers to a compound used to provide an alkaline medium. Such compounds include, but are not limited to, ammonia solution, ammonium carbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium hydroxide, as well as other compounds known to those of ordinary skill in the art.

[0051] The suspension may contain one or more acidulants to adjust the pH. As used herein, the term "acidulant" refers to a compound used to provide an acidic medium. Such compounds include, but are not limited to, acetic acid, amino acids, citric acid, nitric acid, fumaric acid and other α-hydroxy acids, hydrochloric acid, ascorbic acid and nitric acid, and other compounds known to those of ordinary skill in the art.

[0052] The suspension may contain one or more defoaming agents. As used herein, the term "defoaming agent" refers to one or more compounds that prevent or reduce the amount of foam formed on the surface of the filling composition. Suitable defoaming agents include, but are not limited to, dimethyl siloxane, Octanol and other defoamers known to those of ordinary skill in the art.

[0053] The suspension may include one or more viscosity modifiers which increase or decrease the viscosity of the suspension. Suitable viscosity modifiers include methylcellulose, hydroxypropylmethylcellulose, mannitol and polyvinylpyrrolidone.

[0054] The suspension may contain one or more osmotic agents, such as those used in peritoneal dialysis. Suitable osmotic agents include icosadextrin (a glucose polymer), sodium chloride, potassium chloride, and salts that also serve as buffers.

[0055] As used herein, the "pharmaceutically acceptable salt" of Sorafenib is suitable for use in contact with patient tissues within the scope of reasonable medical judgment, without excessive toxicity, irritation, allergic reaction, etc., in accordance with a reasonable benefit / risk ratio, and effective for its intended use, and if possible, also applies to the zwitterionic form of Sorafenib. The term "salt" refers to relatively non-toxic inorganic and organic acid addition salts of Sorafenib. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, malate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthenate, methanesulfonate, glucoheptanoate, lactobionate and dodecylsulfonate, etc. These can include alkali and alkaline earth metal based cations, such as sodium, lithium, potassium, calcium, magnesium, etc., and non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. (e.g., see Berge SM et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977; 66: 119, which is incorporated herein by reference). In one embodiment, the pharmaceutically acceptable salt of sorafenib includes sorafenib tosylate.

[0056] In one embodiment, the composition comprises a suspension dosage form of sorafenib (ie, with a pharmaceutically acceptable carrier and any other components) at a dosage deemed appropriate for the intended use by the attending physician. Any suitable dosage form may be used; in various non-limiting embodiments, the dosage form is sufficient to provide about 0.01 mg / kg to about 50 mg / kg body weight per day. In various further embodiments, the dosage form is sufficient to provide about 0.01 mg / kg to about 45 mg / kg, 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 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 body weight. The suspension can be administered as is, or can be diluted with a diluent before administration, such as with saline injection, optionally including a buffer and one or more other excipients. For example, the volume ratio of the suspension to the diluent may be in the range of 1: 1–1: 100 (v / v) or other suitable ranges.

[0057] On the other hand, the present disclosure provides a method for treating a tumor, comprising administering to a subject with a tumor a composition or suspension of any embodiment of the present disclosure in an amount effective to treat the tumor or a combination of multiple embodiments. Compared with currently available Sorafenib, the increase in the specific surface area of ​​the Sorafenib particles of the present invention significantly increases the dissolution rate of the particles. This provides a significant improvement in the application of the particles of the present disclosure in, for example, tumor treatment. In addition, in some embodiments, the method of the present disclosure can reduce the frequency of administration and side effects of Sorafenib. As a non-limiting example, compared with oral administration, the dose of Sorafenib administered by direct tumor injection will be significantly reduced, the frequency of administration will also be reduced, and since the systemic concentration will be greatly reduced, the side effects are also expected to be reduced.

[0058] As used herein, "tumor" includes benign tumors, premalignant tumors, non-metastatic malignant tumors, and metastatic malignant tumors.

[0059] The methods of the present disclosure can be used to treat tumors susceptible to sorafenib treatment, including but not limited to thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, pancreatic tumors, prostate tumors, bladder tumors, lung tumors, and ovarian cancer.

[0060] The subject can be any suitable subject having a tumor, including but not limited to humans, primates, dogs, cats, horses, cows, etc.

