Polyphosphate-functionalized nanoparticles and methods of use

Abstract

Provided herein are functionalized nanoparticles and compositions thereof. Also provided are methods of preparing functionalized nanoparticles and methods of using functionalized nanoparticles, e.g., to treat a subject in need thereof.

Description

Docket No.: 410007-001WO (218613) POLYPHOSPHATE-FUNCTIONALIZED NANOPARTICLES AND METHODS OF USE CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional PatentApplication No. 63 / 662,886, filed June 21, 2024, the entire contents of which are hereby incorporated by reference in its entirety. FIELD

[0002] The present disclosure relates to functionalized nanoparticles and compositionsthereof. Also provided are methods of preparing functionalized nanoparticles and methods of using functionalized nanoparticles, e.g., to treat a subject in need thereof. BACKGROUND

[0003] Treatment of bleeding wounds, particularly severely bleeding wounds, can requireimmediate attention to bring the bleeding under control. Severe bleeding poses a very real risk of death if not treated quickly. Although loss of about 10-15% of total blood volume can be endured without clinical sequelae in a healthy person, if a laceration or penetrating trauma (e.g., knife or gun wound) is severe enough or involves critical arteries or veins, this volume of blood can be lost very rapidly. The bleeding must be slowed immediately or irreversible damage to organs and mortality can result.

[0004] Bleeding wounds, even those that may be less severe, can pose serious difficultiesand risks when a severe wound is inflicted in a remote area or in other situations (such as on a battlefield) where full medical assistance may not be immediately available. In such circumstances it can be critical to undertake measures to slow or stop bleeding so that the subject can be transported to a medical facility.

[0005] Each year, nearly two million people die of hemorrhage, the vast majority of whichare preventable. Yet, current standard treatments do not adequately address the top two causes of preventable death. Seventy percent of all preventable deaths are associated with bleeding at non- compressible areas of the body, where tourniquets, gauzes, and topicals are ineffective. Up to 90% of preventable deaths from hemorrhage are due to delayed hemostatic control, in which every 1 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) second is urgent. To date, efforts to develop therapies for major hemorrhage have been limited by safety issues, creating unacceptable risk of off-target clotting in healthy tissues.

[0006] Moreover, more than twenty million people live with inheritable blood or bleedingdisorders. Despite tremendous progress for patients with hemophilia, other patients with bleeding disorders are not candidates for new therapies, are at risk for inhibitor development for mainstay factor-based therapies, and struggle with standard approaches. In addition, more than 10 million people per year are treated with a blood thinner to prevent heart attack, stroke or thromboembolism. Blood thinners compromise the body’s ability to clot and can contribute to severe or life-threatening levels of blood loss in the event of injury or surgery.

[0007] The need remains for compositions that can be used to control bleeding in non-compressible areas of the body and that provide for, for example, rapid initiation of blood clotting, increased rate of blood clotting, sufficient blood clot strength, and / or reduced adverse side effects. Of interest are compositions that can be rapidly and safely applied, e.g., in an emergency situation, such as on the battlefield or at the scene of an accident, without the need for intensive training or equipment. SUMMARY

[0008] The instant disclosure is broadly directed to populations of functionalizednanoparticles (FNP), pharmaceutical compositions thereof, and methods of preparing and using such populations of FNP and pharmaceutical compositions thereof.

[0009] The instant disclosure provides a population of functionalized nanoparticles (FNP)each comprising a population of polyphosphate polymers attached to a nanoparticle, wherein the average chain length of the polyphosphate polymers in the population of FNP is no more than 65 phosphate units. In some embodiments, the average chain length of the polyphosphate polymers in the population of FNP is no more than 60 phosphate units. In some embodiments, the average chain length of the polyphosphate polymers in the population of FNP is between 30 and 60 phosphate units; between 40 and 60 phosphate units; between 45 and 60 phosphate units; between 50 and 60 phosphate units; or between 55 and 60 phosphate units. In some embodiments, the average chain length of the polyphosphate polymers in the population of FNP is between 42 and 59 phosphate units; between 54 and 59 phosphate units; or between 55 and 58 phosphate units. 2 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0010] In some embodiments, the shortest 10% of the polyphosphate polymers in thepopulation of FNP are no longer than a length between 10 and 40 phosphate units; between 15 and 35 phosphate units; between 20 and 30 phosphate units; or between 25 and 35 phosphate units. In some embodiments, the longest 90% of the polyphosphate polymers in the population of FNP are no shorter than a length between 10 and 40 phosphate units; between 15 and 35 phosphate units; between 20 and 30 phosphate units; or between 25 and 35 phosphate units. In some embodiments, the shortest 90% of the polyphosphate polymers in the population of FNP are no longer than a length between 70 and 140 phosphate units; between 75 and 135 phosphate units; between 80 and 130 phosphate units; or between 80 and 100 phosphate units. In some embodiments, the population of FNP comprises an FNP with an average chain length of the polyphosphate polymers attached to the FNP of no more than 60 phosphate units; between 30 and 60 phosphate units; between 40 and 60 phosphate units; between 45 and 60 phosphate units; between 50 and 60 phosphate units; between 55 and 60 phosphate units; between 42 and 59 phosphate units; between 54 and 59 phosphate units; or between 55 and 58 phosphate units.

[0011] In some embodiments, the total mass of polyphosphate polymers in the populationof FNP is no more than 24% of the total mass of the population of FNP. In some embodiments, the total mass of polyphosphate polymers in the population of FNP is between 16% and 24% of the total mass of the population of FNP. In some embodiments, the total mass of polyphosphate polymers in the population of FNP is no more than 22% of the total mass of the population of FNP. In some embodiments, the total mass of polyphosphate polymers in the population of FNP is between 15% and 22% of the total mass of the population of FNP. In some embodiments, the total mass of polyphosphate polymers in the population of FNP is between 17% and 21% of the total mass of the population of FNP. In some embodiments, the total mass of polyphosphate polymers in the population of FNP is between 19% and 21% of the total mass of the population of FNP. In some embodiments, the total mass of polyphosphate polymers in the population of FNP is about 20% of the total mass of the population of FNP.

[0012] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP is 100 nm or less; 90 nm or less; 80 nm or less; 70 nm or less; 60 nm or less; between 30 nm and 70 nm; between 35 nm and 60 nm; between 38 nm and 59 nm; between 45 nm and 58 nm; between 50 nm and 60 nm; about 50 nm; or about 55 nm. In some embodiments, the D10(i) of the nanoparticles in the population of FNP is less than 45 nm, and the D90(i) of the nanoparticles in the population of FNP is less than 180 nm. In some embodiments, the D10(i) of the nanoparticles 3 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) in the population of FNP is greater than 20 nm, and the D90(i) of the nanoparticles in the population of FNP is less than 180 nm.

[0013] In some embodiments, the Z-average size of the FNP in the population of FNP is200 nm or less; 180 nm or less; 100 nm or less; 90 nm or less; 80 nm or less; 70 nm or less; 60 nm or less; between 40 nm and 200 nm; between 40 nm and 80 nm; between 50 nm and 180 nm; between 50 nm and 80 nm; between 55 nm and 75 nm; between 55 nm and 65 nm; between 65 nm and 75 nm; about 55 nm; about 60 nm; about 65 nm; about 70 nm; or about 75 nm. In some embodiments, the D10(i) of the FNP in the population of FNP is less than 45 nm, and the D90(i) of the FNP in the population of FNP is less than 200 nm. In some embodiments, the D10(i) of the FNP in the population of FNP is greater than 20 nm, and the D90(i) of the FNP in the population of FNP is less than 200 nm. In some embodiments, the D10(i) of the FNP in the population of FNP is greater than 20 nm, and the D90(i) of the FNP in the population of FNP is less than 120 nm.

[0014] In some embodiments, the nanoparticles in the population of FNP comprise anoxide of silicon. In some embodiments, the nanoparticles in the population of FNP comprise silica or a silica mixture. In some embodiments, the nanoparticles in the population of FNP are silica nanoparticles. In some embodiments, the polyphosphate polymers are attached to the nanoparticles through non-covalent bonds. In some embodiments, the non-covalent bonds comprise hydrogen bonds, Van der Waals forces, or a combination thereof.

