Cisplatin particles and uses thereof

Abstract

Suspensions and their uses for treating tumors are provided, wherein the suspension comprises: (a) particles of at least 95% by weight of cisplatin, wherein the particles are at least 3.5 mm thick. 2 / g specific surface area (SSA); (b) about 40% to about 60% w / w glycerin; (c) about 20% to about 40% w / w propylene glycol; (d) about 5% to about 20% w / w ethanol; and (e) about 5% to about 10% w / w 0.9% sodium chloride in water.

Description

cross reference

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 380,894, filed October 25, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Dissolution rate is a key parameter that determines the rate and extent of drug absorption and bioavailability.Low aqueous solubility and low in vivo dissolution are limiting factors for the in vivo bioavailability of many drugs.Therefore, in vitro dissolution rate is recognized as an important factor in drug discovery, and there is a need for methods and compositions for increasing the dissolution rate of poorly soluble drugs. Summary of the Invention

[0003] In one aspect, the present disclosure provides a composition comprising particles comprising at least 95% by weight of cisplatin, wherein the particles are at least 3.5 mm 2 / g. In various embodiments, the particles have a specific surface area (SSA) of at least 4 m 2 / g or at least 10m 2 In another embodiment, the particles have an SSA of 3.5 m 2 / g~about 50m 2 / g. In one embodiment, the particles have a mean particle size by volume distribution (Dv50) of about 0.7 microns to about 12.0 microns, about 0.7 microns to about 8.0 microns, or about 1.0 microns to about 12 microns in diameter. In another embodiment, the particles have a mean particle size by volume distribution (Dv50) of about 0.020 g / cm 3 ~about 0.8g / cm 3In one embodiment, the composition comprises a suspension. In one embodiment, the suspension is aerosolized, and the aerosol droplets of the suspension have a mass median aerodynamic diameter (MMAD) of about 0.5 μm to about 6 μm in diameter. In other embodiments, the composition is a dry powder composition, where (a) the dry powder composition does not include a carrier or any excipients; wherein the dry powder composition is aerosolized, and the MMAD of the aerosolized dry powder composition can be any suitable diameter for use, such as about 0.5 μm to about 6 μm in diameter, or (b) the composition is a dry powder composition, and the dry powder composition comprises a pharmaceutically acceptable dry powder carrier including one or more dry powder excipients, and the dry powder composition is aerosolized, and the MMAD of the aerosolized dry powder composition can be any suitable diameter for use, such as about 0.5 μm to about 6 μm in diameter.

[0004] In another embodiment, the suspension comprises: (b) about 40% to about 60% w / w glycerin; (c) about 20% to about 40% w / w propylene glycol; (d) about 5% to about 20% w / w ethanol; and (e) 0.9% sodium chloride in about 5% to about 10% w / w water; Includes:

[0005] In one embodiment, the concentration of the cisplatin particles is at least 2.5 mg / ml in the suspension, or at least 5 mg / ml in the suspension, or at least 10 mg / ml in the suspension.

[0006] In another embodiment, the present disclosure provides a kit comprising: (a) (i) 0.9% sodium chloride in about 30% to about 50% w / w water; (ii) about 30% to about 50% w / w glycerin; and (iii) about 5% to about 25% w / w ethanol; a first solution comprising water; (b) (i) about 40% to about 60% w / w glycerin; (ii) about 30% to about 45% w / w propylene glycol; (iii) about 5% to about 20% w / w ethanol; an anhydrous second solution comprising (c) particles comprising at least 95% by weight cisplatin, At least 3.5m 2 / g specific surface area (SSA).

[0007] The present disclosure also provides a method for making a suspension of the present disclosure, comprising combining particles with a first solution described in any one embodiment to obtain a mixture, and combining the mixture with a second solution described in any one embodiment to obtain a suspension. In one embodiment, the concentration of cisplatin particles is at least 2.5 mg / ml in the resulting suspension.

[0008] In another aspect, the present disclosure provides a method for treating a tumor, comprising administering to a subject having a tumor an amount of a composition of any embodiment or combination of embodiments herein effective to treat the tumor. In one embodiment, a suspension of the present disclosure is administered by intratumoral injection, and the concentration of cisplatin particles in the suspension is at least 2.5 mg / ml, or at least 5 mg / ml, or at least 10 mg / ml.

[0009] In a further aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: (a) (i) introducing into a nozzle inlet a solution comprising at least one solvent, including but not limited to DMF (dimethylformamide), DMSO (dimethyl sulfoxide), acetone, or a combination thereof, and at least one solute, including cisplatin, and (ii) a compressed fluid into an inlet of a vessel defining a pressurizable chamber; (b) passing the solution through a nozzle orifice and into a pressurizable chamber to create an output stream of atomized droplets, the nozzle orifice being located 2 mm to 20 mm from an acoustic energy source located within the output stream, the acoustic energy source generating acoustic energy at an amplitude of 10% to 100% during said passing, and the nozzle orifice having a diameter of 20 μm to 125 μm; (c) contacting the spray droplets with a compressed fluid to cause solvent depletion from the spray droplets to produce cisplatin particles containing at least 95% cisplatin, wherein the cisplatin particles are dispersed within a range of 3.5 m. 2 / g specific surface area (SSA) and an average particle size of about 0.7 μm to about 8 μm. a method for preparing a compound particle, the method comprising: Steps (a), (b), and (c) are carried out at temperatures and pressures that are supercritical for the compressed fluid. [Brief explanation of the drawings]

[0010] [Figure 1] Scanning electron microscope images. (A) Raw cisplatin, 1000x magnification; (B) Raw cisplatin, 5000x magnification. [Figure 2] Scanning electron microscopy images of cisplatin SC1 treated with DMF as a solvent. (A) 2000x magnification; and (B) 10,000x magnification. [Figure 3] Scanning electron microscopy images of cisplatin SC2 treated with DMSO as a solvent. (A) 2000x magnification; and (B) 10,000x magnification. [Figure 4] Scanning electron microscopy images of cisplatin SC3 treated with DMSO:acetone = 3:2. (A) 2000x magnification; and (B) 10,000x magnification. [Figure 5] Scanning electron microscope images of cisplatin SC4 processed using high pressure. (A) 2000x magnification; and (B) 10,000x magnification. [Figure 6]Scanning electron microscope images of cisplatin SC5 processed using low pressure. (A) 2000x magnification; and (B) 10,000x magnification. [Figure 7] Scanning electron microscopy images of cisplatin SC6 treated using low temperature. (A) 2000x magnification; and (B) 10,000x magnification. [Figure 8] Scanning electron microscopy images of cisplatin SC7 treated with elevated temperatures. (A) 2000x magnification; and (B) 10,000x magnification. [Figure 9] Scanning electron microscopy images of cisplatin SC8 treated with high scCO2 flow rates. (A) 2000x magnification; and (B) 10,000x magnification. [Figure 10] Scanning electron microscopy images of cisplatin SC9 treated with low scCO2 flow rate. (A) 2000x magnification; and (B) 10,000x magnification. [Figure 11] Scanning electron microscopy images of cisplatin SC10 treated with high-intensity ultrasound. (A) 2000x magnification; and (B) 10,000x magnification. [Figure 12] Scanning electron micrographs of cisplatin SC11 treated with low ultrasound. (A) 2000x magnification; and (B) 10,000x magnification. [Figure 13] Scanning electron microscopy images of cisplatin SC12 treated without ultrasound. (A) 2000x magnification; and (B) 10,000x magnification. [Figure 14] Scanning electron microscopy images of cisplatin SC13 treated with low temperature and low ultrasound. (A) 2000x magnification; and (B) 10,000x magnification. [Figure 15] Powder X-ray diffraction patterns for (A) cisplatin runs SC1-SC6, and (B) cisplatin runs SC7-SC13, compared to the cisplatin raw material. [Figure 16] Graph showing treatment efficacy on mean tumor volume as a function of time. [Figure 17] Graph showing the effect of IT cisplatin treatment on mean tumor volume as a function of time in individual study subjects. [Figure 18] Graph showing the efficacy of IT LSAM-cisplatin low-dose treatment on mean tumor volume as a function of time in individual study subjects. [Figure 19] Graph showing the effect of high-dose IT LSAM-cisplatin treatment on mean tumor volume as a function of time in individual study subjects. [Figure 20]Groups of female athymic nude mice were sacrificed on days 1 (1 hour after administration), 8 (before the second IP cycle), 16 (before the second LSAM-cisplatin administration), and 28. The groups were treated as follows: Group 3 received 6 mg / kg IP cisplatin on days 1, 8, and 15; Group 4 received approximately 5.7 mg / kg LSAM-cisplatin on day 1; Group 5 received approximately 8.5 mg / kg LSAM-cisplatin on day 1; Group 6 received approximately 11.3 mg / kg LSAM-cisplatin on day 1; Group 8 received approximately 5.7 mg / kg LSAM-cisplatin on days 1 and 16; Group 9 received approximately 8.5 mg / kg LSAM-cisplatin on days 1 and 16; and Group 10 received approximately 11.3 mg / kg LSAM-cisplatin on days 1 and 16. Mean data for the single-dose IT LSAM-cisplatin approx. 5.7 mg / kg group are plotted from Day 1 (N=5), Day 8 (N=5), Day 16 pre-dose (N=5) for Group 8, and Day 28 (N=5) for Group 4; mean concentration data for the single-dose IT LSAM-cisplatin approx. 8.5 mg / kg group are plotted from Day 1 (N=5), Day 8 (N=5), Day 16 pre-dose (N=5) for Group 9, and Day 28 (N=4) for Group 5; mean concentration data for the IT LSAM-cisplatin approx. 11.3 mg / kg group are plotted from Day 1 (N=5), Day 8 (N=5), Day 16 (N=5) for Group 10, and Day 28 (N=5) for Group 6. Mean data for the 6 mg / kg IP cisplatin group of SOC are plotted from Group 3 (N=5 animals / day) on days 1, 8 (pre-dose), 16, and 28. Group error bars = ±1 standard deviation. BLQ = below limit of quantitation (<50 ng / mL), treated as zero for statistical purposes. [Figure 21]Groups of female athymic nude mice were sacrificed on days 1 (1 hour after administration), 8 (before the second IP cycle), 16 (before the second LSAM-cisplatin administration), and 28. The groups were treated as follows: Group 3 received 6 mg / kg IP cisplatin on days 1, 8, and 15; Group 4 received approximately 5.7 mg / kg LSAM-cisplatin on day 1; Group 5 received approximately 8.5 mg / kg LSAM-cisplatin on day 1; Group 6 received approximately 11.3 mg / kg LSAM-cisplatin on day 1; Group 8 received approximately 5.7 mg / kg LSAM-cisplatin on days 1 and 16; Group 9 received approximately 8.5 mg / kg LSAM-cisplatin on days 1 and 16; and Group 10 received approximately 11.3 mg / kg LSAM-cisplatin on days 1 and 16. Mean data for the single-dose IT LSAM-cisplatin approx. 5.7 mg / kg group are plotted from Day 1 (N=5), Day 8 (N=5), Day 16 pre-dose (N=5) for Group 8, and Day 28 (N=5) for Group 4; mean concentration data for the single-dose IT LSAM-cisplatin approx. 8.5 mg / kg group are plotted from Day 1 (N=5), Day 8 (N=5), Day 16 pre-dose (N=5) for Group 9, and Day 28 (N=4) for Group 5; mean concentration data for the IT LSAM-cisplatin approx. 11.3 mg / kg group are plotted from Day 1 (N=5), Day 8 (N=5), Day 16 (N=5) for Group 10, and Day 28 (N=5) for Group 6. Mean data for the 6 mg / kg IP cisplatin group of SOC are plotted from days 1, 8 (pre-dose), 16, and 28 for Group 3 (N=5 animals / day). Group error bars = ±1 standard deviation. BLQ = below limit of quantitation (<0.650 μg / g), treated as zero for statistical purposes. [Figure 22]Groups of female athymic nude mice were sacrificed on days 1 (1 hour after administration), 8 (before the second IP cycle), 16 (before the second LSAM-cisplatin administration), and 28. The groups were treated as follows: Group 8 received approximately 5.7 mg / kg of LSAM-cisplatin on days 1 and 16; Group 9 received approximately 8.5 mg / kg of LSAM-cisplatin on days 1 and 16; Group 10 received approximately 11.3 mg / kg of LSAM-cisplatin on days 1 and 16; and Group 7 received approximately 1.1 mg / kg of cisplatin on days 1 and 16. Mean concentration data for the multiple-dose IT LSAM-cisplatin approx. 5.7 mg / kg group are plotted from days 1, 8, 16 (pre-dose), and 28 for Group 8 (N=5 animals / day); mean concentration data for the multiple-dose IT LSAM-cisplatin approx. 8.5 mg / kg group are plotted from days 1 (N=5), 8 (N=5), 16 (N=5), and 28 (N=3) for Group 9; mean concentration data for the IT LSAM-cisplatin approx. 11.3.5 mg / kg group are plotted from days 1, 8, 16 (pre-dose), and 28 for Group 10 (N=5 animals / day); mean concentration data for the IT cisplatin approx. 1.1 mg / kg group are plotted from days 1, 8, 16 (pre-dose), and 28 for Group 7 (N=5 animals / day). Mean data for the 6 mg / kg IP cisplatin group of SOC are plotted from Days 1, 8 (pre-dose), 16, and 28 for Group 3 (N=5 animals / day). Group error bars = ±1 standard deviation. BLQ = below limit of quantitation. [Figure 23]Groups of female athymic nude mice were sacrificed on days 1 (1 hour after administration), 8 (before the second IP cycle), 16 (before the second LSAM-cisplatin administration), and 28. The groups were treated as follows: Group 8 received approximately 5.7 mg / kg of LSAM-cisplatin on days 1 and 16; Group 9 received approximately 8.5 mg / kg of LSAM-cisplatin on days 1 and 16; Group 10 received approximately 11.3 mg / kg of LSAM-cisplatin on days 1 and 16; and Group 7 received 1.1 mg / kg of cisplatin on days 1 and 16. Mean concentration data for the multiple-dose IT LSAM-cisplatin approx. 5.7 mg / kg group are plotted from days 1, 8, 16 (pre-dose), and 28 for Group 8 (N=5 animals / day); mean concentration data for the multiple-dose IT LSAM-cisplatin approx. 8.5 mg / kg group are plotted from days 1 (N=5), 8 (N=5), 16 (N=5), and 28 (N=3) for Group 9; mean concentration data for the multiple-dose IT LSAM-cisplatin approx. 11.3.5 mg / kg group are plotted from days 1, 8, 16 (pre-dose), and 28 for Group 10 (N=5 animals / day); mean concentration data for the IT cisplatin approx. 1.1 mg / kg group are plotted from days 1, 8, 16 (pre-dose), and 28 for Group 7 (N=5 animals / day). Mean data for the 6 mg / kg IP cisplatin group of SOC are plotted from days 1, 8 (pre-dose), 16, and 28 for Group 3 (N=5 animals / day). Group error bars = ±1 standard deviation. BLQ = below limit of quantitation (<0.650 μg / g), treated as zero for statistical purposes. DETAILED DESCRIPTION OF THE INVENTION

[0011] All references cited herein are incorporated by reference in their entirety. As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. All embodiments of any one aspect of the present disclosure may be used in combination unless the context clearly dictates otherwise.