[0061] As used herein, "treat" or "treating" means to accomplish one or more of the following: (a) reduce the severity of disease; (b) limit or prevent the development of symptoms characteristic of the condition being treated; (c) inhibit the progression of symptoms of the condition being treated; (d) limit or prevent recurrence of disease in patients who previously had the disease; and (e) limit or prevent recurrence of symptoms in patients who previously had symptoms.

[0062] The effective dose for these purposes depends on various factors, including but not limited to the properties of Sorafenib (specific activity, etc.), the route of administration, the stage and severity of the disease, the weight and general health of the subject, and the judgment of the prescribing physician. It should be understood that the amount of the suspension composition of the present disclosure actually administered will be determined by the physician based on the above-mentioned relevant circumstances. In a non-limiting embodiment, the effective amount is an amount that provides 0.01 mg / kg to about 50 mg / kg body weight per day.

[0063] The composition can be administered by any suitable route, including but not limited to oral, pulmonary, intraperitoneal, intratumoral, peritumoral, subcutaneous injection, intramuscular injection or any other form of injection, such as the most appropriate route considered by the medical staff based on all factors of a given subject. The administration period is the time period for the administration of the dose of sorafenib particles in the composition or suspension. The administration period can be a single time period for the administration of the entire dose, or can be divided into two or more time periods, with a portion of the dose administered in each time period.

[0064] The post-administration period refers to a period of time that begins after the completion of the previous administration period and ends after the subsequent administration period begins. The duration after administration can vary according to the clinical response of the subject to Sorafenib. During the post-administration period, no suspension is applied. The post-administration period can last for 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-administration period can remain constant for the subject, or two or more different post-administration periods can be used for the subject.

[0065] The administration cycle includes an administration cycle and a post-administration cycle. Therefore, the duration of the administration cycle will be the sum of the administration cycle and the post-administration cycle. The administration cycle can remain constant for the subject, or two or more different administration cycles can be used for the subject.

[0066] In one embodiment, the administration is performed multiple times, and wherein each administration is separated in time by at least 21 days.

[0067] In another aspect, the present disclosure provides a method for preparing Sorafenib, comprising:

[0068] (a) introducing (i) a solution comprising at least one solvent and at least one solute comprising sorafenib or a pharmaceutically acceptable salt thereof into an inlet of a nozzle, and (ii) introducing a compressed fluid into an inlet of a container defining a pressurizable chamber;

[0069] (b) causing the solution to flow out of a nozzle orifice and into the pressurizable chamber to produce an output stream of atomized droplets, wherein the nozzle orifice is located 2 mm to 20 mm from an acoustic energy source located within the output stream, wherein the acoustic energy source generates acoustic energy with an amplitude of between 10% and 100% during the passage, and wherein the nozzle orifice has a diameter of between 20 μm and 125 μm;

[0070] (c) contacting the atomized droplets with a compressed fluid to deplete the solvent from the atomized droplets to produce compound particles comprising at least 95% sorafenib or a pharmaceutically acceptable salt thereof, wherein the particles have a particle size of at least 2 m 2 / g specific surface area (SSA), and having a volume distribution of an average particle size of about 0.7 μm to about 8 μm,

[0071] Steps (a), (b) and (c) are carried out at supercritical temperature and pressure of the compressed fluid.

[0072] The method utilizes a sonic energy source directly located in the output stream of the solute dissolved in the solvent. Any suitable sonic energy source compatible with the method of the present disclosure can be used, including but not limited to a sonic horn, a sonic probe, or a sonic plate. In various embodiments, the nozzle hole is located about 2 mm to about 20 mm, about 2 mm to about 18 mm, about 2 mm to about 16 mm, about 2 mm to about 14 mm, about 2 mm to about 12 mm, about 2 mm to about 10 mm, about 2 mm to about 8 mm, about 2 mm to about 6 mm, about 2 mm to about 4 mm, about 4 mm to about 20 mm, about 4 mm to about 18 mm, about 4 mm to about 16 mm, about 4 mm to about 14 mm, about 4 mm to about 12 mm, about 4 mm to about 10 mm, about 4 mm to about 8 mm, about 4 mm to about 6 mm, about 6 mm to about 20 mm, about 6 mm to about 18 mm, about 6 mm to about 16 mm, about 6 mm to about 14 mm, about 6 mm to about 12 mm, about 6 mm to about In some embodiments, the nozzle assembly of any embodiment of WO2016 / 197091 can be used.