[0015] The instant disclosure also provides a population of functionalized nanoparticles(FNP) each comprising a population of polyphosphate polymers attached to a nanoparticle, wherein the total mass of polyphosphate polymers in the population of FNP is no more than 24% of the total mass of the population of FNP. In some embodiments, the total mass of polyphosphate polymers in the population of FNP is between 16% and 24% of the total mass of the population of FNP. In some embodiments, the total mass of polyphosphate polymers in the population of FNP is no more than 22% of the total mass of the population of FNP. In some embodiments, the total mass of polyphosphate polymers in the population of FNP is between 15% and 22% of the total mass of the population of FNP. In some embodiments, the total mass of polyphosphate polymers in the population of FNP is between 17% and 21% of the total mass of the population of FNP. In some embodiments, the total mass of polyphosphate polymers in the population of FNP is between 19% and 21% of the total mass of the population of FNP. In some embodiments, the total mass of polyphosphate polymers in the population of FNP is about 20% of the total mass of the population of FNP. 4 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0016] In some embodiments, the Z-average size of the nanoparticles is 100 nm or less; 90nm or less; 80 nm or less; 70 nm or less; 60 nm or less; between 30 nm and 70 nm; between 35 nm and 60 nm; between 38 nm and 59 nm; between 45 nm and 58 nm; between 50 nm and 60 nm; about 50 nm; or about 55 nm. In some embodiments, the D10(i) of the nanoparticles in the population of FNP is less than 45 nm, and the D90(i) of the nanoparticles in the population of FNP is less than 180 nm.

[0017] In some embodiments, the Z-average size of the FNP in the population of FNP is200 nm or less; 180 nm or less; 100 nm or less; 90 nm or less; 80 nm or less; 70 nm or less; 60 nm or less; between 40 nm and 200 nm; between 50 nm and 180 nm; between 50 nm and 80 nm; between 55 nm and 75 nm; between 55 nm and 65 nm; between 65 nm and 75 nm; about 55 nm; about 60 nm; about 65 nm; about 70 nm; or about 75 nm. In some embodiments, the D10(i) of the FNP in the population of FNP is less than 45 nm, and the D90(i) of the FNP is less than 200 nm. In some embodiments, the D10(i) of the FNP in the population of FNP is greater than 20 nm, and the D90(i) of the FNP in the population of FNP is less than 200 nm. In some embodiments, the D10(i) of the FNP in the population of FNP is greater than 20 nm, and the D90(i) of the FNP in the population of FNP is less than 120 nm.

[0018] In some embodiments, the nanoparticles in the population of FNP comprise anoxide of silicon. In some embodiments, the nanoparticles in the population of FNP comprise silica or a silica mixture. In some embodiments, the nanoparticles in the population of FNP are silica nanoparticles. In some embodiments, the polyphosphate polymers are attached to the nanoparticles through non-covalent bonds. In some embodiments, the non-covalent bonds comprise hydrogen bonds, Van der Waals forces, or a combination thereof.

[0019] The instant disclosure also provides a population of functionalized nanoparticles(FNP) each comprising a population of polyphosphate polymers attached to a nanoparticle, wherein the Z-average size of the nanoparticles is 200 nm or less; 180 nm or less; 100 nm or less; 90 nm or less; 80 nm or less; 70 nm or less; 60 nm or less; between 30 nm and 70 nm; between 35 nm and 60 nm; between 38 nm and 59 nm; between 45 nm and 58 nm; between 50 nm and 60 nm; about 50 nm; or about 55 nm. In some embodiments, the D10(i) of the nanoparticles in the population of FNP is less than 45 nm, and the D90(i) of the nanoparticles in the population of FNP is less than 180 nm. In some embodiments, the Z-average size of the FNP in the population of FNP is 200 nm or less; 180 nm or less; 100 nm or less; 90 nm or less; 80 nm or less; 70 nm or less; 60 nm or less; between 40 nm and 200 nm; between 40 nm and 80 nm; between 50 nm and 180 nm; 5 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) between 50 nm and 80 nm; between 55 nm and 75 nm; between 55 nm and 65 nm; between 65 nm and 75 nm; about 55 nm; about 60 nm; about 65 nm; about 70 nm; or about 75 nm. In some embodiments, the D10(i) of the FNP in the population of FNP is less than 45 nm, and the D90(i) of the FNP in the population of FNP is less than 200 nm. In some embodiments, wherein the D10(i) of the FNP in the population of FNP is greater than 20 nm, and the D90(i) of the FNP in the population of FNP is less than 200 nm. In some embodiments, the D10(i) of the FNP in the population of FNP is greater than 20 nm, and the D90(i) of the FNP in the population of FNP is less than 120 nm.

[0020] In some embodiments, the nanoparticles in the population of FNP comprise anoxide of silicon. In some embodiments, the nanoparticles in the population of FNP comprise silica or a silica mixture. In some embodiments, the nanoparticles in the population of FNP are silica nanoparticles. In some embodiments, the polyphosphate polymers are attached to the nanoparticles through non-covalent bonds. In some embodiments, the non-covalent bonds comprise hydrogen bonds, Van der Waals forces, or a combination thereof.

[0021] The instant disclosure also provides a pharmaceutical composition comprising thepopulation of FNP as described above and herein and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is an aqueous suspension. In some embodiments, the population of FNP is present in the pharmaceutical composition at a concentration between 0.1% and 10% w / v, between 0.5% and 5% w / v, between 1% and 3% w / v, between 1.5% and 2.5% w / v, between 1.6% and 2.2% w / v, or between 1.8% and 2.2% w / v. In some embodiments, the pharmaceutical composition is stable for at least 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 15 days, 20 days, 25 days, or 30 days at 5°C or 25°C. In some embodiments, the pH of the pharmaceutical composition is between 4.0 and 8.0, between 5.0 and 7.5, between 5.0 and 7.0, between 5.0 and 6.5, between 5.0 and 6.0, between 5.5 and 8.0, between 5.5 and 7.5, between 5.5 and 7.0, between 5.5 and 6.5, between 5.5 and 6.0, between 5.75 and 5.95, between 5.81 and 5.91, or about 5.85. In some embodiments, the zeta potential of the pharmaceutical composition is between -60 mV and -25 mV, between -60 mV and -40 mV, between -50 mV and -40 mV, between -49 mV to -41 mV, between -49 mV to -44 mV, or between -48 mV to -45 mV. In some embodiments, the polydispersity index (PDI) of the pharmaceutical composition is no more than 0.3, no more than 0.25, no more than 0.2, less than 0.2, or between 0.1 and 0.2. In some embodiments, the osmolality of the pharmaceutical composition is between 100 mOsm / kg and 500 mOsm / kg, between 250 mOsm / kg and 500 6 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) mOsm / kg, between 225 and 350 mOsm / kg, between 250 and 350 mOsm / kg, or between 275 and 300 mOsm / kg.

[0022] In some embodiments, the pharmaceutical composition further comprises apopulation of free polyphosphate polymers, wherein the mass of the population of free polyphosphate polymers is no more than 55%, 40%, 25%, 20%, 10%, 7.5%, 5%, 2%, or 1.5% of the total mass of polyphosphate polymers in the pharmaceutical composition. In some embodiments, the concentration of the population of free polyphosphate polymers in the pharmaceutical composition is less than 0.08% w / v. In some embodiments, the total concentration of polyphosphate polymers in the pharmaceutical composition is between 0.36% and 0.44% w / v.

[0023] In some embodiments, (i) the average chain length of the polyphosphate polymersin the population of FNP is no more than 65 phosphate units; (ii) the Z-average size of the population of FNP is between 50 nm and 80 nm; (iii) the polydispersity index (PDI) of the pharmaceutical composition is no more than 0.3, no more than 0.25, no more than 0.2, less than 0.2, or between 0.1 and 0.2; (iv) the zeta potential of the pharmaceutical composition is between - 60 mV and -25 mV; (v) the total mass of polyphosphate polymers in the population of FNP is between 16% and 24% of the total mass of the population of FNP; (vi) the pH of the pharmaceutical composition is between 5.0 and 7.5; (vii) the mass of the population of free polyphosphate polymers is no more than 25%, 20%, 10%, 7.5%, 5%, 2%, or 1.5% of the total mass of polyphosphate polymers in the pharmaceutical composition; and (viii) the osmolality of the pharmaceutical composition is between 250 and 350 mOsm / kg.