[0012] As used herein, "about" means ±5% of the stated value.

[0013] In one aspect, the present disclosure provides a composition comprising particles comprising at least 95% by weight of cisplatin, the particles having a thickness of at least 3.5 mm. 2 / g specific surface area (SSA).

[0014] As used herein, "cisplatin" includes any ionization state of cisplatin, including the base, acid, and neutral states.

[0015] The structure of cisplatin [ka]

[0016] Molecular formula of cisplatin: Pt(NH3)2Cl2

[0017] "Cisplatin particles" refers to particles of cisplatin without added excipients. Cisplatin particles differ from "particles containing cisplatin," which are particles containing cisplatin and at least one added excipient. The cisplatin particles of the present disclosure do not contain polymeric, waxy, or proteinaceous excipients, and are not embedded, contained, enclosed, or encapsulated within a solid excipient. The cisplatin particles of the present disclosure may, however, contain impurities and by-products commonly found during the preparation of cisplatin. Even so, the cisplatin particles may contain at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% cisplatin, meaning that the cisplatin particles consist of substantially pure cisplatin or consist essentially of substantially pure cisplatin.

[0018] As used herein, "specific surface area" is the total surface area of ​​cisplatin particles per unit of cisplatin mass (i.e., BET SSA) as measured by the Brunauer-Emmett-Teller ("BET") adsorption isotherm. As will be understood by those skilled in the art, SSA is measured per gram and takes into account both aggregated and non-aggregated cisplatin particles in the composition. The BET specific surface area test method is an official method contained in both the United States Pharmacopoeia and the European Pharmacopoeia. Cisplatin particles should have a surface area of ​​at least 3.5 m 2 / g. In various further embodiments, the cisplatin particles have a specific surface area (SSA) of at least 4 m 2 / g, 5m 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, 14m 2 / g, 15m 2 / g, 16m 2 / g, 17m 2 / g, 18m 2 / g, 19m2 / g, 20m 2 / g, 21m 2 / g, 22m 2 / g, 23m 2 / g, or 24m 2 / g SSA.

[0019] In a further embodiment, the cisplatin particles are 3.5m 2 / g~about 50m 2 / g, approx. 4m 2 / g~about 50m 2 / g, approx. 5m 2 / g~about 50m 2 / g, approx. 6m 2 / g~about 50m 2 / g, about 7m 2 / g~about 50m 2 / g, approx. 8m 2 / g~about 50m 2 / g, about 7m 2 / g~about 50m 2 / g, approx. 9m 2 / g~about 50m 2 / g, approx. 10m 2 / g~about 50m 2 / g, approx. 11m 2 / g~about 50m 2 / g, approx. 12m 2 / g~about 50m 2 / g, approx. 13m 2 / g~about 50m 2 / g, approx. 14m 2 / g~about 50m 2 / g, approx. 15m 2 / g~about 50m 2 / g, approx. 16m 2 / g~about 50m 2 / g, approx. 17m 2 / g~about 50m 2 / g, approx. 18m 2 / g~about 50m 2 / g, approx. 19m 2 / g~about 50m 2 / g, approx. 20m 2 / g~about 50m 2 / g, approx. 21m 2 / g~about 50m 2 / g, approx. 22m2 / g~approximately 50m 2 / g, approximately 23m 2 / g~approximately 50m 2 / g, approximately 24m 2 / g~approximately 50m 2 / g、 3.5m 2 / g~approximately 45m 2 / g, approximately 4m 2 / g~approximately 45m 2 / g, approximately 5m 2 / g~approximately 45m 2 / g, approximately 6m 2 / g~approximately 45m 2 / g, approximately 7m 2 / g~approximately 45m 2 / g, approximately 8m 2 / g~approximately 45m 2 / g, approximately 7m 2 / g~approximately 45m 2 / g, approximately 9m 2 / g~approximately 45m 2 / g, approximately 10m 2 / g~approximately 45m 2 / g, approximately 11m 2 / g~approximately 45m 2 / g, approximately 12m 2 / g~approximately 45m 2 / g, approximately 13m 2 / g~approximately 45m 2 / g, approximately 14m 2 / g~approximately 45m 2 / g, approximately 15m 2 / g~approximately 45m 2 / g, approximately 16m 2 / g~approximately 45m 2 / g, approximately 17m 2 / g~approximately 45m 2 / g, approximately 18m 2 / g~approximately 45m 2 / g, approximately 19m 2 / g~approximately 45m 2 / g, approximately 20m 2 / g~approximately 45m 2 / g, approximately 21m 2 / g~approximately 45m 2 / g, approximately 22m 2 / g~approximately 45m 2 / g, approximately 23m 2 / g~approximately 45m 2 / g, approximately 24m 2 / g~approximately 45m 2 / g、 3.5m 2 / g~approximately 40m 2 / g, approximately 4m 2 / g~approximately 40m 2 / g, approximately 5m 2 / g~approximately 40m 2 / g, approximately 6m 2 / g~approximately 40m 2 / g, approximately 7m 2 / g~approximately 40m 2 / g, approximately 8m 2 / g~approximately 40m 2 / g, approximately 7m 2 / g~approximately 40m 2 / g, approximately 9m 2 / g~approximately 40m 2 / g, approximately 10m 2 / g~approximately 40m 2 / g, approximately 11m 2 / g~approximately 40m 2 / g, approximately 12m 2 / g~approximately 40m 2 / g, approximately 13m 2 / g~approximately 40m 2 / g, approximately 14m 2 / g~approximately 40m 2 / g, approximately 15m 2 / g~approximately 40m 2 / g, approximately 16m 2 / g~approximately 40m 2 / g, approximately 17m 2 / g~approximately 40m 2 / g, approximately 18m 2 / g~approximately 40m 2 / g, approximately 19m 2 / g~approximately 40m 2 / g, approximately 20m 2 / g~approximately 40m 2 / g, approximately 21m 2 / g~approximately 40m 2 / g, approximately 22m 2 / g~approximately 40m 2 / g, approximately 23m 2 / g~approximately 40m 2 / g, approximately 24m 2 / g~approximately 40m 2 / g、 3.5m 2 / g~approximately 35m 2 / g, approximately 4m 2 / g~approximately 35m 2 / g, approximately 5m 2 / g~approximately 35m 2 / g, approximately 6m 2 / g~approximately 35m 2 / g, approximately 7m 2 / g~approximately 35m 2 / g, approximately 8m 2 / g~approximately 35m 2 / g, approximately 7m 2 / g~approximately 35m 2 / g, approximately 9m 2 / g~approximately 35m 2 / g, approximately 10m 2 / g~approximately 35m 2 / g, approximately 11m 2 / g~approximately 35m 2 / g, approximately 12m 2 / g~approximately 35m 2 / g, approximately 13m 2 / g~approximately 35m 2 / g, approximately 14m 2 / g~approximately 35m 2 / g, approximately 15m 2 / g~approximately 35m 2 / g, approximately 16m 2 / g~approximately 35m 2 / g, approximately 17m 2 / g~approximately 35m 2 / g, approximately 18m 2 / g~approximately 35m 2 / g, approximately 19m 2 / g~approximately 35m 2 / g, approximately 20m 2 / g~approximately 35m 2 / g, approximately 21m 2 / g~approximately 35m 2 / g, approximately 22m 2 / g~approximately 35m 2 / g, approximately 23m 2 / g~approximately 35m 2 / g, approximately 24m 2 / g~approximately 35m 2 / g、 3.5m 2 / g~approximately 30m 2 / g, approximately 4m 2 / g~approximately 30m 2 / g, approximately 5m2 / g ~ about 30 m 2 / g, about 6 m 2 / g ~ about 30 m 2 / g, about 7 m 2 / g ~ about 30 m 2 / g, about 8 m 2 / g ~ about 30 m 2 / g, about 7 m 2 / g ~ about 30 m<000023s> / g, about 9 m 2 / g ~ about 30 m 2 / g, about 10 m 2 / g ~ about 30 m 2 / g, about 11 m 2 / g ~ about 30 m 2 / g, about 12 m 2 / g ~ about 30 m 2 / g, about 13 m 2 / g ~ about 30 m 2 / g, about 14 m 2 / g ~ about 30 m 2 / g, about 15 m 2 / g ~ about 30 m 2 / g, about 16 m 2 / g ~ about 30 m 2 / g, about 17 m 2 / g ~ about 30 m 2 / g, about 18 m 2 / g ~ about 30 m 2 / g, about 19 m 2 / g ~ about 30 m 2 / g, about 20 m 2 / g ~ about 30 m 2 / g, about 21 m 2 / g ~ about 30 m 2 / g, about 22 m<l 2 / g ~ about 30 m 2 / g, about 23 m 2 / g ~ about 30 m 2 / g, or about 24 m 2 / g ~ about 30 m 2 has an SSA of / g.

[0020] In one embodiment, the cisplatin particles have a mean particle size by volume distribution (Dv50) of about 0.7 microns to about 12.0 microns in diameter, about 0.7 microns to about 8.0 microns, or about 1.0 microns to about 12.0 microns in diameter. In some embodiments, the cisplatin particles have a mean particle size by volume distribution of about 1 micron to about 6 microns in diameter, or about 1 micron to about 3.5 or 3.0 microns in diameter. The cisplatin particles are in a size range such that they are unlikely to be cleared from the tumor via systemic circulation but benefit from a high specific surface area, which provides enhanced solubilization and release of the drug.

[0021] In one embodiment, the cisplatin particles have a density of about 0.020 g / cm 3 ~about 0.8g / cm 3 It has an average bulk density of

[0022] As used herein, the bulk density of cisplatin particles is the mass of all particles in a composition divided by the total volume they would occupy if poured into a graduated cylinder and not tapped. The total volume includes particle volume, interparticle void volume, and internal pore volume.

[0023] The increased specific surface area and reduced bulk density of cisplatin particles result in a significantly increased dissolution rate compared to, for example, raw cisplatin or milled cisplatin products. Dissolution occurs exclusively at the solid / liquid interface. Therefore, increased specific surface area will increase the dissolution rate due to the large number of molecules on the surface of the particles that come into contact with the dissolution medium. Bulk density takes into account the powder's macrostructure and interparticle space. Parameters that contribute to bulk density include particle size distribution, particle shape, and particle-to-particle affinity (i.e., cohesion). A lower powder bulk density results in a faster dissolution rate. This is due to the ability of the dissolution medium to more easily penetrate the interstitial or interparticle space and have greater contact with the particle surface. This provides a significant improvement for the cisplatin particles disclosed herein, for example, for use in tumor therapy.

[0024] In any of these various embodiments, the cisplatin particles may be, for example, at least 5×10 per cisplatin particle. -15 gram of cisplatin, or approximately 1x10 per cisplatin particle -8 ~about 5X10 -15 The compound may contain 10 grams of cisplatin.

[0025] In one embodiment, the particles are uncoated and free of polymers, proteins, polyethoxylated castor oil and polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol.

[0026] In a further embodiment, the composition comprises a liquid suspension further comprising a pharmaceutically acceptable liquid carrier. The suspension of the present disclosure comprises cisplatin particles and a liquid carrier. The liquid carrier can be aqueous or non-aqueous. Even if the cisplatin particles do not contain an excipient, the liquid carrier of the suspension can comprise water or a non-aqueous liquid, and can optionally include one or more excipients selected from the group consisting of buffers, isotonicity agents, preservatives, analgesics, viscosity modifiers, osmotic agents, surfactants, antioxidants, alkalinizing agents, acidifiers, antifoaming agents, and colorants. For example, the suspension can comprise cisplatin particles, water, a buffer, and a salt. It can optionally further comprise a surfactant. In some embodiments, the suspension consists essentially of, or consists of, water, cisplatin particles suspended in water, and a buffer. The suspension can further include an osmotic salt. In another example, the suspension may contain cisplatin particles and a non-aqueous liquid, such as a liquefied gas propellant. Examples of liquefied gas propellants include, but are not limited to, hydrofluoroalkanes (HFAs). Examples of other non-aqueous liquids include, but are not limited to, mineral oil, vegetable oils, glycerin, polyethylene glycol, room-temperature liquid poloxamer (e.g., poloxamer 124), and room-temperature liquid polyethylene glycols (e.g., PEG400 and PEG600).