[0073] Any suitable sonic energy source compatible with the methods of the present disclosure can be used, including but not limited to sonic horns, sonic probes, or sonic plates. In various further embodiments, the amplitude of the sonic energy generated by the sonic energy source is about 10% to about 100% of the total power that can be generated using the sonic energy source. Based on the teachings herein, those skilled in the art can determine the appropriate sonic energy source with a specific total power output to be used. In one embodiment, the sonic energy source has a total power output of about 500 watts to about 900 watts; in various further embodiments, about 600 watts to about 800 watts, about 650-750 watts, or about 700 watts.

[0074] In various further embodiments, the sonic energy source generates a power output of sonic energy in the range of about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 90% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, about 60% to about about 80%, about 70% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, about 50% to about 70%, about 60% to about 70%, about 10% to about 60%, about 20% to about 60%, about 30% to about 60%, about 40% to about 60%, about 50% to about 60%, about 10% to about 50% %, about 20% to about 50%, about 30% to about 50%, about 40% to about 50%, about 10% to about 40%, about 20% to about 40%, about 30% to about 40%, about 10% to about 30%, about 20% to about 30%, about 10% to about 20%, or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 100%. Based on the teachings herein, one skilled in the art can determine the appropriate frequency to use on the sonic energy source. In one embodiment, the frequency on the sonic energy source is between about 18 to about 22 kHz. In various other embodiments, a frequency of about 19 to about 21 kHz, about 19.5 to about 20.5 kHz, or about 20 kHz of the sonic energy source is utilized.

[0075] In various further embodiments, the diameter of the nozzle hole is from about 20 μm to about 125 μm, from about 20 μm to about 125 μm, from about 20 μm to about 115 μm, from about 20 μm to about 100 μm, from about 20 μm to about 90 μm, from about 20 μm to about 80 μm, from about 20 μm to about 70 μm, from about 20 μm to about 60 μm, from about 20 μm to about 50 μm, from about 20 μm to about 40 μm, from about 20 μm to about 30 μm, from about 30 μm to about 125 μm, from about 30 μm to about 115 μm, from about 3 ... 30μm to about 90μm, about 30μm to about 80μm, about 30μm to about 70μm, about 30μm to about 60μm, about 30μm to about 50μm, about 30μm to about 40μm, about 40μm to about 125μm, about 40μm to about 115μm, about 40μm to about 100μm, about 40μm to about 90μm, about 40μm to about 80μm, about 40μm to about 70μm, about 40μm to about 60μm, about 40μm to about 50μm, about 50μm to about 125μm, about 50μm to about 115μm, From about 50 μm to about 100 μm, from about 50 μm to about 90 μm, from about 50 μm to about 80 μm, from about 50 μm to about 70 μm, from about 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, from about 60 μm to about 80 μm, from about 60 μm to about 70 μm, from about 70 μm to about 125 μm, from about 70 μm to about 115 μm, from about 70 μm to about 100 μm, from about 70 μm to about 90 μm, from about 70 μm to about 80 The nozzle may be inert to the solvent and the compressed fluid used in the method.

[0076] In one embodiment, the solvent may include, but is not limited to, acetone, ethanol, methanol, or a combination thereof. In a particular embodiment, the solvent includes acetone. The solvent should account for at least about 80%, 85%, or 90% by weight of the total solution.

[0077] The compressed fluid can form a supercritical fluid under the conditions used, and the solute that forms the particles is poorly soluble or insoluble in the compressed fluid. As known to those skilled in the art, a supercritical fluid is any substance whose temperature and pressure are above its critical point, in which there are no different liquid and gas phases. Steps (a), (b) and (c) of the inventive method are carried out at the supercritical temperature and pressure of the compressed fluid so that the compressed fluid exists in the form of a supercritical fluid during these processing steps.

[0078] Compressed fluid can be used as solvent, and can be used to remove unwanted components in particles. Any suitable compressed fluid can be used in the method of the present disclosure; U.S. Patent No.5833891 and No.5874029 disclose exemplary such compressed fluids. In a non-limiting embodiment, suitable supercritical fluids form compressed fluids and / or anti-solvents and can include carbon dioxide, ethane, propane, butane, isobutane, nitrous oxide, xenon, sulfur hexafluoride and trifluoromethane. The anti-solvent causing further solvent depletion described in step (d) is a compressed fluid as described above, and can be the same compressed fluid used in step (ac), or can be different. In one embodiment, the anti-solvent used in step (d) is the same as the compressed fluid used in step (ac). In a preferred embodiment, the compressed fluid and the anti-solvent are both supercritical carbon dioxide.