[0024] In some embodiments, (i) the average chain length of the polyphosphate polymersin the population of FNP is no more than 60 phosphate units; (ii) the Z-average size of the population of FNP is between 65 nm and 75 nm; (iii) the polydispersity index (PDI) of the pharmaceutical composition is less than 0.2; (iv) the zeta potential of the pharmaceutical composition is between -60 mV and -40 mV; (v) the total mass of polyphosphate polymers in the population of FNP is between 16% and 24% of the total mass of the population of FNP; (vi) the pH of the pharmaceutical composition is between 5.0 and 7.5; (vii) the mass of the population of free polyphosphate polymers is no more than 25%, 20%, 10%, 7.5%, 5%, 2%, or 1.5% of the total mass of polyphosphate polymers in the pharmaceutical composition; and (viii) the osmolality of the pharmaceutical composition is between 250 and 350 mOsm / kg.

[0025] In some embodiments, the concentration of the population of FNP in thepharmaceutical composition is between 1.8% and 2.2% w / v; the concentration of the population 7 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) of free polyphosphate polymers in the pharmaceutical composition is less than 0.08% w / v; and the total concentration of polyphosphate polymers in the pharmaceutical composition is between 0.36% and 0.44% w / v.

[0026] In some embodiments, the pharmaceutical composition is lyophilized. In someembodiments, the pharmaceutical composition is produced by lyophilizing the pharmaceutical composition in aqueous suspension described above and herein. In some embodiments, the pharmaceutical composition is stable for at least 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days, 45 days, 50 days, 55 days, or 60 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, 4 years, or 5 years at 5°C or 25°C. In some embodiments, the pharmaceutical composition has been reconstituted as an aqueous suspension by adding water to the pharmaceutical composition described above and herein.

[0027] The instant disclosure also provides a pharmaceutical composition comprising: a)a population of functionalized nanoparticles (FNP) each comprising a population of polyphosphate polymers attached to a nanoparticle; b) a population of free polyphosphate polymers, wherein the mass of the population of free polyphosphate polymers is no more than 20% of the total mass of polyphosphate polymers in the pharmaceutical composition; and c) a pharmaceutically acceptable excipient.

[0028] In some embodiments, the nanoparticles in the population of FNP are silicananoparticles. In some embodiments, the ratio of the total mass of polyphosphate polymers in the pharmaceutical composition to the mass of silica nanoparticles in the pharmaceutical composition is about 1:4.

[0029] In some embodiments, the average chain length of the polyphosphate polymers inthe pharmaceutical composition is between 40 and 60 phosphate units. In some embodiments, the shortest 10% of the polyphosphate polymers in the pharmaceutical composition are no longer than a length between 10 and 40 phosphate units; between 15 and 35 phosphate units; between 20 and 30 phosphate units; or between 25 and 35 phosphate units. In some embodiments, the longest 90% of the polyphosphate polymers in the pharmaceutical composition are no shorter than a length between 10 and 40 phosphate units; between 15 and 35 phosphate units; between 20 and 30 phosphate units; or between 25 and 35 phosphate units. In some embodiments, the shortest 90% of the polyphosphate polymers in the pharmaceutical composition are no longer than a length 8 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) between 70 and 140 phosphate units; between 75 and 135 phosphate units; between 80 and 130 phosphate units; or between 80 and 100 phosphate units.

[0030] In some embodiments, the Z-average size of the FNP in the population of FNP isbetween 40 nm and 80 nm. In some embodiments, the D10(i) of the FNP in the population of FNP is greater than 20 nm, and the D90(i) of the FNP in the population of FNP is less than 120 nm.

[0031] In some embodiments, the pH of the pharmaceutical composition is between 5.0and 7.0. In some embodiments, the PDI of the pharmaceutical composition is less than or equal to 0.2. In some embodiments, the osmolality of the pharmaceutical composition is between 250 mOsm / kg and 500 mOsm / kg.

[0032] In some embodiments, the pharmaceutical composition is an aqueous suspension.In some embodiments, the total concentration of polyphosphate polymers in the pharmaceutical composition is between 0.36% and 0.44% w / v. In some embodiments, the concentration of the population of free polyphosphate polymers in the pharmaceutical composition is less than 0.08% w / v, and wherein the concentration of the nanoparticles in the pharmaceutical composition is about 1.6% w / v, optionally wherein the nanoparticles in the pharmaceutical composition are silica nanoparticles.

[0033] In some embodiments, the pharmaceutical composition is lyophilized. In someembodiments, the pharmaceutical composition is produced by lyophilizing the pharmaceutical composition described above and herein. In some embodiments, the pharmaceutical composition is capable of being reconstituted into a clear suspension substantially free from visible particulates no more than 30 seconds after addition of water to the pharmaceutical composition. In some embodiments, the pharmaceutical composition has been reconstituted as an aqueous suspension by adding water to the pharmaceutical composition described above and herein.

[0034] The instant disclosure also provides a pharmaceutical composition comprising: a)a population of functionalized nanoparticles (FNP) each comprising a population of polyphosphate polymers attached to a nanoparticle; and b) a pharmaceutically acceptable excipient comprising at least one cryoprotectant. In some embodiments, the at least one cryoprotectant comprises an amino acid selected from the group consisting of glycine, phenylalanine, leucine, and isoleucine. In some embodiments, the amino acid is glycine. In some embodiments, the at least one cryoprotectant comprises at least one sugar or sugar alcohol. In some embodiments, the at least one sugar or sugar alcohol comprises dextrose, trehalose (e.g., trehalose dihydrate), sucrose, mannitol, galactose, 9 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) sorbitol, lactose, glycerol, maltose, or isomalt. In some embodiments, the at least one sugar or sugar alcohol comprises dextrose and trehalose (e.g., trehalose dihydrate).

[0035] In some embodiments, the pharmaceutical composition is an aqueous suspension.In some embodiments, the population of FNP is present in the pharmaceutical composition at a concentration between 0.1% and 10% w / v, between 0.5% and 5% w / v, between 1% and 3% w / v, between 1.5% and 2.5% w / v, between 1.6% and 2.2% w / v, or between 1.8% and 2.2% w / v.

[0036] In some embodiments, the at least one cryoprotectant comprises glycine at aconcentration between 0.1% and 10% w / v, between 0.2% and 5% w / v, between 0.5% and 2% w / v, or about 0.75% w / v. In some embodiments, the at least one cryoprotectant comprises at least one sugar or sugar alcohol, and wherein each sugar or sugar alcohol is present in the pharmaceutical composition at a concentration between 0.1% and 10% w / v, between 0.5% and 5% w / v, or between 2% and 5% w / v. In some embodiments, the at least one sugar or sugar alcohol comprises dextrose, and wherein the dextrose is present in the pharmaceutical composition at a concentration of between 1% and 6% w / v, between 2% and 5% w / v, between 2% and 4% w / v, between 2.5% and 3.5% w / v, between 2.8% and 3.2% w / v, or about 3% w / v. In some embodiments, the at least one sugar or sugar alcohol comprises trehalose (e.g., trehalose dihydrate), and wherein the trehalose is present in the pharmaceutical composition at a concentration of between 0.5% and 5% w / v, between 3% and 5% w / v, between 4% and 5% w / v, or about 5% w / v.

[0037] In some embodiments, the population of FNP is present in the pharmaceuticalcomposition at a concentration between 0.1% and 10% w / v, between 0.5% and 5% w / v, between 1% and 3% w / v, between 1.5% and 2.5% w / v, between 1.6% and 2.2% w / v, or between 1.8% and 2.2% w / v. In some embodiments, the pharmaceutical composition is stable for at least 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 15 days, 20 days, 25 days, or 30 days at 5°C or 25°C. In some embodiments, the pH of the pharmaceutical composition is between 4.0 and 8.0, between 5.0 and 7.5, between 5.0 and 7.0, between 5.0 and 6.5, between 5.0 and 6.0, between 5.5 and 8.0, between 5.5 and 7.5, between 5.5 and 7.0, between 5.5 and 6.5, between 5.5 and 6.0, between 5.75 and 5.95, between 5.81 and 5.91, or about 5.85. In some embodiments, the zeta potential of the pharmaceutical composition is between -60 mV and -25 mV, between -60 mV and -40 mV, between -50 mV and -40 mV, between -49 mV to -41 mV, between -49 mV to -44 mV, or between -48 mV to -45 mV. In some embodiments, the polydispersity index (PDI) of the pharmaceutical composition is no more than 0.3, no more than 0.25, no more than 0.2, less than 0.2, or between 0.1 and 0.2. In some embodiments, the osmolality of the pharmaceutical 10 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) composition is between 100 mOsm / kg and 500 mOsm / kg, between 250 mOsm / kg and 500 mOsm / kg, between 225 and 350 mOsm / kg, between 250 and 350 mOsm / kg, or between 275 and 300 mOsm / kg.