[0027] In one embodiment, the suspension further comprises one or more ingredients selected from the group consisting of polysorbates, methylcellulose, polyvinylpyrrolidone, mannitol, and hydroxypropylmethylcellulose.

[0028] The suspension may include one or more surfactants. Examples of suitable surfactants include, but are not limited to, polysorbates, lauryl sulfates, acetylated monoglycerides, diacetylated monoglycerides, and poloxamers.

[0029] The suspension may contain one or more isotonicity agents. Examples of suitable isotonicity agents 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, e.g., calcium salts and magnesium salts), mannitol, dextrose, glycerin, propylene glycol, and mixtures thereof.

[0030] In an embodiment particularly suitable for intraperitoneal (IP) administration, the suspension may be formulated to be hyperosmotic (hypertonic), hypoosmotic (hypotonic), or isotonic (isotonic) relative to the fluid in the peritoneal cavity. In some embodiments, the suspension may be isotonic relative to the fluid in the peritoneal 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.

[0031] The suspension may contain one or more buffers. Examples of suitable buffers include, but are not limited to, dibasic sodium phosphate, sodium dihydrogen phosphate, citric acid, sodium citrate hydrochloride, sodium hydroxide, tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)iminotris-(hydroxymethyl)methane, and sodium bicarbonate, as well as other buffers known to those skilled in the art. Buffers are generally used to adjust the pH to a desired range for intraperitoneal use. Typically, a pH of about 5-9, 5-8, 6-7.4, 6.5-7.5, or 6.9-7.4 is desired.

[0032] The suspension may include one or more demulcents, which are agents that form a pain-relieving film on mucous membranes, such as the membranes that cover the peritoneum and the organs therein. Demulcents can relieve mild pain and inflammation and are sometimes called mucoprotective agents. Suitable analgesics include cellulose derivatives (such as sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, and methylcellulose) in the range of about 0.2 to about 2.5%; about 0.01% gelatin; about 0.05 to about 1% polyols (including about 0.05 to about 1% glycerin, 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; and, when used with another polymeric analgesic described herein, from about 0.1% dextran 70.

[0033] The suspension may contain one or more alkalizing agents to adjust the pH. As used herein, the term "alkalinizing agent" is intended to mean a compound used to provide an alkaline medium. Such compounds include, but are not limited to, for example, ammonia solution, ammonium carbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium hydroxide, as well as other alkalizing agents known to those skilled in the art.

[0034] The suspension may contain one or more acidifying agents to adjust pH.As used herein, the term "acidifying agent" refers to a compound that is used to provide an acidic medium.Such compounds include, but are not limited to, for example, acetic acid, amino acids, citric acid, nitric acid, fumaric acid and other alphahydroxy acids, hydrochloric acid, ascorbic acid, and nitric acid, and other acidifying agents known to those skilled in the art.

[0035] The suspension may contain one or more antifoaming agents.As used herein, the term "antifoaming agent" is intended to mean a compound or compounds that prevent or reduce the amount of foaming that forms on the surface of the fill composition.Suitable antifoaming agents include, but are not limited to, for example, dimethicone, SIMETHICONE®, octoxynol, and other antifoaming agents known to those skilled in the art.

[0036] Suspensions may contain one or more viscosity modifiers, which increase or decrease the viscosity of the suspension. Suitable viscosity modifiers include methylcellulose, hydroxypropylmethylcellulose, mannitol and polyvinylpyrrolidone.

[0037] The suspension may include one or more osmotic agents, such as those used in peritoneal dialysis. Suitable osmotic agents include icodextrin (a glucose polymer), sodium chloride, potassium chloride, and salts also used as buffering agents.

[0038] In one embodiment, a liquid suspension of cisplatin particles may be aerosolized for pulmonary administration by inhalation, and the mass median aerodynamic diameter (MMAD) of the aerosol droplets of the liquid suspension may be a diameter suitable for use. In one embodiment, the MMAD of the aerosol droplets has a diameter of about 0.5 μm to about 6 μm. In various further embodiments, the aerosol droplets have a diameter of about 0.5 μm to about 5.5 μm, about 0.5 μm to about 5 μm, about 0.5 μm to about 4.5 μm, about 0.5 μm to about 4 μm, about 0.5 μm to about 3.5 μm, about 0.5 μm to about 3 μm, about 0.5 μm to about 2.5 μm, about 0.5 μm to about 2 μm, about 1 μm to about 5.5 μm, about 1 μm to about 5 μm, about 1 μm to about 4.5 μm, about 1 μm to about 4 μm, about 1 μm to about 3.5 μm, about 1 μm to about 3 μm, or about 1 μm to about 2.5 μm. , having a MMAD of about 1 μm to about 2 μm diameter, about 1.5 μm to about 5.5 μm diameter, about 1.5 μm to about 5 μm diameter, about 1.5 μm to about 4.5 μm diameter, about 1.5 μm to about 4 μm diameter, about 1.5 μm to about 3.5 μm diameter, about 1.5 μm to about 3 μm diameter, about 1.5 μm to about 2.5 μm diameter, about 1.5 μm to about 2 μm diameter, about 2 μm to about 5.5 μm diameter, about 2 μm to about 5 μm diameter, about 2 μm to about 4.5 μm diameter, about 2 μm to about 4 μm diameter, about 2 μm to about 3.5 μm diameter, about 2 μm to about 3 μm diameter, and about 2 μm to about 2.5 μm diameter. A suitable device for measuring the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of aerosol droplets is a seven-stage aerosol sampler (such as a Mercer-type cascade impactor). The liquid suspension of cisplatin particles delivered by aerosol can be deposited in the respiratory tract by gravitational settling, inertial impaction, and / or diffusion. Any suitable device for generating aerosols can be used, including, but not limited to, metered-dose inhalers (MDIs), pressurized metered-dose inhalers (pMDIs), nebulizers, and soft-mist metered-dose inhalers.

[0039] In one embodiment, the dry powder composition of cisplatin particles may be aerosolized for pulmonary administration by inhalation, and the aerodynamic mass median diameter (MMAD) of the aerosolized dry powder composition may be any suitable diameter for use. The dry powder composition is formulated as a dry powder. The dry powder composition may contain cisplatin particles alone without a carrier, or may contain a pharmaceutically acceptable dry powder carrier containing cisplatin particles and one or more dry powder excipients. In one embodiment, the aerosolized dry powder composition has an MMAD with a diameter of from about 0.5 μm to about 6 μm. In various further embodiments, the aerosolized dry powder composition has a diameter of from about 0.5 μm to about 5.5 μm, from about 0.5 μm to about 5 μm, from about 0.5 μm to about 4.5 μm, from about 0.5 μm to about 4 μm, from about 0.5 μm to about 3.5 μm, from about 0.5 μm to about 3 μm, from about 0.5 μm to about 2.5 μm, from about 0.5 μm to about 2 μm, from about 1 μm to about 5.5 μm, from about 1 μm to about 5 μm, from about 1 μm to about 4.5 μm, from about 1 μm to about 4 μm, from about 1 μm to about 3.5 μm, from about 1 μm to about 3 μm, from about 1 μm to about 2.5 μm, from about 1 μm to about 2 μm, from about 1.5 μm to about 5.5 μm, from about 1.5 μm to about 5 μm, from about 1.5 μm to about 4.5 μm, from about 1.5 μm to about 4 μm, from about 1.5 μm to about 3.5 μm, from about 1.5 μm to about 3 μm, from about 1.5 μm to about 2.5 μm, from about 1.5 μm to about 2 μm, from about 2 μm to about 5.5 μm, from about 2 μm to about 5 μm, from about 2 μm to about 4.5 μm, from about 2 μm to about 4 μm, from about 2 μm to about 3.5 μm, from about 2 μm to about 3 μm, and from about 2 μm to about 2.5 μm. Suitable equipment for measuring the aerodynamic mass median diameter (MMAD) and geometric standard deviation (GSD) of the dry powder composition is a 7-stage aerosol sampler (such as a Mercer-type cascade impactor) or an aerodynamic particle size analyzer spectrometer (such as the APS® model 3321 spectrometer available from TSI). The dry powder composition delivered by the aerosol may be deposited in the airways by gravitational sedimentation, inertial impaction, and / or diffusion.Any suitable device for generating an aerosol of the dry powder composition may be used, including, but not limited to, a dry powder inhaler (DPI). Examples of suitable excipients for inhalable dry powder compositions include, but are not limited to, lactose of a grade suitable for inhalation. In one embodiment, the composition is a dry powder composition suitable for pulmonary delivery by inhalation via aerosolization.

[0040] In one embodiment, the composition comprises a cisplatin dosage form in suspension (i.e., together with a pharmaceutically acceptable carrier and any other ingredients) at a dosage deemed appropriate by the attending physician for the intended use. Any suitable dosage form can be used, and in various non-limiting embodiments, the dosage form is suitable for administration of 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 administration of about 0.01 mg / kg to about 45 mg / kg body weight, about 0.01 mg / kg to about 40 mg / kg body weight, about 0.01 mg / kg to about 35 mg / kg body weight, about 0.01 mg / kg to about 30 mg / kg body weight, about 0.01 mg / kg to about 25 mg / kg body weight, about 0.01 mg / kg to about 20 mg / kg body weight, about 0.01 mg / kg to about 15 mg / kg body weight, about 0.01 mg / kg to about 10 mg / kg body weight, about 0.01 mg / kg to about 5 mg / kg body weight, or about 0.01 mg / kg to about 1 mg / kg body weight per day. The suspension can be administered neat or diluted with a diluent.

[0041] In another embodiment, the suspension comprises: (a) particles comprising at least 95% by weight of cisplatin, At least 3.5m 2 / g, 4m 2 / g, 5m 2 / g, 6m 2 / g, 7m 2 / g, 8m 2 / g, 9m 2 / g, 10m 2 / g, 11m 2 / g, 12m2 / g, 13m 2 / g, 14m 2 / g, 15m 2 / g, 16m 2 / g, 17m 2 / g, 18m 2 / g, 19m 2 / g, 20m 2 / g, 21m 2 / g, 22m 2 / g, 23m 2 / g, or 24m 2 particles having a specific surface area (SSA) of 1 / g; (b) about 40% to about 60% w / w glycerin; (c) about 20% to about 40% w / w propylene glycol; (d) about 5% to about 20% w / w ethanol; and (e) 0.9% sodium chloride in about 5% to about 10% w / w water Includes: In a further embodiment, the suspension comprises: (b) about 45% to about 55% w / w glycerin; (c) about 25% to about 35% w / w propylene glycol; (d) about 10% to about 15% w / w ethanol; and (e) 0.9% sodium chloride in about 7% to about 9% w / w water Includes:

[0042] In a further embodiment, the suspension comprises: about 48% to about 52% w / w glycerin; about 28% to about 32% w / w propylene glycol; about 12% to about 14% w / w ethanol; and 0.9% sodium chloride in approximately 7.5% to approximately 8.5% w / w water Includes:

[0043] In a further embodiment, the suspension comprises: approximately 49% w / w glycerin; approximately 30% w / w propylene glycol; Approximately 13% w / w ethanol; and 0.9% sodium chloride in approximately 8% w / w water Includes:

[0044] In various embodiments, the concentration of cisplatin particles is at least 2.5 mg / ml in the suspension, or at least 5 mg / ml in the suspension, or at least 10 mg / ml in the suspension. The suspensions of this embodiment provide higher concentrations of cisplatin than are currently available due to solubility issues.

[0045] In another embodiment, the present disclosure provides a method for manufacturing a semiconductor device comprising: (a) (i) 0.9% sodium chloride in about 30% to about 50% w / w water; (ii) about 30% to about 50% w / w glycerin; and (iii) about 5% to about 25% w / w ethanol; a first solution comprising water; (b) (i) about 40% to about 60% w / w glycerin; (ii) about 30% to about 45% w / w propylene glycol; (iii) about 5% to about 20% w / w ethanol; a second water-free solution comprising: (c) particles containing at least 95% by weight of cisplatin and having a particle size of at least 3.5 mm 2 / g, 4m 2 / g, 5m 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, 14m 2 / g, 15m 2 / g, 16m 2 / g, 17m 2 / g, 18m 2 / g, 19m 2 / g, 20m2 / g, 21m 2 / g, 22m 2 / g, 23m 2 / g, or 24m 2 / g specific surface area (SSA) of particles A kit comprising:

[0046] The first solution facilitates wetting of the cisplatin particles, and the second solution slows the dissolution of the particles and provides the viscosity required for content uniformity of the suspension.

[0047] In one embodiment, the first solution comprises: 0.9% sodium chloride in about 35% to about 45% w / w water; about 40% to about 50% w / w glycerin; and Approximately 10% to 20% w / w ethanol Includes:

[0048] In another embodiment, the first solution comprises: 0.9% sodium chloride in about 37.5% to about 42.5% w / w water; about 42.5% to about 47.5% w / w glycerin; and About 12.5% ​​to about 17.5% w / w ethanol Includes:

[0049] In a further embodiment, the first solution comprises: 0.9% sodium chloride in approximately 40% w / w water; about 45% w / w glycerin; and Approximately 15% w / w ethanol Includes:

[0050] In one embodiment, the second solution comprises: about 45% to about 55% w / w glycerin; about 32.5% to about 42.5% w / w propylene glycol; Approximately 8% to approximately 18% w / w ethanol Includes:

[0051] In another embodiment, the second solution comprises: about 47.5% to about 52.5% w / w glycerin; about 35% to about 40% w / w propylene glycol; and Approximately 10% to 15% w / w ethanol Includes:

[0052] In a further embodiment, the second solution comprises: approximately 50% w / w glycerin; about 37.5% w / w propylene glycol; and Approximately 12.5% ​​w / w ethanol Includes:

[0053] In another embodiment, the present disclosure provides a method for manufacturing a semiconductor device comprising: (a) combining particles and a first solution according to any of the above embodiments to form a mixture; and (b) combining the mixture with a second solution according to any of the above embodiments to form a suspension; The present disclosure provides a method for preparing a suspension comprising:

[0054] As discussed above, the second solution stabilizes the dissolution of the cisplatin particles and provides a viscosity that provides content uniformity to the suspension.