[0079] In all cases, the compressed fluid and anti-solvent should be substantially miscible with the solvent, and the compound to be precipitated should be substantially insoluble in the compressed fluid, i.e., under the selected solvent / compressed fluid contact conditions, the compound should not exceed about 5% by weight in the compressed fluid or anti-solvent, and is preferably substantially completely insoluble.

[0080] The supercritical conditions used in the process of the present invention are generally in the range of 1X to about 1.4X or 1X to about 1.2X the critical temperature of the supercritical fluid and 1X to about 7X or 1X to about 2X the supercritical pressure of the compressed fluid.

[0081] Determining the critical temperature and pressure of a given compressed fluid or anti-solvent is well within the level of those skilled in the art. In one embodiment, the compressed fluid and the anti-solvent are both supercritical carbon dioxide, with a critical temperature of at least 31.1°C to about 60°C and a critical pressure of at least 1071psi to about 1800psi. In another embodiment, the compressed fluid and the anti-solvent are both supercritical carbon dioxide, with a critical temperature of at least 35°C and up to about 55°C, and a critical pressure of at least 1070psi and up to 1500psi. Those skilled in the art will appreciate that specific critical temperatures and pressures may be different at different steps in the process.

[0082] Any suitable pressurizable chamber may be used, including but not limited to the chambers disclosed in WO2016 / 197091 or U.S. Patent Nos. 5833891 and 5874029. Similarly, the step of contacting the atomized droplets with a compressed fluid to deplete the solvent in the droplets; and the droplets may be contacted with an anti-solvent under any suitable conditions, including but not limited to the conditions disclosed in WO2016 / 197091 or U.S. Patent Nos. 5833891 and 5874029, to further deplete the solvent in the droplets, thereby producing compound particles.

[0083] The flow rate can be adjusted as high as possible to optimize output, but lower than the pressure limit of equipment (including nozzle orifice). In one embodiment, the flow rate range of solution through nozzle is about 0.5mL / min to about 30mL / min. In various further embodiments, the flow rate is about 0.5mL / min to about 25mL / min, 0.5mL / min to about 20mL / min, 0.5mL / min to about 15mL / min, 0.5mL / min to about 10mL / min, 0.5mL / min to about 4mL / min, about 1mL / min to about 30mL / min, about 1mL / min to about 25mL / min, about 1mL / min to about 20mL / min, 1mL / min to about 15mL / min, about 1mL / min to about 10mL / min, about 2mL / min to about 30mL / min, about 2mL / min to about 25mL / min, about 2mL / min to about 20mL / min, about 2mL / min to about 15mL / min, or about 2mL / min to about 10mL / min. The drug solution affected by the flow rate can be of any suitable concentration, for example, from about 1 mg / ml to about 80 mg / ml.

[0084] In one embodiment, the method further comprises receiving the plurality of particles through an outlet of the pressurizable chamber; and collecting the plurality of particles in a collection device such as disclosed in WO2016 / 197091.

[0085] In another aspect, the present disclosure provides compound particles prepared by the method of any embodiment or combination of embodiments of the present disclosure.

[0086] Example

[0087] Sorafenib free base (FB) was obtained from Chemcia and BOC Sciences. Materials were stored in a temperature and humidity monitored cabinet and protected from light.

[0088] Compound Name: Sorafenib free base

[0089] Molecular formula: C 21 H16 CIF3N4O3

[0090] Molecular weight: 464.8 g / mol

[0091] In a specific exemplary method, a solution of 15 mg / ml sorafenib is dissolved in acetone. The nozzle and the sonic probe are located in a pressurizable chamber, about 9 mm apart. A sintered stainless steel mesh filter coated with titanium dioxide and having about 20 nm pores is connected to the pressurizable chamber to collect precipitated sorafenib particles. Supercritical carbon dioxide is placed in a pressurized chamber of a manufacturing device and reaches about 1200 pounds per square inch at about 37°C and a flow rate of 4-12 kg per hour. At a frequency of 20 kHz, the sonic probe is adjusted to an amplitude of 60% of the maximum output. The acetone solution containing sorafenib is pumped through the nozzle at a flow rate of 2 mL / min for about 20 minutes. Then, when the mixture is pumped through the stainless steel mesh filter, the precipitated sorafenib particles are collected from the supercritical carbon dioxide. The filter containing the sorafenib particles is opened and the resulting product is collected from the filter.