[0038] In some embodiments, the pharmaceutical composition further comprises apopulation of free polyphosphate polymers, wherein the mass of the population of free polyphosphate polymers is no more than 55%, 40%, 25%, 20%, 10%, 7.5%, 5%, 2%, or 1.5% of the total mass of polyphosphate polymers in the pharmaceutical composition. In some embodiments, the concentration of the population of free polyphosphate polymers in the pharmaceutical composition is less than 0.08% w / v. In some embodiments, the total concentration of polyphosphate polymers in the pharmaceutical composition is between 0.36% and 0.44% w / v.

[0039] In some embodiments, (i) the average chain length of the polyphosphate polymersin the population of FNP is no more than 65 phosphate units; (ii) the Z-average size of the population of FNP is between 50 nm and 80 nm; (iii) the polydispersity index (PDI) of the pharmaceutical composition is no more than 0.3, no more than 0.25, no more than 0.2, less than 0.2, or between 0.1 and 0.2; (iv) the zeta potential of the pharmaceutical composition is between - 60 mV and -25 mV; (v) the total mass of polyphosphate polymers in the population of FNP is between 16% and 24% of the total mass of the population of FNP; (vi) the pH of the pharmaceutical composition is between 5.0 and 7.5; (vii) the mass of the population of free polyphosphate polymers is no more than 25%, 20%, 10%, 7.5%, 5%, 2%, or 1.5% of the total mass of polyphosphate polymers in the pharmaceutical composition; and (viii) the osmolality of the pharmaceutical composition is between 250 and 350 mOsm / kg.

[0040] In some embodiments, (i) the average chain length of the polyphosphate polymersin the population of FNP is no more than 60 phosphate units; (ii) the Z-average size of the population of FNP is between 65 nm and 75 nm; (iii) the polydispersity index (PDI) of the pharmaceutical composition is less than 0.2; (iv) the zeta potential of the pharmaceutical composition is between -60 mV and -40 mV; (v) the total mass of polyphosphate polymers in the population of FNP is between 16% and 24% of the total mass of the population of FNP; (vi) the pH of the pharmaceutical composition is between 5.0 and 7.5; (vii) the mass of the population of free polyphosphate polymers is no more than 25%, 20%, 10%, 7.5%, 5%, 2%, or 1.5% of the total mass of polyphosphate polymers in the pharmaceutical composition; and (viii) the osmolality of the pharmaceutical composition is between 250 and 350 mOsm / kg. 11 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0041] In some embodiments, the concentration of the population of FNP in thepharmaceutical composition is between 1.8% and 2.2% w / v; the concentration of the population of free polyphosphate polymers in the pharmaceutical composition is less than 0.08% w / v; and the total concentration of polyphosphate polymers in the pharmaceutical composition is between 0.36% and 0.44% w / v.

[0042] In some embodiments, the pharmaceutical composition is lyophilized. In someembodiments, the pharmaceutical composition is produced by lyophilizing the pharmaceutical composition in aqueous suspension described above and herein. In some embodiments, the population of FNP is present in the pharmaceutical composition at a concentration between 5% and 50% w / w, between 10% and 25% w / w, or between 15% and 20% w / w. In some embodiments, the population of polyphosphate polymers is present in the pharmaceutical composition at a concentration between 1% and 20% w / w, between 2% and 10% w / w, or between 3% and 5% w / w. In some embodiments, the nanoparticle is present in the pharmaceutical composition at a concentration between 2% and 40% w / w, between 10% and 25% w / w, or between 12% and 16% w / w.

[0043] In some embodiments, the at least one cryoprotectant comprises glycine, whereinthe glycine is present in the pharmaceutical composition at a concentration between 1% and 20% w / w, between 2% and 10% w / w, or between 5% and 10% w / w. In some embodiments, the at least one cryoprotectant comprises at least one sugar or sugar alcohol, wherein the at least one sugar or sugar alcohol is present in the pharmaceutical composition at a concentration between 5% and 80% w / w, between 10% and 60% w / w, or between 20% and 50% w / w. In some embodiments, the at least one sugar or sugar alcohol comprises a combination of dextrose and trehalose (e.g., trehalose dihydrate), wherein each of dextrose and trehalose are present in the pharmaceutical composition at a concentration between 5% and 80% w / w, between 10% and 60% w / w, or between 20% and 50% w / w. In some embodiments, the dextrose is present in the pharmaceutical composition at a concentration between 25% and 30% w / w, between 27.5% and 28.5% w / w, or between 27.8% and 28.0% w / w. In some embodiments, the trehalose (e.g., trehalose dihydrate) is present in the pharmaceutical composition at a concentration between 40 and 50% w / w, between 45% and 47% w / w, or between 46.4% and 46.6% w / w.

[0044] In some embodiments, the pharmaceutical composition is stable for at least 12hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days, 45 days, 50 days, 55 days, or 60 days, 2 weeks, 3 weeks, 4 weeks, 5 12 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, 4 years, or 5 years at 5°C or 25°C.

[0045] In some embodiments, the pharmaceutical composition is reconstituted as anaqueous suspension by adding water to the pharmaceutical composition described above and herein.

[0046] In some embodiments, the nanoparticles in the population of FNP are silicananoparticles. In some embodiments, the ratio of the total mass of polyphosphate polymers in the pharmaceutical composition to the mass of silica nanoparticles in the pharmaceutical composition is about 1:4.

[0047] In some embodiments, the average chain length of the polyphosphate polymers inthe pharmaceutical composition is between 40 and 60 phosphate units. In some embodiments, the shortest 10% of the polyphosphate polymers in the pharmaceutical composition are no longer than a length between 10 and 40 phosphate units; between 15 and 35 phosphate units; between 20 and 30 phosphate units; or between 25 and 35 phosphate units. In some embodiments, the longest 90% of the polyphosphate polymers in the pharmaceutical composition are no shorter than a length between 10 and 40 phosphate units; between 15 and 35 phosphate units; between 20 and 30 phosphate units; or between 25 and 35 phosphate units. In some embodiments, the shortest 90% of the polyphosphate polymers in the pharmaceutical composition are no longer than a length between 70 and 140 phosphate units; between 75 and 135 phosphate units; between 80 and 130 phosphate units; or between 80 and 100 phosphate units.

[0048] In some embodiments, the Z-average size of the FNP in the population of FNP isbetween 40 nm and 80 nm. In some embodiments, the D10(i) of the FNP in the population of FNP is greater than 20 nm, and the D90(i) of the FNP in the population of FNP is less than 120 nm.

[0049] In some embodiments, the pH of the pharmaceutical composition is between 5.0and 7.0. In some embodiments, the PDI of the pharmaceutical composition is less than or equal to 0.2. In some embodiments, the osmolality of the pharmaceutical composition is between 250 mOsm / kg and 500 mOsm / kg.

[0050] In some embodiments, the pharmaceutical composition is an aqueous suspension.In some embodiments, the total concentration of polyphosphate polymers in the pharmaceutical composition is between 0.36% and 0.44% w / v. In some embodiments, the concentration of the population of free polyphosphate polymers in the pharmaceutical composition is less than 0.08% w / v, and wherein the concentration of the nanoparticles in the pharmaceutical composition is about 13 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 1.6% w / v, optionally wherein the nanoparticles in the pharmaceutical composition are silica nanoparticles.

[0051] In some embodiments, the pharmaceutical composition is lyophilized. In someembodiments, the pharmaceutical composition is produced by lyophilizing the pharmaceutical composition described above and herein. In some embodiments, the pharmaceutical composition is capable of being reconstituted into a clear suspension substantially free from visible particulates no more than 30 seconds after addition of water to the pharmaceutical composition. In some embodiments, the pharmaceutical composition has been reconstituted as an aqueous suspension by adding water to the pharmaceutical composition described above and herein.