[0055] In one embodiment, the second solution is combined with the mixture in a volume ratio of about 4:1. In another embodiment, the method further comprises shaking and / or sonicating the suspension. In some embodiments, the method may comprise placing the suspension in an ultrasonic bath. In other embodiments, if particle agglomerates are found to be present in the cisplatin particles, they may be passed through an air jet mill to break down agglomerated particles before adding the cisplatin particles to the first solution.

[0056] In various embodiments, the concentration of cisplatin particles after preparation of the suspension is at least 2.5 mg / ml in the suspension, or at least 5 mg / ml in the suspension, or at least 10 mg / ml in the suspension.

[0057] In another aspect, the present disclosure provides a method for treating a tumor, comprising administering to a subject having a tumor an effective amount of a composition or suspension of any one embodiment or combination of embodiments of the present disclosure. The increased specific surface area of ​​the cisplatin particles of the present disclosure results in a significant increase in the dissolution rate of the particles compared to currently available cisplatins. This provides a significant improvement, for example, in the use of the particles of the present disclosure in tumor treatment. Furthermore, in some embodiments, the methods of the present disclosure can reduce the frequency of cisplatin administration and side effects. As a non-limiting example, a dose of cisplatin administered by direct intratumoral injection would provide significant benefits and reduced side effects because systemic concentrations are significantly reduced. Cisplatin particles of the present disclosure that dissolve inside the tumor create a higher concentration of dissolved cisplatin compared to the concentration of cisplatin in surrounding body fluids. Locally depots with higher cisplatin concentrations interact with rapidly dividing tumor cells to a greater extent than cisplatin delivered systemically to the tumor. This reduces the intracellular interactions of cisplatin outside the tumor. Dissolved cisplatin binds to proteins and DNA of tumor cells inside the tumor in greater amounts than cisplatin binds to proteins and cellular DNA outside the tumor. The larger surface area of ​​the particles reduces the time required to reach higher localized concentrations of cisplatin inside the tumor. In one embodiment, the method comprises intratumoral injection of a suspension of the present disclosure, wherein the concentration of cisplatin particles in the suspension is at least 2.5 mg / ml, or at least 5 mg / ml, or at least 10 mg / ml.

[0058] As used herein, "tumor" includes benign tumors, pre-cancerous tumors, malignant tumors that have not metastasized, and malignant tumors that have metastasized.

[0059] The disclosed methods can be used to treat tumors that are sensitive to cisplatin treatment, including, but not limited to, carcinoma, breast tumor, pancreatic tumor, prostate tumor, bladder tumor, lung tumor, ovarian tumor, gastrointestinal tumor, testicular tumor, cervical tumor, head and neck tumor, esophageal tumor, mesothelioma, brain tumor, neuroblastoma, or renal cell tumor. In certain embodiments, the tumor is metastatic testicular tumor, metastatic ovarian tumor, advanced bladder cancer, diffuse intrinsic pontine glioma, pediatric high-grade astrocytoma, or glioblastoma.

[0060] In another embodiment, the method further comprises administering an additional therapeutic agent to the subject, including but not limited to anthracyclines, antimetabolites, alkylating agents, alkaloids, taxanes (including but not limited to paclitaxel, docetaxel, cabazitaxel, and combinations thereof), poly ADP-ribose polymerase (PARP) inhibitors, and / or topoisomerase inhibitors.

[0061] In certain embodiments, the one or more additional therapeutic agents may include one of durvalumab, tremelimumab, and / or etoposide.

[0062] The subject may be any suitable subject having a tumor, including, but not limited to, a human, a primate, a dog, a cat, a horse, a cow, etc. In one embodiment, the subject is a human subject.

[0063] As used herein, "treat" or "treating" means accomplishing one or more of the following: (a) reducing the severity of the disability; (b) inhibiting or preventing the occurrence of symptoms characteristic of the disorder being treated; (c) preventing the worsening of symptoms characteristic of the disorder being treated; (d) inhibiting or preventing the recurrence of the disorder in a patient who previously had the disorder; and (e) reducing or preventing the recurrence of symptoms in a patient previously symptomatic of the disorder.

[0064] Amounts effective for these uses will depend on factors including, but not limited to, the properties of cisplatin (such as specific activity), the route of administration, the stage and severity of the disorder, the subject's weight and general health, and the judgment of the attending physician. It will be understood that the amount of the suspension composition of the present disclosure actually administered will be determined by a physician, taking into account the relevant circumstances described above. In one non-limiting embodiment, an effective amount is an amount providing 0.01 mg / kg to about 50 mg / kg of body weight per day.

[0065] The composition comprises: Administration may be by any suitable route, including but not limited to oral, pulmonary, intraperitoneal, intratumoral, peritumoral, subcutaneous injection, intramuscular injection, intravesical administration, administration into the mammary fat pad, or any other form of injection, as deemed most appropriate by the attending physician considering all factors for a given subject.

[0066] In one embodiment, pulmonary administration includes inhalation of a single dose of cisplatin particles, such as by nasal inhalation, oral inhalation, or both. The cisplatin particles can be administered in two or more different doses (multiple doses). In this embodiment, the particles can be formulated as an aerosol (i.e., droplets of a stable dispersion or suspension of particles in a gaseous medium). The cisplatin particles delivered by aerosol can be deposited in the respiratory tract by gravitational settling, inertial impaction, and / or diffusion. Any suitable device for generating an aerosol can be used, including, but not limited to, a metered-dose inhaler (MDI), a pressurized metered-dose inhaler (pMDI), a nebulizer, and a soft-mist metered-dose inhaler.

[0067] In one particular embodiment, the method involves inhalation of aerosolized cisplatin particles by nebulization. Nebulizers generally use compressed gas or ultrasonic power to generate inhalable aerosol droplets of the particles or a suspension thereof. In this embodiment, nebulization results in pulmonary delivery of the aerosol droplets of the cisplatin particles or a suspension thereof to the subject.

[0068] In another embodiment, the method involves inhalation of aerosolized cisplatin particles through a pMDI, the particles or a suspension thereof being suspended in a suitable propellant system (including but not limited to hydrofluoroalkanes (HFAs) containing at least one liquefied gas in a pressurized container sealed by a metering valve), actuation of the valve resulting in delivery of a metered dose of the aerosol spray of cisplatin particles or a suspension thereof.

[0069] In another embodiment, the method comprises inhaling a cisplatin dry powder composition with a DPI, the dry powder composition comprising only cisplatin particles without a carrier. In yet another embodiment, the method comprises inhaling a cisplatin dry powder composition with a DPI, the dry powder composition comprising cisplatin particles and optionally a pharmaceutically acceptable dry powder carrier comprising one or more dry powder excipients. Examples of dry powder excipients suitable for inhalable dry powder compositions include, but are not limited to, lactose of a grade suitable for inhalation.

[0070] An administration period is the period during which a dose of cisplatin particles in a composition or suspension is administered. The administration period can be a single period during which the entire dose is administered, or it can be divided into two or more periods during each of which a portion of the dose is administered.

[0071] The post-administration period is a period that begins after the completion of the previous administration period and ends after the start of the next administration period. The duration of the post-administration period can vary depending on the subject's clinical response to cisplatin. No suspension is administered during the post-administration period. 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 be kept constant for a subject, or two or more different post-administration times can be used for a subject.

[0072] A dosing cycle includes an administration period and a post-administration period. Thus, the duration of a dosing cycle is the sum of the administration period and the post-administration period. The administration cycle can be kept constant for a given subject, or two or more different administration cycles can be used for a given subject.

[0073] In one embodiment, the administering is performed one or more times, with each administration separated by at least 21 days.

[0074] The cisplatin particles are as follows: (a) (i) introducing into a nozzle inlet a solution comprising at least one solvent, including but not limited to DMF (dimethylformamide), DMSO (dimethyl sulfoxide), acetone, or combinations thereof, and at least one solute, including cisplatin, and (ii) a compressed fluid into an inlet of a vessel defining a pressurizable chamber; (b) passing the solution through a nozzle orifice into a pressurizable chamber to create an output stream of atomized droplets, the nozzle orifice being located 2 mm to 20 mm from an acoustic energy source located within the output stream, the acoustic energy source generating acoustic energy at an amplitude of 10% to 100% during said passing, and the nozzle orifice having a diameter of 20 μm to 125 μm; (c) contacting the sprayed droplets with a compressed fluid to cause solvent depletion from the sprayed droplets to produce cisplatin particles containing at least 95% cisplatin, wherein the cisplatin particles are within 3.5 m 2 / g specific surface area (SSA) and an average particle size of about 0.7 μm to about 8 μm;

[0033] Steps (a), (b), and (c) are carried out under supercritical temperatures and pressures for the compressed fluid.

[0075] The method utilizes an acoustic energy source located directly in the output stream of solute dissolved in a solvent. Any suitable source of acoustic energy compatible with the methods of the present disclosure may be used, including, but not limited to, an acoustic horn, an acoustic probe, or an acoustic plate. In various embodiments, the nozzle opening is located within a range of 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 The thickness of the adhesive layer may be in the range of about 10 mm to about 10 mm, about 6 mm to about 8 mm, about 8 mm to about 20 mm, about 8 mm to about 18 mm, about 8 mm to about 16 mm, about 8 mm to about 14 mm, about 8 mm to about 12 mm, about 8 mm to about 10 mm, about 10 mm to about 20 mm, about 10 mm to about 18 mm, about 10 mm to about 16 mm, about 10 mm to about 14 mm, about 10 mm to about 12 mm, about 12 mm to about 20 mm, about 12 mm to about 18 mm, about 12 mm to about 16 mm, about 12 mm to about 14 mm, about 14 mm to about 20 mm, about 14 mm to about 18 mm, about 14 mm to about 16 mm, about 16 mm to about 20 mm, about 16 mm to about 18 mm, and about 18 mm to about 20 mm. In a further embodiment, the nozzle assembly of any one embodiment of WO2016 / 197091 may be used.

[0076] Any suitable source of acoustic energy compatible with the methods of the present disclosure may be used, including, but not limited to, an acoustic horn, an acoustic probe, or an acoustic plate. In various further embodiments, the acoustic energy source generates acoustic energy at an amplitude of about 10% to about 100% of the total power that can be generated using the acoustic energy source. Given the present disclosure, one of ordinary skill in the art will be able to determine an appropriate acoustic energy source having a particular total power output for use. In one embodiment, the acoustic energy source has a total power output of about 500 to about 900 watts; in various further embodiments, it has a total power output of about 600 to about 800 watts, about 650 to 750 watts, or about 700 watts.

[0077] In various further embodiments, the acoustic energy source is configured to generate between about 20% and about 100%, between about 30% and about 100%, between about 40% and about 100%, between about 50% and about 100%, between about 60% and about 100%, between about 70% and about 100%, between about 80% and about 100%, between about 90% and about 100%, between 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 80%, about 60% to about 80%, about 70 % to approximately 80%, approximately 10% to approximately 70%, approximately 20% to approximately 70%, approximately 30% to approximately 70%, approximately 40% to approximately 70%, approximately 50% to approximately 70%, approximately 60% to approximately 70%, approximately 10% to approximately 60%, approximately 20% to approximately 60%, approximately 30% to approximately 60%, approximately 40% to approximately 60%, approximately 50% to approximately 60%, approximately 10% to approximately 50%, approximately 20% to approximately 50%, approximately 30% to The acoustic energy source generates acoustic energy having an output of 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%. In light of the present disclosure, one of ordinary skill in the art can determine the appropriate frequency to use in the acoustic energy source. In one embodiment, the acoustic energy source uses a frequency of about 18 to about 22 kHz. In various other embodiments, the acoustic energy source uses a frequency of about 19 to about 21 kHz, about 19.5 to about 20.5 kHz, or about 20 kHz.

[0078] In various further embodiments, the nozzle opening has a diameter of about 20 μm to about 125 μm, about 20 μm to about 115 μm, about 20 μm to about 100 μm, about 20 μm to about 90 μm, about 20 μm to about 80 μm, about 20 μm to about 70 μm, about 20 μm to about 60 μm, about 20 μm to about 50 μm, about 20 μm to about 40 μm, about 20 μm to about 30 μm, about 30 μm to about 125 μm, about 30 μm to about 115 μm, about 30 μm to about 100 μm, about 30 μm to about 90 μm, μm, approximately 30 μm to approximately 80 μm, approximately 30 μm to approximately 70 μm, approximately 30 μm to approximately 60 μm, approximately 30 μm to approximately 50 μm, approximately 30 μm to approximately 40 μm, approximately 40 μm to approximately 125 μm, approximately 40 μm to approximately 115 μm, approximately 40 μm to approximately 10 0μm, 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, about 50μm to about 1 00μm, about 50μm to about 90μm, about 50μm to about 80μm, about 50μm to about 70μm, about 50μm to about 60μm, about 60μm to about 125μm, about 60μm to about 115μm, about 60μm to about 100μm, about 60μm Approximately 90μm, approximately 60μm to approximately 80μm, approximately 60μm to approximately 70μm, approximately 70μm to approximately 125μm, approximately 70μm to approximately 115μm, approximately 70μm to approximately 100μm, approximately 70μm to approximately 90μm, approximately 70μm to approximately 80μm, approximately 80μm The nozzle has a diameter of 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 compressed fluid used in the method.