[0092] In another specific exemplary method, a solution of 6 mg / ml sorafenib is dissolved in ethanol. The nozzle and the sonic probe are located in a pressurizable chamber, about 9 mm apart. A sintered stainless steel mesh filter coated with titanium dioxide and having about 20 nm pores is connected to the pressurizable chamber to collect precipitated sorafenib particles. Supercritical carbon dioxide is placed in a pressurized chamber of a manufacturing device and reaches about 1200 pounds per square inch at about 37°C and a flow rate of 4-12 kg per hour. At a frequency of 20 kHz, the sonic probe is adjusted to an amplitude of 60% of the maximum output. The ethanol solution containing sorafenib is pumped through the nozzle at a flow rate of 2 mL / min for about 50 minutes. Then, when the mixture is pumped through the stainless steel mesh filter, the precipitated sorafenib particles are collected from the supercritical carbon dioxide. The filter containing the sorafenib particles is opened and the resulting product is collected from the filter.

[0093] In a specific exemplary method, a solution of 6 mg / ml sorafenib is dissolved in methanol. The nozzle and the sonic probe are located in a pressurizable chamber, about 9 mm apart. A sintered stainless steel mesh filter coated with titanium dioxide and having about 20 nm pores is connected to the pressurizable chamber to collect precipitated sorafenib particles. Supercritical carbon dioxide is placed in a pressurized chamber of a manufacturing device and reaches about 1200 pounds per square inch at about 37°C and a flow rate of 4-12 kg per hour. At a frequency of 20 kHz, the sonic probe is adjusted to an amplitude of 60% of the maximum output. A methanol solution containing sorafenib is pumped through the nozzle at a flow rate of 2 mL / min for about 50 minutes. Then, when the mixture is pumped through the stainless steel mesh filter, the precipitated sorafenib particles are collected from the supercritical carbon dioxide. The filter containing the sorafenib particles is opened and the resulting product is collected from the filter.

[0094] Feasibility study

[0095] The solubility of Sorafenib free base in supercritical fluid carbon dioxide (scCO2) and various organic solvents was evaluated. Three precipitation trials (approximately 600-700 mg) were performed on an RC612B precipitation apparatus based on the examples provided on the previous pages. The solvent was the single variable modified between each set of three precipitations. The precipitate was analyzed by laser diffraction to determine the PSD, BET absorptiometry to determine the SSA, SEM to determine the habit and support the PSD and SSA data, and PXRD to determine the crystalline / amorphous form.

[0096] The slurry was dispersed in a Malvern Mastersizer using an Aero S dispersion device according to the manufacturer's instructions. TM PSD analysis was performed on 3000.

[0097] According to the manufacturer's instructions, TM SSA assay analysis was performed on a LX2 BET absorbance meter or an automatic BET absorbance meter BET-202A from Porous Materials, Inc.

[0098] PXRD analysis was performed on a Siemens D 5000 X-ray diffractometer. PXRD scanned from 5 to 352θ degrees at a rate of 0.022θ degrees / second and 1 second per second. The data are shown in Figure 2. Figure 3 shown.

[0099] SEM was performed on a Hitachi 8130 SEM. SEM micrographs are shown in Figure 1-2 .

[0100] Bulk density / tapped density. Since samples were available, bulk density / tapped density analysis was performed using an Agilent 350 tap density tester and a 10 mL graduated cylinder. The results are shown in Table 1.

[0101] Sorafenib was precipitated from three solvents: acetone, ethanol, and methanol. The yields for all three trials were greater than 58%. After precipitation, the produced material was analyzed using the techniques described above.

[0102] After conducting an initial feasibility study, sorafenib was precipitated from acetone at 15.1 mg / mL on a 7 g scale. The scaled-up precipitate was analyzed by laser diffraction to determine PSD, SEM to support the PSD data and determine the state of habit, and PXRD to determine crystalline / amorphous form, as well as bulk / tapped (B / T) density. These materials were also used for dissolution to compare with the unprocessed / raw material. In addition, at three time points (excluding T0), namely T 1d , T 7d and T 14d Short-term stability studies (14 days) were performed using open and closed containers. PXRD and appearance tests were performed at each time point. There was no change in PXRD or appearance of any sample.