[0052] In some embodiments, the population of FNP is the population of FNP describedabove or herein.

[0053] The instant disclosure also provides a method of promoting blood clotting in asubject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the population of functionalized nanoparticles (FNP) or the pharmaceutical composition described above or herein, thereby promoting blood clotting in the subject.

[0054] The instant disclosure also provides a method of preventing or controlling bleedingin a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the population of functionalized nanoparticles (FNP) or the pharmaceutical composition described above or herein, thereby preventing or controlling bleeding in the subject.

[0055] The instant disclosure also provides a method of reducing blood loss in a subject inneed thereof, the method comprising administering to the subject a therapeutically effective amount of the population of functionalized nanoparticles (FNP) or the pharmaceutical composition described above or herein, thereby reducing blood loss in the subject.

[0056] The instant disclosure also provides a method of promoting hemostasis in a subjectin need thereof, the method comprising administering to the subject a therapeutically effective amount of the population of functionalized nanoparticles (FNP) or the pharmaceutical composition described above or herein, thereby promoting hemostasis in the subject.

[0057] The instant disclosure also provides a method of treating hemorrhage in a subjectin need thereof, the method comprising administering to the subject a therapeutically effective amount of the population of functionalized nanoparticles (FNP) or pharmaceutical composition of described above or herein, thereby treating hemorrhage in the subject. In some embodiments, the hemorrhage is selected from acute major hemorrhage, hemorrhage after traumatic injury, GI 14 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) hemorrhage, hemorrhagic stroke, cerebral hemorrhage, intracranial hemorrhage, and postpartum hemorrhage.

[0058] The instant disclosure also provides a method of treating a subject in need thereof,the method comprising administering to the subject a therapeutically effective amount of the population of functionalized nanoparticles (FNP) or pharmaceutical composition described above or herein, thereby treating the subject.

[0059] In some embodiments of the methods described above or herein, the population ofFNP or pharmaceutical composition is administered at a flat dose of 10 mg to 1000 mg, 25 mg to 500 mg, 50 mg to 250 mg, or about 100 mg. In some embodiments, the flat dose of 10 mg to 1000 mg, 25 mg to 500 mg, 50 mg to 250 mg, or about 100 mg includes a combination of total polyphosphate and nanoparticle present in the pharmaceutical composition. In some embodiments, the population of FNP or pharmaceutical composition is administered at a dose of 0.1 mg / kg to 100 mg / kg, 0.5 mg / kg to 80 mg / kg, or 1 mg / kg to 50 mg / kg. In some embodiments, the dose of 0.1 mg / kg to 100 mg / kg, 0.5 mg / kg to 80 mg / kg, or 1 mg / kg to 50 mg / kg includes a combination of total polyphosphate and nanoparticle present in the pharmaceutical composition. In some embodiments, the population of FNP or pharmaceutical composition is administered intravenously, e.g., as a bolus injection, as a continuous infusion, or as a combination thereof. In some embodiments, the population of FNP or pharmaceutical composition is administered intraosseously, intramuscularly, intra-articularly, intrathecally, or intra-arterially. In some embodiments, the population of FNP or pharmaceutical composition is administered as a single administration or in repeated administrations.

[0060] The instant disclosure also provides a method of producing a compositioncomprising a population of functionalized nanoparticles (FNP), the method comprising suspending a population of silica nanoparticles in an acidic aqueous solution prior to addition of a population of polyphosphate polymers. In some embodiments, the silica nanoparticle suspension is adjusted to a pH of less than 7.0, between 4.0 and 7.0, between 5.0 and 6.0, about 6.0, about 5.5, or about 5.0 prior to addition of the population of polyphosphate polymers. In some embodiments, the silica nanoparticle and the population of polyphosphate polymers are mixed at a temperature between 20℃ and 35℃. In some embodiments, the silica nanoparticle and the population of polyphosphate polymers are mixed for at least 1 minute, for at least 5 minutes, for at least 15 minutes, for at least 30 minutes, for at least 1 hour, for at least 2 hours, for at least 6 hours, at least 12 hours, or at least 18 hours. In some embodiments, the population of polyphosphate polymers is filtered with an 15 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) appropriate filter to narrow the molecular weight distribution of the polyphosphate polymers prior to addition to the silica nanoparticle suspension.

[0061] The instant disclosure also provides the population of FNP or the pharmaceuticalcomposition described above or herein for use in promoting blood clotting in a subject in need thereof, preventing bleeding in a subject in need thereof, controlling bleeding in a subject in need thereof, reducing blood loss in a subject in need thereof, promoting hemostasis in a subject in need thereof, treating hemorrhage in a subject in need thereof, and / or treating a subject in need thereof.

[0062] The instant disclosure also provides the population of FNP or the pharmaceuticalcomposition described above or herein for use in the manufacture of a medicament for promoting blood clotting in a subject in need thereof, preventing bleeding in a subject in need thereof, controlling bleeding in a subject in need thereof, reducing blood loss in a subject in need thereof, promoting hemostasis in a subject in need thereof, treating hemorrhage in a subject in need thereof, and / or treating a subject in need thereof.

[0063] The instant disclosure also provides use of the population of FNP or thepharmaceutical composition described above or herein for promoting blood clotting in a subject in need thereof, preventing bleeding in a subject in need thereof, controlling bleeding in a subject in need thereof, reducing blood loss in a subject in need thereof, promoting hemostasis in a subject in need thereof, treating hemorrhage in a subject in need thereof, and / or treating a subject in need thereof.

[0064] The instant disclosure also provides use of the population of FNP or thepharmaceutical composition described above or herein for the manufacture of a medicament for promoting blood clotting in a subject in need thereof, preventing bleeding in a subject in need thereof, controlling bleeding in a subject in need thereof, reducing blood loss in a subject in need thereof, promoting hemostasis in a subject in need thereof, treating hemorrhage in a subject in need thereof, and / or treating a subject in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] FIG. 1A-1B are traces showing polyphosphate chain length distributions of twobatches of polyphosphate as analyzed with gel permeation chromatography using an HPLC-RI system. 16 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0066] FIG.2 is a set of traces showing size distribution of eight batches of polyphosphate-functionalized silica nanoparticles.

[0067] FIGs. 3A-3C are graphs showing data from an in vivo study examining the effectof a polyphosphate-functionalized silica nanoparticle composition (FNP-G3F-31) in a P2Y12 inhibitor-treated rat injury model. FIG.3A shows survival rate. FIG.3B shows normalized blood loss. FIG.3C shows bleeding times across various FNP-G3F-31 doses indicated under each bar in mg / kg; the number inside each bar equals number of subjects per group. CAN: cangrelor; VEH: vehicle; FNP: FNP-G3F-31; * = p <0.05, ** = p <0.01, *** = p <0.001, **** = p <0.0001.

[0068] FIGs. 4A-4E are graphs showing the effect of a polyphosphate-functionalizedsilica nanoparticle composition (FNP-G3F-31) on thrombin generation as measured using CAT. Each CAT parameter measured, namely, lag time (FIG. 4A), time-to-peak (FIG. 4B), velocity index (FIG.4C), peak (FIG.4D), and endogenous thrombin potential (ETP) (FIG.4E), is plotted as a function of FNP-G3F-31 concentration (mg / mL) from thrombin generation with three different tissue factor (TF) concentrations: PPP-Reagent (5 pM TF), PPP-Low (1 pM TF), and MP (no TF). FNP: FNP-G3F-31.

[0069] FIG. 5A is a graph showing the effect of a polyphosphate-functionalized silicananoparticle (FNP-G3F-31) on tissue factor pathway inhibitor (TFPI) activity. FIG.5B is a graph showing the effect of a polyphosphate-functionalized silica nanoparticle (FNP-G3F-31) on D- dimer activity. FNP: FNP-G3F-31. DETAILED DESCRIPTION

[0070] The present disclosure provides functionalized nanoparticles (FNP) andpharmaceutical compositions thereof which are, e.g., optimized for safety, efficacy, and stability. Methods of producing FNP and methods of using FNP, e.g., to promote blood clotting are also provided herein. Definitions

[0071] As used herein, the term “nanoparticle” refers to a particle that has dimensions inthe nanometer scale, i.e., a particle less than 1000 nm in size, e.g., Z-average size.