[0079] The solvent comprises DMF (dimethylformamide), DMSO (dimethyl sulfoxide), acetone, or a combination thereof, and the solvent constitutes at least about 80%, 85%, or 90% by weight of the total solution.

[0080] The compressed fluid can form a supercritical fluid under the conditions used, and the solutes that form the particles are poorly soluble or insoluble in the compressed fluid. As known to those skilled in the art, a supercritical fluid is any substance at a temperature and pressure above its critical point where distinct liquid and gas phases do not exist. Steps (a), (b), and (c) of the disclosed method are carried out at a supercritical temperature and pressure for the compressed fluid, so that the compressed fluid exists as a supercritical fluid during these processing steps.

[0081] The compressed fluid can act as a solvent and be used to remove unwanted components in the particles. Any suitable compressed fluid can be used in the method of the present disclosure; exemplary such compressed fluids are disclosed in U.S. Patent Nos. 5,833,891 and 5,874,029. In a non-limiting embodiment, suitable supercritical fluid-forming compressed fluids and / or anti-solvents can include carbon dioxide, ethane, propane, butane, isobutane, nitrous oxide, xenon, sulfur hexafluoride, and trifluoromethane. The anti-solvent described in step (d) to cause further solvent depletion is a compressed fluid as defined above, and can be the same compressed fluid used in steps (a) to (c) or different. In one embodiment, the anti-solvent used in step (d) is the same as the compressed fluid used in steps (a) to (c). In a preferred embodiment, both the compressed fluid and the anti-solvent are supercritical carbon dioxide. In all cases, the compressed fluid and anti-solvent must be substantially miscible with the solvent, while the cisplatin must be substantially insoluble in the compressed fluid, i.e., cisplatin must be about 5% by weight or less soluble in the compressed fluid or anti-solvent at the selected solvent / compressed fluid contact conditions, and preferably essentially completely insoluble.

[0082] The supercritical conditions used in the methods of the present disclosure are typically in the range of 1 to about 1.4 times, or 1 to about 1.2 times, the critical temperature of the supercritical fluid, and 1 to about 7 times, or 1 to about 2 times, the supercritical pressure for the compressed fluid.

[0083] Determining the critical temperature and pressure for a given compressed fluid or anti-solvent is well within the capabilities of one skilled in the art. In one embodiment, both the compressed fluid and the anti-solvent are supercritical carbon dioxide, with a critical temperature of at least 31.1°C and a maximum of about 60°C, and a critical pressure of at least 1071 psi and a maximum of about 1800 psi. In another embodiment, both the compressed fluid and the anti-solvent are supercritical carbon dioxide, with a critical temperature of at least 35°C and a maximum of about 55°C, and a critical pressure of at least 1070 psi and a maximum of about 1500 psi. One skilled in the art will understand that the specific critical temperatures and pressures will be different at different steps during processing.

[0084] Any suitable pressurizable chamber may be used, including, but not limited to, those disclosed in WO2016 / 197091 or U.S. Patent Nos. 5,833,891 and 5,874,029. Similarly, the steps of contacting the spray liquid with a compressed fluid to deplete the solvent from the droplets and contacting the droplets with an antisolvent to further deplete the solvent from the droplets may be carried out under any suitable conditions, including, but not limited to, those disclosed in U.S. Patent Nos. 5,833,891 and 5,874,029, to produce particles of the compound.

[0085] The flow rate can be adjusted to be as high as possible to optimize output, but below the pressure limits for the equipment containing the nozzle opening. 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 various further embodiments, the flow rate is 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 15 mL / min, or about 2 mL / min to about 10 mL / min. The drug solution subjected to the flow rate can be of any suitable concentration, such as about 1 mg / ml to about 80 mg / ml.

[0086] In one embodiment, the method further includes receiving the plurality of particles through an outlet of the pressurizable chamber; and collecting the plurality of particles with a collection device such as disclosed in WO2016 / 197091.

[0087] In another aspect, the present disclosure provides cisplatin particles prepared by the method of any one embodiment or combination of embodiments of the present disclosure.

[0088] Example 1 Substance Description Compound name: Cisplatin Molecular formula: Pt(NH3)2Cl2 Molecular weight: 300.05g / mol

[0089] Material Testing Particle Size Distribution (PSD) by Laser Diffraction Image analysis by scanning electron microscopy (SEM) Measurement of specific surface area (SSA) by BET sorptometry Determination of crystalline / amorphous phase by powder X-ray diffraction (PXRD) Revised United States Pharmacopoeia <616> Bulk density analysis of powders by method I

[0090] test [1] Solvent solubility test of cisplatin in various solvents. [2] demonstrate the precipitation of cisplatin from three solvent systems and then analyze the corresponding materials with respect to / by PSD, SEM, PXRD, SSA, and bulk density.

[0091] The solubility of cisplatin was tested in the following solvent mixtures: 1:3 DMSO:acetone; 1:1 DMSO:acetone; 3:1 DMSO:acetone; DMF alone; and DMSO alone.

[0092] Three small-scale sedimentation studies were performed with cisplatin in the RC612B sedimentation apparatus.

[0093] The precipitates from the above tests were analyzed by laser diffraction to measure PSD, SEM to support the PSD data and determine shape / trend, BET sorptometry to determine SSA, PXRD to determine the crystalline / amorphous phase of the material, and bulk density analysis to reveal further physical properties of the precipitate.

[0094] Experimental Method Obtaining materials Cisplatin was purchased from BOC Sciences and stored in a temperature / humidity monitored cabinet.

[0095] Solvent Selection Solubility in organic solvents greater than about 8 mg / mL at room temperature was deemed suitable for further testing, with greater solvent solubility resulting in reduced formation times. Solubility was determined by visual observation and tested according to standard operating procedures.

[0096] Sedimentation Thirteen small scale precipitates of cisplatin were generated in the RC612B SCP apparatus according to the RC612B standard operating procedure EQP-002, Operation, Maintenance, and Calibration.

[0097] In a specific exemplary method, a 16.8 mg / mL solution of cisplatin was prepared in DMF. The nozzle and acoustic probe were placed approximately 9 mm apart in a pressurizable chamber. A stainless steel membrane filter with a nominal rating of approximately 20 nm was attached to the pressurizable chamber to collect precipitated cisplatin particles. Supercritical carbon dioxide was placed in the pressurizable chamber of the manufacturing facility and subjected to approximately 1200 psi at approximately 38°C and a flow rate of 4 to 12 kg / h. The acoustic probe was adjusted to a frequency of 20 kHz and an amplitude of 60% of maximum output. The DMF solution containing cisplatin was injected through the nozzle at a flow rate of 2 mL / min for approximately 15 minutes. The precipitated cisplatin particles were then collected from the supercritical carbon dioxide as the mixture was injected through the stainless steel mesh filter. The filter containing the cisplatin particles was opened, and the resulting product was collected from the filter.

[0098] In another exemplary method, a 100.4 mg / mL solution of cisplatin was prepared in DMSO. The nozzle and acoustic probe were placed approximately 9 mm apart in a pressurizable chamber. A stainless steel membrane filter with a nominal rating of approximately 20 nm was attached to the pressurizable chamber to collect precipitated cisplatin particles. Supercritical carbon dioxide was placed in the pressurizable chamber of the manufacturing facility and subjected to approximately 1200 psi at approximately 38°C and a flow rate of 4 to 12 kg / h. The acoustic probe was adjusted to a frequency of 20 kHz and an amplitude of 60% of maximum output. The DMSO solution containing cisplatin was injected through the nozzle at a flow rate of 2 mL / min for approximately 3 minutes. The precipitated cisplatin particles were then collected from the supercritical carbon dioxide as the mixture was injected through the stainless steel mesh filter. The filter containing the cisplatin particles was opened, and the resulting product was collected from the filter.

[0099] In another exemplary method, a 49.7 mg / mL solution of cisplatin was prepared in 3:2 (v / v) DMSO:acetone. The nozzle and acoustic probe were placed approximately 9 mm apart in a pressurizable chamber. A stainless steel membrane filter with a nominal rating of approximately 20 nm was attached to the pressurizable chamber to collect precipitated cisplatin particles. Supercritical carbon dioxide was placed in the pressurizable chamber of the manufacturing facility and subjected to approximately 1200 psi at approximately 38°C and a flow rate of 4 to 12 kg / h. The acoustic probe was adjusted to a frequency of 20 kHz and an amplitude of 60% of maximum output. A 3:2 DMSO:acetone solution containing cisplatin was injected through the nozzle at a flow rate of 2 mL / min for approximately 5 minutes. The precipitated cisplatin particles were then collected from the supercritical carbon dioxide as the mixture was injected through the stainless steel mesh filter. The filter containing the cisplatin particles was opened, and the resulting product was collected from the filter.

[0100] In another exemplary method, a 16.7 mg / mL solution of cisplatin was prepared in DMF. The nozzle and acoustic probe were placed approximately 9 mm apart in a pressurizable chamber. A stainless steel membrane filter with a nominal rating of approximately 20 nm was attached to the pressurizable chamber to collect precipitated cisplatin particles. Supercritical carbon dioxide was placed in the pressurizable chamber of the manufacturing facility and subjected to approximately 1300 psi at approximately 39°C and a flow rate of 4 to 12 kg / h. The acoustic probe was adjusted to a frequency of 20 kHz and an amplitude of 60% of maximum output. The DMF solution containing cisplatin was injected through the nozzle at a flow rate of 2 mL / min for approximately 15 minutes. The precipitated cisplatin particles were then collected from the supercritical carbon dioxide as the mixture was injected through the stainless steel mesh filter. The filter containing the cisplatin particles was opened, and the resulting product was collected from the filter.

[0101] In another exemplary method, a 16.8 mg / mL solution of cisplatin was prepared in DMF. The nozzle and acoustic probe were placed approximately 9 mm apart in a pressurizable chamber. A stainless steel membrane filter with a nominal rating of approximately 20 nm was attached to the pressurizable chamber to collect precipitated cisplatin particles. Supercritical carbon dioxide was placed in the pressurizable chamber of the manufacturing facility and subjected to approximately 1100 psi at approximately 38°C and a flow rate of 4 to 12 kg / h. The acoustic probe was adjusted to a frequency of 20 kHz and an amplitude of 60% of maximum output. The DMF solution containing cisplatin was injected through the nozzle at a flow rate of 2 mL / min for approximately 15 minutes. The precipitated cisplatin particles were then collected from the supercritical carbon dioxide as the mixture was injected through the stainless steel mesh filter. The filter containing the cisplatin particles was opened, and the resulting product was collected from the filter.

[0102] In another exemplary method, a 16.8 mg / mL solution of cisplatin was prepared in DMF. The nozzle and acoustic probe were placed approximately 9 mm apart in a pressurizable chamber. A stainless steel membrane filter with a nominal rating of approximately 20 nm was attached to the pressurizable chamber to collect precipitated cisplatin particles. Supercritical carbon dioxide was placed in the pressurizable chamber of the manufacturing facility and subjected to approximately 1200 psi at approximately 37°C and a flow rate of 4 to 12 kg / h. The acoustic probe was adjusted to a frequency of 20 kHz and an amplitude of 60% of maximum output. The DMF solution containing cisplatin was injected through the nozzle at a flow rate of 2 mL / min for approximately 15 minutes. The precipitated cisplatin particles were then collected from the supercritical carbon dioxide as the mixture was injected through the stainless steel mesh filter. The filter containing the cisplatin particles was opened, and the resulting product was collected from the filter.

[0103] In another exemplary method, a 16.8 mg / mL solution of cisplatin was prepared in DMF. The nozzle and acoustic probe were placed approximately 9 mm apart in a pressurizable chamber. A stainless steel membrane filter with a nominal rating of approximately 20 nm was attached to the pressurizable chamber to collect precipitated cisplatin particles. Supercritical carbon dioxide was placed in the pressurizable chamber of the manufacturing facility and subjected to approximately 1200 psi at approximately 42°C and a flow rate of 4 to 12 kg / h. The acoustic probe was adjusted to a frequency of 20 kHz and an amplitude of 60% of maximum output. The DMF solution containing cisplatin was injected through the nozzle at a flow rate of 2 mL / min for approximately 15 minutes. The precipitated cisplatin particles were then collected from the supercritical carbon dioxide as the mixture was injected through the stainless steel mesh filter. The filter containing the cisplatin particles was opened, and the resulting product was collected from the filter.

[0104] In another exemplary method, a 16.7 mg / mL solution of cisplatin was prepared in DMF. The nozzle and acoustic probe were placed approximately 9 mm apart in a pressurizable chamber. A stainless steel membrane filter with a nominal rating of approximately 20 nm was attached to the pressurizable chamber to collect precipitated cisplatin particles. Supercritical carbon dioxide was placed in the pressurizable chamber of the manufacturing facility and subjected to approximately 1200 psi at approximately 39°C and a flow rate of 4 to 12 kg / h. The acoustic probe was adjusted to a frequency of 20 kHz and an amplitude of 20% of maximum output. The DMF solution containing cisplatin was injected through the nozzle at a flow rate of 2 mL / min for approximately 15 minutes. The precipitated cisplatin particles were then collected from the supercritical carbon dioxide as the mixture was injected through the stainless steel mesh filter. The filter containing the cisplatin particles was opened, and the resulting product was collected from the filter.