[0103] The particle size distribution results are shown in Table 1

[0104] Table 1. Sorafenib particle characteristics

[0105]

[0106]

[0107] The results showed that the sorafenib particles produced in this paper had significantly increased specific surface area.

[0108] Solubility studies

[0109] Evaluation of FDA Dissolution Methods

[0110] The dissolution of sorafenib solid oral dosage forms was evaluated using an FDA-approved method, such as Figure 4 As shown, good discrimination was shown between materials with different specific surface areas. The method was performed in acidic medium. A differential dissolution method was developed at neutral pH (6.8 to 7.4), which is relevant for the potential intratumoral delivery of drugs. Organic solvents were added to increase the solubility of the compounds at neutral pH. Solubility studies were performed under the following conditions:

[0111] Methanol / water ratios of 25 / 75, 50 / 50 and 75 / 25 (v / v)

[0112] Ethanol / water ratios of 25 / 75, 50 / 50 and 75 / 25 (v / v)

[0113] Solubility was determined using the shake bottle method. Excess drug was added to each solution prepared in duplicate. The vials were placed on a mechanical shaker at 20-25 °C for 24 h. After shaking, the solution was removed and filtered through a 0.2 μm PTFE syringe filter and analyzed by UV / Vis spectrophotometry.

[0114] The organic solvent modifier solubility results of Sorafenib are shown in Table 2. For both solvents, Sorafenib showed concentration-dependent solubility. Ethanol had a slightly higher overall solubility.

[0115]

[0116] The medium selected for dissolution was 500 mL of 50% ethanol in water, with a paddle speed of 50 rpm and pH = 7 at 37 °C. To meet the sinking condition, 50 mg of drug was added directly to each container. The two containers contained a specific surface area of ​​9.97 m 2 / g of processed material, two containers are filled with a specific surface area of ​​0.88m 2 / g of unprocessed material. The time points were 10, 20, 30, 45, 60 and 120 minutes. At each time point, a 5 mL aliquot was drawn and immediately filtered through a 0.45 μm PTFE syringe filter, and the first 1 mL of filtrate was discarded. The solution was then analyzed by UV / Vis spectrophotometry at a wavelength of 293 nm. The dissolution curve is shown in Figure 5 As shown, it was shown that the Sorafenib particles of the present disclosure showed significantly improved solubility compared to unprocessed Sorafenib.

Claims

1. A composition comprising particles comprising at least 95% by weight of sorafenib or a pharmaceutically acceptable salt thereof, wherein the particles have at least 2 m 2 / g of specific surface area (SSA), and having a volume distribution of an average particle size of about 0.7 μm to about 8 μm.

2. The composition of claim 1, wherein the particles have a particle size of at least 5 μm. 2 / g of SSA.

3. The composition of claim 1, wherein the particles have a diameter of at least 10 μm. 2 / g of SSA.

4. The composition according to any one of claims 1 to 3, wherein the SSA of the particles is 2 m 2 / g to about 50m 2 / g, about 3m 2 / g to 50m 2 / g,5m 2 / g to 50m 2 / g, 7m 2 / g to 50m 2 / g, or 10m 2 / g to 50m 2 / g.

5. The composition of any one of claims 1 to 4, wherein the particles have an average particle size of about 1 μm to about 8 μm in volume distribution.

6. The composition of any one of claims 1-5, wherein the particles comprise at least 96%, 97%, 98%, 99% or 100% sorafenib or a pharmaceutically acceptable salt thereof.

7. The composition of any one of claims 1-6, wherein the particles are uncoated and do not include polymers, proteins, polyethoxylated castor oil, and polyethylene glycol glycerides consisting of mono-, di-, and triglycerides and mono- and diesters of polyethylene glycol.

8. The composition according to any one of claims 1-7, wherein the composition comprises a suspension further comprising a pharmaceutically acceptable liquid carrier.

9. The composition according to any one of claims 1 to 8, further comprising one or more components selected from the group consisting of polysorbate, methylcellulose, polyvinylpyrrolidone, mannitol and hydroxypropylmethylcellulose.