[0072] As used herein, the term “average” refers to the arithmetic mean unless statedotherwise. As used herein, the term “Z-average” or “Z-average size” refers to the intensity 17 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) weighted mean hydrodynamic size of a population of particles, optionally as measured by dynamic light scattering (DLS).

[0073] As used herein, the term “DN”, in the context of a particle size distribution, refersto the particle size (e.g., hydrodynamic size, or diameter) up to and including which N% of the particle size distribution as determined by a particular characteristic (e.g., scattered light intensity, volume, number of particles, mass, surface area, surface charge, or zeta potential) is observed, e.g., by dynamic light scattering (DLS). For example, D10 refers to the particle size (e.g., hydrodynamic size, or diameter) up to and including which 10% of the particle size distribution as determined by a particular characteristic is observed, e.g., by DLS. D50 refers to the particle size (e.g., hydrodynamic size, or diameter) up to and including which 50% of the particle size distribution as determined by a particular characteristic is observed, e.g., by DLS. D90 refers to the particle size (e.g., hydrodynamic size, or diameter) up to and including which 90% of the particle size distribution as determined by a particular characteristic is observed, e.g., by DLS. The term “DN” may be followed by the relevant measured or calculated characteristic or abbreviation thereof; for example, in reference to scattered light intensity, the term “DN(i)” may be used; in reference to volume, the term “DN(v)” may be used; and in reference to number of particles, the term “DN(n)” may be used. Specific examples follow. As used herein, the term “DN(i)”, in the context of a particle size distribution, refers to the particle size (e.g., hydrodynamic size, or diameter) up to and including which N% of the particle size distribution as determined by scattered light intensity is observed, e.g., by DLS. For example, D10(i) refers to the particle size (e.g., hydrodynamic size, or diameter) up to and including which 10% of the particle size distribution as determined by scattered light intensity is observed, e.g., by DLS. D50(i) refers to the particle size (e.g., hydrodynamic size, or diameter) up to and including which 50% of the particle size distribution as determined by scattered light intensity is observed, e.g., by DLS. D90(i) refers to the particle size (e.g., hydrodynamic size, or diameter) up to and including which 90% of the particle size distribution as determined by scattered light intensity is observed, e.g., by DLS. As used herein, the term “DN(v)”, in the context of a particle size distribution, refers to the particle size (e.g., hydrodynamic size, or diameter) up to and including which N% of the particle size distribution as determined by particle volume is observed, e.g., by DLS. For example, D10(v) refers to the particle size (e.g., hydrodynamic size, or diameter) up to and including which 10% of the particle size distribution as determined by particle volume is observed, e.g., by DLS. D50(v) refers to the particle size (e.g., hydrodynamic size, or diameter) 18 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) up to and including which 50% of the particle size distribution as determined by particle volume is observed, e.g., by DLS. D90(v) refers to the particle size (e.g., hydrodynamic size, or diameter) up to and including which 90% of the particle size distribution as determined by particle volume is observed, e.g., by DLS. As used herein, the term “DN(n)”, in the context of a particle size distribution, refers to the particle size (e.g., hydrodynamic size, or diameter) up to and including which N% of the particle size distribution as determined by number of particles is observed, e.g., by DLS. For example, D10(n) refers to the particle size (e.g., hydrodynamic size, or diameter) up to and including which 10% of the particle size distribution as determined by number of particles is observed, e.g., by DLS. D50(n) refers to the particle size (e.g., hydrodynamic size, or diameter) up to and including which 50% of the particle size distribution as determined by number of particles is observed, e.g., by DLS. D90(n) refers to the particle size (e.g., hydrodynamic size, or diameter) up to and including which 90% of the particle size distribution as determined by number of particles is observed, e.g., by DLS.

[0074] As used herein, the term “baseline” refers to a measurement (e.g., clotting time) ina subject prior to the first administration (e.g., intravenous administration) of a treatment (e.g., a functionalized nanoparticle).

[0075] As used herein, the term “less than” refers to a value less than the reference valueprovided. The instant disclosure further contemplates values less than or equal to the reference value provided. In the disclosure where the term “less than” is used, in some embodiments, “less than or equal to” is substituted.

[0076] As used herein, the term “greater than” refers to a value greater than the referencevalue provided. The instant disclosure further contemplates values greater than or equal to the reference value provided. In the disclosure where the term “greater than” is used, in some embodiments, “greater than or equal to” is substituted.

[0077] As used herein, the term “between” refers to a range of values that includes bothendpoints. For example, when referring to a characteristic such as length, diameter, or any measurable attribute, “between” indicates that the values at both the lower and upper boundaries of the specified range are included.

[0078] As used herein, the term “population of free polyphosphate polymers” refers to apopulation of polyphosphate polymers that are not attached to FNP within the same composition. For example, such a population of free polyphosphate polymers may be separated from the FNP, 19 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) e.g., by centrifugation, chromatography, or other suitable methods for separating free components from attached components in a composition.

[0079] As used herein, the terms “treat,” “treating,” and “treatment” refer to therapeutic orpreventative measures described herein. The methods of “treatment” employ administration of a composition, e.g., a pharmaceutical composition, to a subject having a disease or disorder, or predisposed to having such a disease or disorder, in order to prevent, cure, delay, reduce the severity of, or ameliorate one or more symptoms of the disease or disorder or recurring disease or disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.

[0080] As used herein, the term “effective amount” in the context of the administration ofa therapy to a subject refers to the amount of a therapy that achieves a desired prophylactic or therapeutic effect.

[0081] As used herein, the terms “dose” or “dosing” refer to an amount of an agentadministered to a subject in a single administration.

[0082] As used herein, the terms “fixed dose” or “flat dose” both refer to a dose that doesnot vary based upon a characteristic (e.g., body mass, e.g., within a set range; sex; age, e.g., within a set range; etc.) of the subject.

[0083] As used herein, the term “subject” or “patient” includes any human or non-humananimal. In an embodiment, the subject or patient is a human or non-human mammal. In an embodiment, the subject or patient is a human.

[0084] As used herein, the terms “a”, “an”, and “the” refer to “one or more” when used inthis application, including the claims. Thus, for example, reference to “a nanoparticle” includes a plurality of such nanoparticles, and so forth.

[0085] As used herein, the term “about” or “approximately” when referring to ameasurable value, encompasses variations of ±10% of a given value or range. In some embodiments, for any measurable values (e.g. of size, mass, number, pH etc.) recited herein, values that are about that measurable value are also contemplated and may be indicated by preceding such measurable value with the term “about.” 20 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) Functionalized Nanoparticles

[0086] In an aspect, the instant disclosure provides functionalized nanoparticles (FNP)which promote blood clotting. These FNP comprise a nanoparticle (i.e., core nanoparticle) with one or more attached polyphosphate polymers. Nanoparticles and Populations Thereof

[0087] In some embodiments, the nanoparticle has a size, e.g., hydrodynamic size, ordiameter, of about 200 nm or less. In some embodiments, the nanoparticle has a size, e.g., hydrodynamic size, or diameter, of about 190 nm or less, about 180 nm or less, about 170 nm or less, about 160 nm or less, about 150 nm or less, about 140 nm or less, about 130 nm or less, about 120 nm or less, about 110 nm or less, about 100 nm or less, about 95 nm or less, about 90 nm or less, about 85 nm or less, about 80 nm or less, about 75 nm or less, about 70 nm or less, about 65 nm or less, about 60 nm or less, about 55 nm or less, about 50 nm or less, about 45 nm or less, about 40 nm or less, about 35 nm or less, about 30 nm or less, or about 25 nm or less.

[0088] In some embodiments, the nanoparticle has a size, e.g., hydrodynamic size, ordiameter, of 200 nm or less. In some embodiments, the nanoparticle has a size, e.g., hydrodynamic size, or diameter, of 190 nm or less, 180 nm or less, 170 nm or less, 160 nm or less, 150 nm or less, 140 nm or less, 130 nm or less, 120 nm or less, 110 nm or less, 100 nm or less, 95 nm or less, 90 nm or less, 85 nm or less, 80 nm or less, 75 nm or less, 70 nm or less, 65 nm or less, 60 nm or less, 55 nm or less, 50 nm or less, 45 nm or less, 40 nm or less, 35 nm or less, 30 nm or less, or 25 nm or less.