[0105] In another exemplary method, a 16.8 mg / mL solution of cisplatin was prepared in DMF. The nozzle and acoustic probe were placed approximately 9 mm apart in a pressurizable chamber. A stainless steel membrane filter with a nominal rating of approximately 20 nm was attached to the pressurizable chamber to collect precipitated cisplatin particles. Supercritical carbon dioxide was placed in the pressurizable chamber of the manufacturing facility and subjected to approximately 1200 psi at approximately 38°C and a flow rate of 4 to 12 kg / h. The acoustic probe was adjusted to a frequency of 20 kHz and an amplitude of 80% of maximum output. The DMF solution containing cisplatin was injected through the nozzle at a flow rate of 2 mL / min for approximately 15 minutes. The precipitated cisplatin particles were then collected from the supercritical carbon dioxide as the mixture was injected through the stainless steel mesh filter. The filter containing the cisplatin particles was opened, and the resulting product was collected from the filter.

[0106] In another exemplary method, a 16.7 mg / mL solution of cisplatin was prepared in DMF. The nozzle and acoustic probe were placed approximately 9 mm apart in a pressurizable chamber. A stainless steel membrane filter with a nominal rating of approximately 20 nm was attached to the pressurizable chamber to collect precipitated cisplatin particles. Supercritical carbon dioxide was placed in the pressurizable chamber of the manufacturing facility and subjected to approximately 1200 psi at approximately 37°C and a flow rate of 4 to 12 kg / h. The acoustic probe was adjusted to a frequency of 20 kHz and an amplitude of 0% of maximum output. The DMF solution containing cisplatin was injected through the nozzle at a flow rate of 2 mL / min for approximately 15 minutes. The precipitated cisplatin particles were then collected from the supercritical carbon dioxide as the mixture was injected through the stainless steel mesh filter. The filter containing the cisplatin particles was opened, and the resulting product was collected from the filter.

[0107] In another exemplary method, a 16.7 mg / mL solution of cisplatin was prepared in DMF. The nozzle and acoustic probe were placed approximately 9 mm apart in a pressurizable chamber. A stainless steel membrane filter with a nominal rating of approximately 20 nm was attached to the pressurizable chamber to collect precipitated cisplatin particles. Supercritical carbon dioxide was placed in the pressurizable chamber of the manufacturing facility and subjected to approximately 1200 psi at approximately 36°C and a flow rate of 4 to 12 kg / h. The acoustic probe was adjusted to a frequency of 20 kHz and an amplitude of 20% of maximum output. The DMF solution containing cisplatin was injected through the nozzle at a flow rate of 2 mL / min for approximately 15 minutes. The precipitated cisplatin particles were then collected from the supercritical carbon dioxide as the mixture was injected through the stainless steel mesh filter. The filter containing the cisplatin particles was opened, and the resulting product was collected from the filter.

[0108] Analytical Testing After three cisplatin precipitation runs, the material was analyzed for / by appropriate PSD, SEM, PXRD, SSA, and bulk density.

[0109] Results and Discussion Sedimentation The first and second precipitation tests were performed with DMF (SC1) and DMSO (SC2), respectively. The final test (SC3) was performed using a 3:2 DMSO:acetone mixture to achieve a concentration of 50 mg / mL. SC1 gave a yield of 85.6%, which is a good yield on a small scale. SC2 gave a yield of 54.1%, which is clearly lower than SC1 but is an acceptable yield on a small scale. SC3 gave a yield of 18.6%.

[0110] Particle Size Distribution Particle size analysis was performed on a Malvern Mastersizer® 3000 using a Hydro MV dispersion unit. A non-validated generic PSD / dispersion method was used to analyze the cisplatin samples. The sample preparation method performed was as follows: Weigh 10-20 mg of cisplatin into a 30 mL vial and add 20 mL of ethyl acetate. Disperse the sample by vortexing and then sonicate the suspension in an ultrasonic bath for 1 minute. The sample suspension is then transferred to a Malvern Hydro MV dispersion unit to obtain 5-15% obscuration.

[0111] The results from the PSD of SC1 and SC3 were relatively similar, with the only difference between SC1 and SC3 being Dv90. SC1 and SC3 showed a significant decrease in PSD compared to the raw material.

[0112] Scanning electron microscopy Scanning electron microscopy was performed on a Joel NeoScope® SEM. Overall, imaging supported the particle size distribution results, with various distributions and different particle shapes / trends. Scanning electron micrographs of SC1 and SC2 showed particles in the sub-1 μm range, which was observed in the PSD results, but not at the levels predicted based on SEM. Development of the PSD method will help clarify whether the method used lacked sufficient dispersion energy necessary to disaggregate the aggregates, or whether the Dv90 of 9.18 and 10.83 μm was true and the material aggregated into fused larger particles. Scanning electron micrographs are shown in Figures 1-14; the solvents used and magnifications are indicated in the corresponding figure legends.

[0113] Powder X-ray diffraction Powder X-ray diffraction analysis was performed on a Siemens D5000 X-ray diffractometer. PXRD was scanned from 5 to 35 (2θ degrees) at a speed of 0.02 (2θ degrees / sec) and 1 second per step. The raw material and all three LSAM samples appeared to exhibit the same crystalline pattern, with discernible differences in intensity and broadening resulting primarily from particle size effects and secondarily from preferred orientation. An overlay of the diffraction patterns is shown in Figure 15.

[0114] specific surface area Surface area analysis was performed on a Quantachrome NOVAtouch™ LX2 BET Sorptometer. SC1 produced a 6.3-fold increase in SSA compared to the raw material, and SC2 produced a 4.4-fold increase. SC3 did not yield enough material for analysis, but based on the decrease in PSD, it is estimated that it also had a significant increase in SSA. Surface area results are shown in Table 1.

[0115] Bulk density Bulk density analysis was performed using a 10 mL graduated cylinder due to the low sample volume. SC1 was the only sediment measured due to insufficient material available for analysis from SC2 and SC3. SC1 showed a bulk density reduction of approximately 75% compared to the raw cisplatin. The bulk density results are shown in Table 1.

[0116] conclusion Cisplatin precipitated well from all three solvent systems tested, with DMF showing the most promising results.

[0117] [Table 1]

[0118] MMAD decision Two samples of cisplatin particles as described herein, one with a lower specific surface area (4.41 m 2 / gm) and SC9, which has a much higher surface area (20.54 m 2 Approximately 100 mg (total of 3 replicates) of each of SC12, which had a bulk density of 0.346 gm / cm for SC9, and SC12, which had a bulk density of 0.346 gm / cm for SC9, were analyzed for MMAD using an APS 3321 spectrometer. 3 and 0.223 gm / cm for SC12. 3 The results were as follows: Low surface area sample: MMAD of 1.73 μm, GSD (geometric standard deviation) of 1.44. Higher surface area sample: MMAD of 1.71 μm, GSD of 1.64. These MMAD values ​​were very close to the Dv50 values ​​we obtained for the physical particle size distribution of the particles, 1.50 μm and 1.81 μm. This data demonstrates that particles can be made with an MMAD that allows for delivery by inhalation of a dry powder.

[0119] Pilot study of LSAM-cisplatin On the starting day, 55 CR female NCr nu / nu mice, 8-12 weeks old, were treated with 1x10 ... 7 H69 tumor cells were injected subcutaneously in the flank; the cell injection volume was 0.1 mL / mouse. Pair-matching was performed on mice with tumors between 100 and 150 mm. 3 Treatment was then initiated as detailed in Table 2.

[0120] [Table 2]

[0121] Tumor cells were implanted on day 0 and treatment began on day 18 (mean TV = 126 mm 3 There were five treatment groups (n = 5 / group); all received IT injection (= 25 μL; 27G needle). The IT vehicle group received ethanol / glycerin / water. Animals were placed in a 2000 mm 3 The animals were euthanized at the endpoint or on study day 51. The data are shown in Figures 16-19. On day 51 after a single IT injection: Three of the five animals in group 3 survived, each with an increase in tumor volume; 0 of 5 animals in Group 4 survived; and Five of the five animals in Group 5 survived. Three of the five animals had increased tumor volume, while the other two did not show measurable tumors (see Figure 19).

[0122] Example 2 overview A total of 130 female athymic nude mice bearing human lung cancer H69 xenografts were assigned to 10 treatment groups. Group 1 (N = 5 females) served as untreated controls. All intratumoral (IT) injections were delivered as a single 25 μL injection. Multiple injection sites and / or increased injection volumes were not performed to prevent leakage from multiple injection sites or reflux from a single injection. The maximum concentrations of cisplatin solution and LSAM-cisplatin suspension were 1 mg / mL and 10 mg / mL, respectively. The maximum feasible dose (MFD) for IT was 25 μg for cisplatin solution and 250 μg for LSAM-cisplatin suspension. Group 2 (N = 10 females) received 47.5% ethanol / 47.5% glycerin / 5% water IT on days 1 and 16 of the study and served as controls. Group 3 (N = 20 females) received 133 μg of cisplatin intraperitoneally (IP) once weekly for three cycles (days 1, 8, and 15), considered standard of care (SOC). Group 4 (N = 5) received a single 125 μg IT injection of large surface area microparticle (LSAM)-cisplatin on day 1. Group 5 (N = 5 females) received a single 187.5 μg IT injection of LSAM-cisplatin on day 1. Group 6 (N = 5 females) received a single 250 μg IT injection of LSAM-cisplatin on day 1. Group 7 (N = 20 females) received a single 25 μg IT injection of cisplatin on days 1 and 16. Group 8 (N = 20 females) received a single IT injection of 125 μg of LSAM-cisplatin on days 1 and 16. Group 9 (N = 20 females) received a single IT injection of 187.5 μg of LSAM-cisplatin on days 1 and 16. Group 10 (N = 20 females) received a single IT injection of 250 μg of LSAM-cisplatin on days 1 and 16. One hour after dosing on day 1, blood and tumor tissues were collected for platinum concentration determination from three Group 2 females and five females from Groups 3 and 7-10. On days 8, 16 (pre-dose), and 28, blood and tumor tissues were collected for platinum concentration determination from five females per study day from Groups 3 and 7-10.Total platinum concentrations in blood and tumor tissue were measured by inductively coupled plasma mass spectrometry (ICP-MS).

[0123] The eight-fold difference in administered cisplatin dose (6 mg / kg IP cisplatin on days 1, 8, and 15 vs. approximately 1.1 mg / kg IT cisplatin on days 1 and 16) resulted in higher blood platinum concentrations on day 28. However, mean platinum concentrations in tumor tissue on day 28 after IT administration of approximately 1.1 mg / kg cisplatin were higher compared with those after IP administration.

[0124] On day 28, blood and tumor tissue platinum concentrations were quantifiable after a single IT dose of approximately 5.7, 8.5, or 11.3 mg / kg LSAM-cisplatin on day 1, indicating sustained platinum exposure both systemically and intratumorally. Furthermore, the mean day 28 blood-to-tumor tissue platinum ratios for these three single IT doses of LSAM-cisplatin indicated that LSAM-cisplatin remained primarily in tumor tissue. After repeated IT doses of approximately 5.7, 8.5, or 11.4 mg / kg LSAM-cisplatin on days 1 and 16, mean blood cisplatin concentrations on day 28 were, as expected, greater than after single-dose administration. Platinum concentrations in tumor tissue on day 28 were considered to be similar to the corresponding mean values ​​for a single IT dose of approximately 5.7, 8.5, or 11.3 mg / kg LSAM-cisplatin on day 1, taking into account the variability observed in individual values ​​at each dose. Blood composite platinum AUC values ​​for single IT doses of approximately 5.7, 8.5, and 11.3 mg / kg LSAM-cisplatin on day 1 and for multiple IT doses of approximately 5.7, 8.5, and 11.3 mg / kg LSAM-cisplatin on days 1 and 16 increased more than proportionally. Similarly, increases in tumor tissue composite platinum AUC values ​​were more than dose-proportional after single and repeated IT administration of LSAM-cisplatin.

[0125] In summary, after a single IT dose of approximately 5.7, 8.5, or 11.3 mg / kg LSAM-cisplatin on day 1, platinum exposure persisted in the tumor for at least 28 days, as did the systemic platinum exposure. Based on the mean blood platinum to tumor tissue platinum ratios, systemic exposure to platinum after single or repeated IT doses of approximately 5.7, 8.5, and 11.3 mg / kg LSAM-cisplatin was negligible. This was also the case for repeated IT doses of 1.1 mg / kg cisplatin. Composite platinum AUC0-t values ​​in blood and tumor tissue for single and multiple doses of approximately 5.7, 8.5, and 11.3 mg / kg LSAM-cisplatin increased more than proportionally.

[0126] method Pharmacological studies of LSAM-cisplatin were conducted to: Quantify platinum content in whole blood and tumors from animals receiving IP cisplatin (standard of care, SOC), IT cisplatin at the maximum feasible dose (MFD), and IT LSAM-cisplatin at the maximum feasible dose (MFD) and two lower doses. Evaluate tumor response Evaluate escalated doses of IT LSAM-cisplatin up to 2X the maximum systemically tolerated dose (MTD) Evaluate one versus two injections Evaluate recurrence if tumor shrinks

[0127] The dosing schedule is summarized in Table 3.

[0128] [Table 3]

[0129] Blood and tumor tissues were collected from each treatment group according to Table 4.

[0130] [Table 4]

[0131] Statistical and pharmacokinetic parameters All blood and tumor tissue platinum concentrations reported as BLQ were considered zero for statistical purposes. Means and standard deviations are the only statistics reported for blood and tumor tissue platinum concentrations and blood platinum to tumor tissue ratios. The maximum observed concentration (Cmax), time to Cmax (Tmax), and area under the concentration-time curve (AUC) values ​​for platinum in blood and tumor tissue after single or repeated administration of cisplatin or LSAM-cisplatin of the composite are reported.