10. The composition according to any one of claims 1 to 9, wherein The average bulk density of the particles is (a) About 0.010 g / cm 3 To about 0.200g / cm 3 , about 0.025g / cm 3 To about 0.175g / cm 3 , about 0.050g / cm 3 To about 0.150g / cm 3 , about 0.075g / cm 3 To about 0.125g / cm 3 or about 0.085g / cm 3 About 0.115g / cm 3 , shake solid; (b) About 0.010 g / cm 3 To about 0.200g / cm 3 , about 0.020g / cm 3 Up to 0.175g / cm 3 , about 0.040g / cm 3 Up to 0.125g / cm 3 , about 0.050g / cm 3 Up to 0.100g / cm 3 , or about 0.060g / cm 3 Up to 0.090g / cm 3 , not yet vibrated; (c) less than about 0.200 g / cm 3 , 0.175g / cm 3 、0.150g / cm 3 or 0.125g / cm 3 , compaction; and / or (d) less than about 0.200 g / cm 3 , 0.175g / cm 3 、0.150g / cm 3 or 0.125g / cm 3 , 0.100g / cm 3 or 0.090g / cm 3 , not yet solid.

11. The composition according to any one of claims 1-10, wherein the pharmaceutically acceptable salt of sorafenib comprises sorafenib tosylate.

12. A method for treating a tumor, comprising administering a therapeutically effective amount of the composition of any one of claims 1 to 11 to a subject suffering from the tumor.

13. The method of claim 12, wherein the tumor is selected from the group consisting of thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, pancreatic cancer, prostate tumor, bladder tumor, lung tumor, and ovarian cancer.

14. The method of claim 12 or 13, wherein the subject is a human subject.

15. The method according to any one of claims 12-14, wherein the composition is administered by intratumoral injection, peritumoral injection or intraperitoneal injection.

16. A method for preparing sorafenib particles, comprising: (a) introducing (i) a solution comprising at least one solvent and at least one solute comprising sorafenib or a pharmaceutically acceptable salt thereof into an inlet of a nozzle, and (ii) introducing a compressed fluid into an inlet of a container defining a pressurizable chamber; (b) causing the solution to flow out of a nozzle orifice and into the pressurizable chamber to produce an output stream of atomized droplets, wherein the nozzle orifice is located 2 mm to 20 mm from an acoustic energy source located within the output stream, wherein the acoustic energy source generates acoustic energy having an amplitude of 10% to 100% during the passage, and wherein the nozzle orifice has a diameter between 20 μm and 125 μm; (c) contacting the atomized droplets with a compressed fluid to deplete the solvent from the atomized droplets to produce compound particles comprising at least 95% sorafenib or a pharmaceutically acceptable salt thereof, wherein the particles have a particle size of at least 2 m 2 / g specific surface area (SSA), and having a volume distribution of an average particle size of about 0.7 μm to about 0.8 μm, Steps (a), (b) and (c) are carried out at supercritical temperature and pressure of the compressed fluid.

17. The method according to claim 16, further comprising: (d) contacting the compound particles produced in step (c) with an anti-solvent to further deplete the solvent from the compound particles, wherein step (d) is performed at a supercritical temperature and pressure of the anti-solvent.

18. The method of any one of claims 16-17, wherein the flow rate of the solution through the nozzle ranges from about 0.5 mL / min to about 30 mL / min.

19. The method of any one of claims 16-18, wherein the sonic energy source comprises one of a sonic horn, a sonic probe, or a sonic plate.

20. The method of any one of claims 16-19, wherein the sonic energy source has a frequency between about 18 kHz and about 22 kHz or about 20 kHz.

21. The method according to any one of claims 16 to 20, further comprising: (e) receiving the plurality of particles through an outlet of the pressurizable chamber; as well as (f) collecting the plurality of particles in a collection device.

22. The method of any one of claims 16-21, wherein the compressed fluid is supercritical carbon dioxide.

23. The method of any one of claims 17-22, wherein the anti-solvent is supercritical carbon dioxide.

24. The method of any one of claims 16-23, wherein the solvent may include but is not limited to acetone, ethanol, methanol, or a combination thereof.

25. The method of any one of claims 16-24, wherein the solvent comprises acetone.

26. The method of any one of claims 16-25, wherein the method is conducted at 31.1°C to about 60°C and about 1071 psi to about 1800 psi.

27. The method according to any one of claims 16 to 26, wherein the particles have a diameter of at least 5 μm. 2 / g, at least 7.5m 2 / g or at least 10m 2 / g of SSA, and / or wherein the particle is the particle of any one of claims 1-11.

28. Compound particles prepared by the method of any one of claims 16-27.

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