[0089] In some embodiments, the nanoparticle has a size, e.g., hydrodynamic size, ordiameter, between about 25 nm and about 30 nm, between about 25 nm and about 35 nm, between about 25 nm and about 40 nm, between about 25 nm and about 45 nm, between about 25 nm and about 50 nm, between about 25 nm and about 55 nm, between about 25 nm and about 60 nm, between about 25 nm and about 65 nm, between about 25 nm and about 70 nm, between about 25 nm and about 75 nm, between about 25 nm and about 80 nm, between about 25 nm and about 85 nm, between about 25 nm and about 90 nm, between about 25 nm and about 95 nm, between about 25 nm and about 100 nm, between about 25 nm and about 110 nm, between about 25 nm and about 120 nm, between about 25 nm and about 130 nm, between about 25 nm and about 140 nm, between about 25 nm and about 150 nm, between about 25 nm and about 160 nm, between about 25 nm 21 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) and about 170 nm, between about 25 nm and about 180 nm, between about 25 nm and about 190 nm, or between about 25 nm and about 200 nm.

[0090] In some embodiments, the nanoparticle has a size, e.g., hydrodynamic size, ordiameter, between 25 nm and 30 nm, between 25 nm and 35 nm, between 25 nm and 40 nm, between 25 nm and 45 nm, between 25 nm and 50 nm, between 25 nm and 55 nm, between 25 nm and 60 nm, between 25 nm and 65 nm, between 25 nm and 70 nm, between 25 nm and 75 nm, between 25 nm and 80 nm, between 25 nm and 85 nm, between 25 nm and 90 nm, between 25 nm and 95 nm, between 25 nm and 100 nm, between 25 nm and 110 nm, between 25 nm and 120 nm, between 25 nm and 130 nm, between 25 nm and 140 nm, between 25 nm and 150 nm, between 25 nm and 160 nm, between 25 nm and 170 nm, between 25 nm and 180 nm, between 25 nm and 190 nm, or between 25 nm and 200 nm.

[0091] In some embodiments, the nanoparticle is spherical or substantially spherical. Inother embodiments, the nanoparticle has a shape including, but not limited to, an ellipsoid, a rod, a cone, a cube, a cuboid (e.g., a rectangular box), a pyramid, an irregular shape, etc. In certain instances, combinations of different shapes of nanoparticles may be included.

[0092] In some embodiments, the concentration of nanoparticles in a population ofnanoparticles as described herein is at least 0.01% w / v. In some embodiments, the distribution of nanoparticles in a population of nanoparticles is a normal distribution. In some embodiments, the median nanoparticle size and the mean nanoparticle size are the same or similar.

[0093] In some embodiments, the nanoparticles in a population of nanoparticles have a Z-average size of about 200 nm or less. In some embodiments, the nanoparticles in a population of nanoparticles have a Z-average size of about 190 nm or less, about 180 nm or less, about 170 nm or less, about 160 nm or less, about 150 nm or less, about 140 nm or less, about 130 nm or less, about 120 nm or less, about 110 nm or less, about 100 nm or less, about 95 nm or less, about 90 nm or less, about 85 nm or less, about 80 nm or less, about 75 nm or less, about 70 nm or less, about 65 nm or less, about 60 nm or less, about 55 nm or less, about 50 nm or less, about 45 nm or less, about 40 nm or less, about 35 nm or less, about 30 nm or less, or about 25 nm or less.

[0094] In some embodiments, the nanoparticles in a population of nanoparticles have a Z-average size of 200 nm or less. In some embodiments, the nanoparticles in a population of nanoparticles have a Z-average size of 190 nm or less, 180 nm or less, 170 nm or less, 160 nm or less, 150 nm or less, 140 nm or less, 130 nm or less, 120 nm or less, 110 nm or less, 100 nm or less, 95 nm or less, 90 nm or less, 85 nm or less, 80 nm or less, 75 nm or less, 70 nm or less, 65 22 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) nm or less, 60 nm or less, 55 nm or less, 50 nm or less, 45 nm or less, 40 nm or less, 35 nm or less, 30 nm or less, or 25 nm or less.

[0095] In some embodiments, the Z-average size of the nanoparticles in the population ofnanoparticles is between about 30 nm and about 200 nm, between about 30 nm and about 190 nm, between about 30 nm and about 180 nm, between about 30 nm and about 170 nm, between about 30 nm and about 160 nm, between about 30 nm and about 150 nm, between about 30 nm and about 140 nm, between about 30 nm and about 130 nm, between about 30 nm and about 120 nm, between about 30 nm and about 110 nm, between about 30 nm and about 100 nm, between about 30 nm and about 95 nm, between about 30 nm and about 90 nm, between about 30 nm and about 85 nm, between about 30 nm and about 80 nm, between about 30 nm and about 75 nm, between about 30 nm and about 70 nm, or between about 30 nm and about 65 nm.

[0096] In some embodiments, the Z-average size of the nanoparticles in the population ofnanoparticles is between about 40 nm and about 200 nm, between about 40 nm and about 190 nm, between about 40 nm and about 180 nm, between about 40 nm and about 170 nm, between about 40 nm and about 160 nm, between about 40 nm and about 150 nm, between about 40 nm and about 140 nm, between about 40 nm and about 130 nm, between about 40 nm and about 120 nm, between about 40 nm and about 110 nm, between about 40 nm and about 100 nm, between about 40 nm and about 95 nm, between about 40 nm and about 90 nm, between about 40 nm and about 85 nm, between about 40 nm and about 80 nm, between about 40 nm and about 75 nm, between about 40 nm and about 70 nm, or between about 40 nm and about 65 nm.

[0097] In some embodiments, the Z-average size of the nanoparticles in the population ofnanoparticles is between about 50 nm and about 200 nm, between about 50 nm and about 190 nm, between about 50 nm and about 180 nm, between about 50 nm and about 170 nm, between about 50 nm and about 160 nm, between about 50 nm and about 150 nm, between about 50 nm and about 140 nm, between about 50 nm and about 130 nm, between about 50 nm and about 120 nm, between about 50 nm and about 110 nm, between about 50 nm and about 100 nm, between about 50 nm and about 95 nm, between about 50 nm and about 90 nm, between about 50 nm and about 85 nm, between about 50 nm and about 80 nm, between about 50 nm and about 75 nm, between about 50 nm and about 70 nm, or between about 50 nm and about 65 nm.

[0098] In some embodiments, the Z-average size of the nanoparticles in the population ofnanoparticles is between about 55 nm and about 200 nm, between about 55 nm and about 190 nm, between about 55 nm and about 180 nm, between about 55 nm and about 170 nm, between about 23 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 55 nm and about 160 nm, between about 55 nm and about 150 nm, between about 55 nm and about 140 nm, between about 55 nm and about 130 nm, between about 55 nm and about 120 nm, between about 55 nm and about 110 nm, between about 55 nm and about 100 nm, between about 55 nm and about 95 nm, between about 55 nm and about 90 nm, between about 55 nm and about 85 nm, between about 55 nm and about 80 nm, between about 55 nm and about 75 nm, between about 55 nm and about 70 nm, or between about 55 nm and about 65 nm.

[0099] In some embodiments, the Z-average size of the nanoparticles in the population ofnanoparticles is between about 60 nm and about 200 nm, between about 60 nm and about 190 nm, between about 60 nm and about 180 nm, between about 60 nm and about 170 nm, between about 60 nm and about 160 nm, between about 60 nm and about 150 nm, between about 60 nm and about 140 nm, between about 60 nm and about 130 nm, between about 60 nm and about 120 nm, between about 60 nm and about 110 nm, between about 60 nm and about 100 nm, between about 60 nm and about 95 nm, between about 60 nm and about 90 nm, between about 60 nm and about 85 nm, between about 60 nm and about 80 nm, between about 60 nm and about 75 nm, between about 60 nm and about 70 nm, or between about 60 nm and about 65 nm.

[0100] In some embodiments, the Z-average size of the nanoparticles in the population ofnanoparticles is between about 65 nm and about 200 nm, between about 65 nm and about 190 nm, between about 65 nm and about 180 nm, between about 65 nm and about 170 nm, between about 65 nm and about 160 nm, between about 65 nm and about 150 nm, between about 65 nm and about 140 nm, between about 65 nm and about 130 nm, between about 65 nm and about 120 nm, between about 65 nm and about 110 nm, between about 65 nm and about 100 nm, between about 65 nm and about 95 nm, between about 65 nm and about 90 nm, between about 65 nm and about 85 nm, between about 65 nm and about 80 nm, between about 65 nm and about 75 nm, or between about 65 nm and about 70 nm.