[0132] Results and Discussion Individual and mean blood platinum concentrations are shown in Table 5. Individual and mean tumor site tissue platinum concentrations are shown in Table 6. Individual and mean blood to tumor site tissue concentration ratios are shown in Table 7. Platinum Cmax, Tmax, and AUC values ​​for single-dose blood and tumor site tissue data are shown in Tables 8 and 9, respectively. Platinum Cmax, Tmax, and AUC values ​​for multiple-dose blood and tumor site tissue data are shown in Tables 10 and 11, respectively. Mean single-dose blood platinum concentrations are plotted in Figure 20. Mean single-dose tumor site tissue platinum concentrations are plotted in Figure 21. Mean multiple-dose blood platinum concentration data are plotted in Figure 22. Mean multiple-dose tumor site tissue platinum concentration data are plotted in Figure 23.

[0133] Administration of 6 mg / kg IP cisplatin on days 1, 7, and 14 (SOC) resulted in higher day 28 blood platinum concentrations than administration of approximately 1.1 mg / kg IT cisplatin on days 1 and 16, which does not appear unexpected given the 8-fold difference in administered doses. However, mean day 28 tumor site tissue platinum concentrations after administration of approximately 1.1 mg / kg IT cisplatin were greater than after administration of 6 mg / kg IP on days 1, 8, and 15.

[0134] On day 28, blood and tumor tissue platinum concentrations were quantifiable after single IT doses of approximately 5.7, 8.5, or 11.3 mg / kg LSAM-cisplatin on day 1, indicating sustained platinum exposure both systemically and within the tumor. Furthermore, mean day 28 blood-to-tumor tissue platinum ratios for these three single IT doses of LSAM-cisplatin indicated that LSAM-cisplatin remained primarily in tumor tissue. After repeated administration of approximately 5.7, 8.5, or 11.4 mg / kg LSAM-cisplatin IT on days 1 and 16, mean day 28 blood platinum concentrations were, as expected, greater than after single-dose administration. Platinum concentrations in tumor-site tissue on day 28 appeared to be similar to the corresponding mean values ​​for single IT doses of approximately 5.7, 8.5, or 11.3 mg / kg LSAM-cisplatin on day 1, taking into account the variability observed in individual values ​​at each dose.

[0135] Blood composite platinum AUC values ​​increased more than proportionally for administration of a single dose of approximately 5.7, 8.5, and 11.3 mg / kg IT LSAM-cisplatin on day 1 and for administration of multiple doses of approximately 5.7, 8.5, and 11.3 mg / kg IT LSAM-cisplatin on days 1 and 16. Similarly, increases in tumor tissue composite platinum AUC values ​​were greater than dose-proportional after single and repeated IT administration of LSAM-cisplatin.

[0136] conclusion After a single IT dose of approximately 5.7, 8.5, or 11.3 mg / kg LSAM-cisplatin on day 1, platinum exposure persisted in the tumor and systemically for at least 28 days. Based on the mean blood platinum to tumor tissue platinum ratios, systemic exposure to platinum after single or repeated IT doses of approximately 5.7, 8.5, and 11.3 mg / kg LSAM-cisplatin was negligible. This was also the case for repeated IT doses of 1.1 mg / kg cisplatin. Composite platinum AUC0-t values ​​in blood and tumor tissue for single and multiple doses of approximately 5.7, 8.5, and 11.3 mg / kg LSAM-cisplatin increased more than proportionally.

[0137] [Table 5] TIFF2026501045000007.tif182159

[0138] [Table 6] TIFF2026501045000009.tif186159

[0139] [Table 7] TIFF2026501045000011.tif67159

[0140] [Table 8]

[0141] [Table 9]

[0142] [Table 10]

[0143] [Table 11]

[0144] Example 3 In one embodiment, the suspension is formulated using two solutions. Solution 1 contains 40% water for injection, including 0.9% sodium chloride, 45% glycerin, and 15% ethanol. 10 mg / ml cisplatin particles are added to Solution 1. The water helps to moisten the cisplatin particles without completely dissolving them. Solution 2 contains 50% glycerin, 37.5% propylene glycol, and 12.55% ethanol. Solution 1 and Solution 2 are mixed in a 1:4 ratio and shaken for 1 minute. If any unwanted particle clumps still exist, the mixture can be sonicated, for example, in an ultrasonic bath for about 2 minutes. If particle clumps are known to exist in the cisplatin particles, they can be passed through an air jet mill to break down agglomerates before adding the cisplatin particles to the first solution. The composition of the final suspension is 10 mg / ml LSAM cisplatin in water for injection, 49% glycerin, 30% propylene glycol, 13% ethanol, and 8% of 0.9% sodium chloride.

[0145] Once suspended, the cisplatin particle suspensions maintain their integrity for more than 4 hours, and the content uniformity of the suspension meets the requirements of the United States Pharmacopoeia. The suspension can be injected using, for example, a 22-gauge needle.

Claims

1. (a) particles comprising at least 95% by weight of cisplatin, the particles having a size of at least 3.5 mm ２ / g, 4m ２ / g, 5m 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, 14m ２ / g, 15m ２ / g, 16m ２ / g, 17m ２ / g, 18m ２ / g, 19m ２ / g, 20m ２ / g, 21m ２ / g, 22m ２ / g, 23m ２ / g, or 24m ２ / g specific surface area (SSA); (b) about 40% to about 60% w / w glycerin; (c) about 20% to about 40% w / w propylene glycol; (d) about 5% to about 20% w / w ethanol; and (e) 0.9% sodium chloride in about 5% to about 10% w / w water; A suspension comprising:

2. (b) about 45% to about 55% w / w glycerin; (c) about 25% to about 35% w / w propylene glycol; (d) about 10% to about 15% w / w ethanol; and (e) 0.9% sodium chloride in about 7% to about 9% w / w water; 2. The suspension of claim 1, comprising:

3. about 48% to about 52% w / w glycerin, or about 49% w / w glycerin; about 28% to about 32% w / w propylene glycol, or about 30% w / w propylene glycol; about 12% to about 14% w / w ethanol, or about 13% w / w ethanol; and 0.9% sodium chloride in about 7.5% to about 8.5% w / w water, or 0.9% sodium chloride in about 8% w / w water; 2. The suspension of claim 1, comprising:

4. The particles are at least 4 m ２ / g, or at least 10 m ２ 4. The suspension according to claim 1, having an SSA of 0.1g / g.

5. The particles, 3.5m ２ / g ~ Approximately 50m ２ / g, approximately 4m ２ / g ~ Approximately 50m ２ / g, approximately 5m ２ / g ~ Approximately 50m ２ / g, approximately 6m ２ / g ~ Approximately 50m ２ / g, approximately 7m ２ / g ~ Approximately 50m ２ / g, approximately 8m ２ / g ~ Approximately 50m ２ / g, approximately 7m ２ / g ~ Approximately 50m ２ / g, approximately 9m ２ / g ~ Approximately 50m ２ / g, approximately 10m ２ / g ~ Approximately 50m ２ / g, approximately 11m ２ / g ~ Approximately 50m ２ / g, approximately 12m ２ / g ~ Approximately 50m ２ / g, approximately 13m ２ / g ~ Approximately 50m ２ / g, approximately 14m ２ / g ~ Approximately 50m ２ / g, approximately 15m ２ / g ~ Approximately 50m ２ / g, approximately 16m ２ / g ~ Approximately 50m ２ / g, approximately 17m ２ / g ~ Approximately 50m ２ / g, approximately 18m ２ / g ~ Approximately 50m ２ / g, approximately 19m ２ / g ~ Approximately 50m ２ / g, approximately 20m ２ / g ~ Approximately 50m ２ / g, approximately 21m ２ / g ~ Approximately 50m ２ / g, approximately 22m ２ / g ~ Approximately 50m ２ / g, approximately 23m ２ / g ~ Approximately 50m ２ / g, approximately 24m ２ / g ~ Approximately 50m ２ / g、 3.5m ２ / g ~ Approximately 45m ２ / g, approximately 4m ２ / g ~ Approximately 45m ２ / g, approximately 5m ２ / g ~ Approximately 45m ２ / g, approximately 6m ２ / g ~ Approximately 45m ２ / g, approximately 7m ２ / g ~ Approximately 45m ２ / g, approximately 8m ２ / g ~ Approximately 45m ２ / g, approximately 7m ２ / g ~ Approximately 45m ２ / g, approximately 9m ２ / g ~ Approximately 45m ２ / g, approximately 10m ２ / g ~ Approximately 45m ２ / g, approximately 11m ２ / g ~ Approximately 45m ２ / g, approximately 12m ２ / g ~ Approximately 45m ２ / g, approximately 13m ２ / g ~ Approximately 45m ２ / g, approximately 14m ２ / g ~ Approximately 45m ２ / g, approximately 15m ２ / g ~ Approximately 45m ２ / g, approximately 16m ２ / g ~ Approximately 45m ２ / g, approximately 17m ２ / g ~ Approximately 45m ２ / g, approximately 18m ２ / g ~ Approximately 45m ２ / g, approximately 19m ２ / g ~ Approximately 45m ２ / g, approximately 20m ２ / g ~ Approximately 45m ２ / g, approximately 21m ２ / g ~ Approximately 45m ２ / g, approximately 22m ２ / g ~ Approximately 45m ２ / g, approximately 23m ２ / g ~ Approximately 45m ２ / g, approximately 24m ２ / g ~ Approximately 45m ２ / g、 3.5m ２ / g ~ Approximately 40m ２ / g, approximately 4m ２ / g ~ Approximately 40m ２ / g, approximately 5m ２ / g ~ Approximately 40m ２ / g, approximately 6m ２ / g ~ Approximately 40m ２ / g, approximately 7m ２ / g ~ Approximately 40m ２ / g, approximately 8m ２ / g ~ Approximately 40m ２ / g, approximately 7m ２ / g ~ Approximately 40m ２ / g, approximately 9m ２ / g ~ Approximately 40m ２ / g, approximately 10m ２ / g ~ Approximately 40m ２ / g, approximately 11m ２ / g ~ Approximately 40m ２ / g, approximately 12m ２ / g ~ Approximately 40m ２ / g, approximately 13m ２ / g ~ Approximately 40m ２ / g, approximately 14m ２ / g ~ Approximately 40m ２ / g, approximately 15m ２ / g ~ Approximately 40m ２ / g, approximately 16m ２ / g ~ Approximately 40m ２ / g, approximately 17m ２ / g ~ Approximately 40m ２ / g, approximately 18m ２ / g ~ Approximately 40m ２ / g, approximately 19m ２ / g ~ Approximately 40m ２ / g, approximately 20m ２ / g ~ Approximately 40m ２ / g, approximately 21m ２ / g ~ Approximately 40m ２ / g, approximately 22m ２ / g ~ Approximately 40m ２ / g, approximately 23m ２ / g ~ Approximately 40m ２ / g, approximately 24m ２ / g ~ Approximately 40m ２ / g、 3.5m ２ / g ~ Approximately 35m ２ / g, approximately 4m ２ / g ~ Approximately 35m ２ / g, approximately 5m ２ / g ~ Approximately 35m ２ / g, approximately 6m ２ / g ~ Approximately 35m ２ / g, approximately 7m ２ / g ~ Approximately 35m ２ / g, approximately 8m ２ / g ~ Approximately 35m ２ / g, approximately 7m ２ / g ~ Approximately 35m ２ / g, approximately 9m ２ / g ~ Approximately 35m ２ / g, approximately 10m ２ / g ~ Approximately 35m ２ / g, approximately 11m ２ / g ~ Approximately 35m ２ / g, approximately 12m ２ / g ~ Approximately 35m ２ / g, approximately 13m ２ / g ~ Approximately 35m ２ / g, approximately 14m ２ / g ~ Approximately 35m ２ / g, approximately 15m ２ / g ~ Approximately 35m ２ / g, approximately 16m ２ / g ~ Approximately 35m ２ / g, approximately 17m ２ / g ~ Approximately 35m ２ / g, approximately 18m ２ / g ~ Approximately 35m ２ / g, approximately 19m ２ / g ~ Approximately 35m ２ / g, approximately 20m ２ / g ~ Approximately 35m ２ / g, approximately 21m ２ / g ~ Approximately 35m ２ / g, approximately 22m ２ / g ~ Approximately 35m ２ / g, approximately 23m ２ / g ~ Approximately 35m ２ / g, approximately 24m ２ / g ~ Approximately 35m ２ / g、 3.5 m ２ / g ~ approx. 30m ２ / g, about 4m ２ / g ~ approx. 30m ２ / g, about 5m ２ / g ~ approx. 30m ２ / g, about 6m ２ / g ~ approx. 30m ２ / g, about 7m ２ / g ~ approx. 30m ２ / g, about 8m ２ / g ~ approx. 30m ２ / g, about 7m ２ / g ~ approx. 30m ２ / g, approximately 9 m ２ / g ~ approx. 30m ２ / g, about 10m ２ / g ~ approx. 30m ２ / g, about 11m ２ / g ~ approx. 30m ２ / g, about 12m ２ / g ~ approx. 30m ２ / g, about 13m ２ / g ~ approx. 30m ２ / g, about 14m ２ / g ~ approx. 30m ２ / g, about 15m ２ / g ~ approx. 30m ２ / g, about 16m ２ / g ~ approx. 30m ２ / g, about 17m ２ / g ~ approx. 30m ２ / g, about 18m ２ / g ~ approx. 30m ２ / g, about 19m ２ / g ~ approx. 30m ２ / g, about 20m ２ / g ~ approx. 30m ２ / g, about 21m ２ / g ~ approx. 30m ２ / g, about 22m ２ / g ~ approx. 30m ２ / g, approx. 23m ２ / g ~ approx. 30m ２ / g, or about 24 m ２ / g ~ approx. 30m ２ 5. The suspension according to claim 1, having an SSA of 0.1g / g.

6. 6. The suspension of any one of claims 1 to 5, wherein the particles have a mean particle size by volume distribution (Dv50) of from about 0.7 microns to about 12.0 microns in diameter, from about 0.7 microns to about 8.0 microns, from about 1.0 microns to about 12 microns in diameter, from about 1 micron to about 6 microns in diameter, or from about 1.0 microns to 3.5 or 3.0 microns in diameter.

7. The particles have a density of about 0.020 g / cm ３ ~Approx. 0.8g / cm ３ 7. The suspension according to claim 1, having an average bulk density of

8. 8. The suspension of any one of claims 1 to 7, wherein the particles comprise at least 96%, 97%, 98%, 99%, or 100% by weight cisplatin.

9. 9. A suspension according to any one of claims 1 to 8, wherein the particles are uncoated and free of polymers, proteins, polyethoxylated castor oil and polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol.

10. 10. The suspension of any one of claims 1 to 9, wherein the concentration of cisplatin particles is at least 2.5 mg / ml in the suspension, or at least 5 mg / ml in the suspension, or at least 10 mg / ml in the suspension.

11. A method for treating a tumor, comprising administering to a subject having a tumor an amount of the suspension according to any one of claims 1 to 10 that is effective for treating the tumor.

12. (a) the tumor is a carcinoma, breast tumor, pancreatic tumor, prostate tumor, bladder tumor, lung tumor, ovarian tumor, gastrointestinal tumor, testicular tumor, cervical tumor, head and neck tumor, esophageal tumor, mesothelioma, brain tumor, neuroblastoma, or renal cell tumor, including, but not limited to, metastatic testicular tumor, metastatic ovarian tumor, advanced bladder cancer, diffuse intrinsic pontine glioma, pediatric high-grade astrocytoma, or glioblastoma; and / or (b) the method further comprises administering to the subject an additional therapeutic agent, including but not limited to, anthracyclines, antimetabolites, alkylating agents, alkaloids, taxanes (including but not limited to paclitaxel, docetaxel, cabazitaxel, and combinations thereof), poly ADP-ribose polymerase (PARP) inhibitors, and / or topoisomerase inhibitors; The method of claim 11.

13. The method of any one of claims 11 to 12, wherein the subject is a human subject.

14. 14. The method of any one of claims 11 to 13, wherein the suspension is administered by intratumoral injection, peritumoral injection, intraperitoneal injection, intravesical administration, or into the mammary fat pad; or wherein the suspension is administered by intratumoral injection and the concentration of cisplatin particles in the suspension is at least 2.5 mg / ml, or at least 5 mg / ml, or at least 10 mg / ml.

15. (a) (i) 0.9% sodium chloride in about 30% to about 50% w / w water; (ii) about 30% to about 50% w / w glycerin; and (iii) about 5% to about 25% w / w ethanol; a first water-containing solution comprising: (b) (i) about 40% to about 60% w / w glycerin; (ii) about 30% to about 45% w / w propylene glycol; (iii) about 5% to about 20% w / w ethanol; a second water-free solution comprising: (c) particles containing at least 95% by weight of cisplatin, the particles having a diameter of at least 3.5 mm ２ / g, 4m ２ / g, 5m 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, 14m ２ / g, 15m ２ / g, 16m ２ / g, 17m ２ / g, 18m ２ / g, 19m ２ / g, 20m ２ / g, 21m ２ / g, 22m ２ / g, 23m ２ / g, or 24m ２ / g specific surface area (SSA) of particles Includes a kit.

16. The first solution is: 0.9% sodium chloride in about 30% to about 50% w / w water; about 30% to about 50% w / w glycerin; and about 5% to about 25% w / w ethanol; 16. The kit of claim 15, comprising:

17. The first solution is: 0.9% sodium chloride in about 37.5% to about 42.5% w / w water, or 0.9% sodium chloride in about 40% w / w water; about 42.5% to about 47.5% w / w glycerin, or about 45% w / w glycerin; and about 12.5% ​​to about 17.5% w / w ethanol, or about 15% w / w ethanol; 17. The kit of claim 15 or 16, comprising:

18. The second solution is: about 40% to about 60% w / w glycerin; about 30% to about 45% w / w propylene glycol; and about 5% to about 20% w / w ethanol; The kit according to any one of claims 15 to 17, comprising:

19. The second solution is: about 47.5% to about 52.5% w / w glycerin, or about 50% w / w glycerin; about 35% to about 40% w / w propylene glycol, or about 37.5% w / w propylene glycol; and about 10% to about 15% w / w ethanol, or about 12.5% ​​w / w ethanol; The kit according to any one of claims 15 to 18, comprising:

20. The particles are at least 4 m ２ The kit according to any one of claims 15 to 19, having an SSA of 1 / g.

21. The particles are at least 10 m ２ The kit according to any one of claims 15 to 19, having an SSA of 1 / g.

22. The particles, 3.5m ２ / g ~ Approximately 50m ２ / g, approximately 4m ２ / g ~ Approximately 50m ２ / g, approximately 5m ２ / g ~ Approximately 50m ２ / g, approximately 6m ２ / g ~ Approximately 50m ２ / g, approximately 7m ２ / g ~ Approximately 50m ２ / g, approximately 8m ２ / g ~ Approximately 50m ２ / g, approximately 7m ２ / g ~ Approximately 50m ２ / g, approximately 9m ２ / g ~ Approximately 50m ２ / g, approximately 10m ２ / g ~ Approximately 50m ２ / g, approximately 11m ２ / g ~ Approximately 50m ２ / g, approximately 12m ２ / g ~ Approximately 50m ２ / g, approximately 13m ２ / g ~ Approximately 50m ２ / g, approximately 14m ２ / g ~ Approximately 50m ２ / g, approximately 15m ２ / g ~ Approximately 50m ２ / g, approximately 16m ２ / g ~ Approximately 50m ２ / g, approximately 17m ２ / g ~ Approximately 50m ２ / g, approximately 18m ２ / g ~ Approximately 50m ２ / g, approximately 19m ２ / g ~ Approximately 50m ２ / g, approximately 20m ２ / g ~ Approximately 50m ２ / g, approximately 21m ２ / g ~ Approximately 50m ２ / g, approximately 22m ２ / g ~ Approximately 50m ２ / g, approximately 23m ２ / g ~ Approximately 50m ２ / g, approximately 24m ２ / g ~ Approximately 50m ２ / g、 3.5m ２ / g ~ Approximately 45m ２ / g, approximately 4m ２ / g ~ Approximately 45m ２ / g, approximately 5m ２ / g ~ Approximately 45m ２ / g, approximately 6m ２ / g ~ Approximately 45m ２ / g, approximately 7m ２ / g ~ Approximately 45m ２ / g, approximately 8m ２ / g ~ Approximately 45m ２ / g, approximately 7m ２ / g ~ Approximately 45m ２ / g, approximately 9m ２ / g ~ Approximately 45m ２ / g, approximately 10m ２ / g ~ Approximately 45m ２ / g, approximately 11m ２ / g ~ Approximately 45m ２ / g, approximately 12m ２ / g ~ Approximately 45m ２ / g, approximately 13m ２ / g ~ Approximately 45m ２ / g, approximately 14m ２ / g ~ Approximately 45m ２ / g, approximately 15m ２ / g ~ Approximately 45m ２ / g, approximately 16m ２ / g ~ Approximately 45m ２ / g, approximately 17m ２ / g ~ Approximately 45m ２ / g, approximately 18m ２ / g ~ Approximately 45m ２ / g, approximately 19m ２ / g ~ Approximately 45m ２ / g, approximately 20m ２ / g ~ Approximately 45m ２ / g, approximately 21m ２ / g ~ Approximately 45m ２ / g, approximately 22m ２ / g ~ Approximately 45m ２ / g, approximately 23m ２ / g ~ Approximately 45m ２ / g, approximately 24m ２ / g ~ Approximately 45m ２ / g、 3.5m ２ / g ~ Approximately 40m ２ / g, approximately 4m ２ / g ~ Approximately 40m ２ / g, approximately 5m ２ / g ~ Approximately 40m ２ / g, approximately 6m ２ / g ~ Approximately 40m ２ / g, approximately 7m ２ / g ~ Approximately 40m ２ / g, approximately 8m ２ / g ~ Approximately 40m ２ / g, approximately 7m ２ / g ~ Approximately 40m ２ / g, approximately 9m ２ / g ~ Approximately 40m ２ / g, approximately 10m ２ / g ~ Approximately 40m ２ / g, approximately 11m ２ / g ~ Approximately 40m ２ / g, approximately 12m ２ / g ~ Approximately 40m ２ / g, approximately 13m ２ / g ~ Approximately 40m ２ / g, approximately 14m ２ / g ~ Approximately 40m ２ / g, approximately 15m ２ / g ~ Approximately 40m ２ / g, approximately 16m ２ / g ~ Approximately 40m ２ / g, approximately 17m ２ / g ~ Approximately 40m ２ / g, approximately 18m ２ / g ~ Approximately 40m ２ / g, approximately 19m ２ / g ~ Approximately 40m ２ / g, approximately 20m ２ / g ~ Approximately 40m ２ / g, approximately 21m ２ / g ~ Approximately 40m ２ / g, approximately 22m ２ / g ~ Approximately 40m ２ / g, approximately 23m ２ / g ~ Approximately 40m ２ / g, approximately 24m ２ / g ~ Approximately 40m ２ / g、 3.5m ２ / g ~ Approximately 35m ２ / g, approximately 4m ２ / g ~ Approximately 35m ２ / g, approximately 5m ２ / g ~ Approximately 35m ２ / g, approximately 6m ２ / g ~ Approximately 35m ２ / g, approximately 7m ２ / g ~ Approximately 35m ２ / g, approximately 8m ２ / g ~ Approximately 35m ２ / g, approximately 7m ２ / g ~ Approximately 35m ２ / g, approximately 9m ２ / g ~ Approximately 35m ２ / g, approximately 10m ２ / g ~ Approximately 35m ２ / g, approximately 11m ２ / g ~ Approximately 35m ２ / g, approximately 12m ２ / g ~ Approximately 35m ２ / g, approximately 13m ２ / g ~ Approximately 35m ２ / g, approximately 14m ２ / g ~ Approximately 35m ２ / g, approximately 15m ２ / g ~ Approximately 35m ２ / g, approximately 16m ２ / g ~ Approximately 35m ２ / g, approximately 17m ２ / g ~ Approximately 35m ２ / g, approximately 18m ２ / g ~ Approximately 35m ２ / g, approximately 19m ２ / g ~ Approximately 35m ２ / g, approximately 20m ２ / g ~ Approximately 35m ２ / g, approximately 21m ２ / g ~ Approximately 35m ２ / g, approximately 22m ２ / g ~ Approximately 35m ２ / g, approximately 23m ２ / g ~ Approximately 35m ２ / g, approximately 24m ２ / g ~ Approximately 35m ２ / g、 3.5 m ２ / g ~ approx. 30m ２ / g, about 4m ２ / g ~ approx. 30m ２ / g, about 5m ２ / g ~ approx. 30m ２ / g, about 6m ２ / g ~ approx. 30m ２ / g, about 7m ２ / g ~ approx. 30m ２ / g, about 8m ２ / g ~ approx. 30m ２ / g, about 7m ２ / g ~ approx. 30m ２ / g, approximately 9 m ２ / g ~ approx. 30m ２ / g, about 10m ２ / g ~ approx. 30m ２ / g, about 11m ２ / g ~ approx. 30m ２ / g, about 12m ２ / g ~ approx. 30m ２ / g, about 13m ２ / g ~ approx. 30m ２ / g, about 14m ２ / g ~ approx. 30m ２ / g, about 15m ２ / g ~ approx. 30m ２ / g, about 16m ２ / g ~ approx. 30m ２ / g, about 17m ２ / g ~ approx. 30m ２ / g, about 18m ２ / g ~ approx. 30m ２ / g, about 19m ２ / g ~ approx. 30m ２ / g, about 20m ２ / g ~ approx. 30m ２ / g, about 21m ２ / g ~ approx. 30m ２ / g, about 22m ２ / g ~ approx. 30m ２ / g, approx. 23m ２ / g ~ approx. 30m ２ / g, or about 24 m ２ / g ~ approx. 30m ２ The kit according to any one of claims 15 to 21, having an SSA of 1 / g.

23. 23. The kit of any one of claims 15 to 22, wherein the particles have a mean particle size by volume distribution (Dv50) of about 0.7 microns to about 12.0 microns in diameter, about 0.7 microns to about 8.0 microns, about 1.0 microns to about 12 microns in diameter, about 1 micron to about 6 microns in diameter, or about 1.0 microns to 3.5 or 3.0 microns in diameter.

24. The particles have a density of about 0.020 g / cm ３ ~Approx. 0.8g / cm ３ The kit according to any one of claims 15 to 23, having an average bulk density of

25. The kit of any one of claims 15 to 24, wherein the particles comprise at least 96%, 97%, 98%, 99%, or 100% cisplatin.

26. 26. The kit of any one of claims 15 to 25, wherein the particles are uncoated and do not contain polymers, proteins, polyethoxylated castor oil and polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol.

27. (a) combining particles with a first solution as defined in any one of claims 15 to 26 to form a mixture; (b) combining the mixture with a second solution as defined in any one of claims 15 to 26 to form a suspension; A method for preparing a suspension according to any one of claims 1 to 10, comprising:

28. 28. The method of claim 27, wherein the second solution is combined with the mixture in a volume ratio of about 4:

1.

29. 29. The method of claim 27 or 28, further comprising shaking the suspension.

30. 30. The method of any one of claims 27 to 29, further comprising sonicating the suspension.

31. The method of any one of claims 27 to 30, wherein the concentration of the cisplatin particles is at least 2.5 mg / ml in suspension, or at least 5 mg / ml in suspension, or at least 10 mg / ml in suspension.

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