[0101] In some embodiments, the Z-average size of the nanoparticles in the population ofnanoparticles is between 30 nm and 200 nm, between 30 nm and 190 nm, between 30 nm and 180 nm, between 30 nm and 170 nm, between 30 nm and 160 nm, between 30 nm and 150 nm, between 30 nm and 140 nm, between 30 nm and 130 nm, between 30 nm and 120 nm, between 30 nm and 110 nm, between 30 nm and 100 nm, between 30 nm and 95 nm, between 30 nm and 90 nm, between 30 nm and 85 nm, between 30 nm and 80 nm, between 30 nm and 75 nm, between 30 nm and 70 nm, or between 30 nm and 65 nm. 24 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0102] In some embodiments, the Z-average size of the nanoparticles in the population ofnanoparticles is between 40 nm and 200 nm, between 40 nm and 190 nm, between 40 nm and 180 nm, between 40 nm and 170 nm, between 40 nm and 160 nm, between 40 nm and 150 nm, between 40 nm and 140 nm, between 40 nm and 130 nm, between 40 nm and 120 nm, between 40 nm and 110 nm, between 40 nm and 100 nm, between 40 nm and 95 nm, between 40 nm and 90 nm, between 40 nm and 85 nm, between 40 nm and 80 nm, between 40 nm and 75 nm, between 40 nm and 70 nm, or between 40 nm and 65 nm.

[0103] In some embodiments, the Z-average size of the nanoparticles in the population ofnanoparticles is between 50 nm and 200 nm, between 50 nm and 190 nm, between 50 nm and 180 nm, between 50 nm and 170 nm, between 50 nm and 160 nm, between 50 nm and 150 nm, between 50 nm and 140 nm, between 50 nm and 130 nm, between 50 nm and 120 nm, between 50 nm and 110 nm, between 50 nm and 100 nm, between 50 nm and 95 nm, between 50 nm and 90 nm, between 50 nm and 85 nm, between 50 nm and 80 nm, between 50 nm and 75 nm, between 50 nm and 70 nm, or between 50 nm and 65 nm.

[0104] In some embodiments, the Z-average size of the nanoparticles in the population ofnanoparticles is between 55 nm and 200 nm, between 55 nm and 190 nm, between 55 nm and 180 nm, between 55 nm and 170 nm, between 55 nm and 160 nm, between 55 nm and 150 nm, between 55 nm and 140 nm, between 55 nm and 130 nm, between 55 nm and 120 nm, between 55 nm and 110 nm, between 55 nm and 100 nm, between 55 nm and 95 nm, between 55 nm and 90 nm, between 55 nm and 85 nm, between 55 nm and 80 nm, between 55 nm and 75 nm, between 55 nm and 70 nm, or between 55 nm and 65 nm.

[0105] In some embodiments, the Z-average size of the nanoparticles in the population ofnanoparticles is between 60 nm and 200 nm, between 60 nm and 190 nm, between 60 nm and 180 nm, between 60 nm and 170 nm, between 60 nm and 160 nm, between 60 nm and 150 nm, between 60 nm and 140 nm, between 60 nm and 130 nm, between 60 nm and 120 nm, between 60 nm and 110 nm, between 60 nm and 100 nm, between 60 nm and 95 nm, between 60 nm and 90 nm, between 60 nm and 85 nm, between 60 nm and 80 nm, between 60 nm and 75 nm, between 60 nm and 70 nm, or between 60 nm and 65 nm.

[0106] In some embodiments, the Z-average size of the nanoparticles in the population ofnanoparticles is between 65 nm and 200 nm, between 65 nm and 190 nm, between 65 nm and 180 nm, between 65 nm and 170 nm, between 65 nm and 160 nm, between 65 nm and 150 nm, between 65 nm and 140 nm, between 65 nm and 130 nm, between 65 nm and 120 nm, between 65 nm and 25 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 110 nm, between 65 nm and 100 nm, between 65 nm and 95 nm, between 65 nm and 90 nm, between 65 nm and 85 nm, between 65 nm and 80 nm, between 65 nm and 75 nm, or between 65 nm and 70 nm.

[0107] In some embodiments, the nanoparticles in a population of nanoparticles have a Z-average size of about 200 nm, about 190 nm, about 180 nm, about 170 nm, about 160 nm, about 150 nm, about 140 nm, about 130 nm, about 120 nm, about 110 nm, about 100 nm, about 99 nm, about 98 nm, about 97 nm, about 96 nm, about 95 nm, about 94 nm, about 93 nm, about 92 nm, about 91 nm, about 90 nm, about 89 nm, about 88 nm, about 87 nm, about 86 nm, about 85 nm, about 84 nm, about 83 nm, about 82 nm, about 81 nm, about 80 nm, about 79 nm, about 78 nm, about 77 nm, about 76 nm, about 75 nm, about 74 nm, about 73 nm, about 72 nm, about 71 nm, about 70 nm, about 69 nm, about 68 nm, about 67 nm, about 66 nm, about 65 nm, about 64 nm, about 63 nm, about 62 nm, about 61 nm, about 60 nm, about 59 nm, about 58 nm, about 57 nm, about 56 nm, about 55 nm, about 54 nm, about 53 nm, about 52 nm, about 51 nm, about 50 nm, about 49 nm, about 48 nm, about 47 nm, about 46 nm, about 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, or about 25 nm.

[0108] In some embodiments, the nanoparticles in a population of nanoparticles have a Z-average size of 200 nm, 190 nm, 180 nm, 170 nm, 160 nm, 150 nm, 140 nm, 130 nm, 120 nm, 110 nm, 100 nm, 99 nm, 98 nm, 97 nm, 96 nm, 95 nm, 94 nm, 93 nm, 92 nm, 91 nm, 90 nm, 89 nm, 88 nm, 87 nm, 86 nm, 85 nm, 84 nm, 83 nm, 82 nm, 81 nm, 80 nm, 79 nm, 78 nm, 77 nm, 76 nm, 75 nm, 74 nm, 73 nm, 72 nm, 71 nm, 70 nm, 69 nm, 68 nm, 67 nm, 66 nm, 65 nm, 64 nm, 63 nm, 62 nm, 61 nm, 60 nm, 59 nm, 58 nm, 57 nm, 56 nm, 55 nm, 54 nm, 53 nm, 52 nm, 51 nm, 50 nm, 49 nm, 48 nm, 47 nm, 46 nm, 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, or 25 nm.

[0109] In some embodiments, the D10 of the nanoparticles in a population of nanoparticlesis less than about 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, about 25 nm, about 24 nm, about 23 nm, about 22 nm, about 21 nm, or about 20 nm. In some embodiments, the D10 of the nanoparticles in a population of nanoparticles is less than 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 26 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, 25 nm, 24 nm, 23 nm, 22 nm, 21 nm, or 20 nm. In some embodiments, the D10 of the nanoparticles in a population of nanoparticles is less than about 32 nm. In some embodiments, the D10 of the nanoparticles in a population of nanoparticles is less than 32 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0110] In some embodiments, the D10 of the nanoparticles in a population of nanoparticlesis greater than about 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, about 25 nm, about 24 nm, about 23 nm, about 22 nm, about 21 nm, or about 20 nm. In some embodiments, the D10 of the nanoparticles in a population of nanoparticles is greater than 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, 25 nm, 24 nm, 23 nm, 22 nm, 21 nm, or 20 nm. In some embodiments, the D10 of the nanoparticles in a population of nanoparticles is greater than about 32 nm. In some embodiments, the D10 of the nanoparticles in a population of nanoparticles is greater than 32 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0111] In some embodiments, the D10 of the nanoparticles in a population of nanoparticlesis between about 20 nm and about 45 nm, between about 25 nm and about 40 nm, or between about 30 nm and about 35 nm. In some embodiments, the D10 of the nanoparticles in a population of nanoparticles is between 20 nm and 45 nm, between 25 nm and 40 nm, or between 30 nm and 35 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0112] In some embodiments, the D10 of the nanoparticles in a population of nanoparticlesis about 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, about 25 nm, about 24 nm, about 23 nm, about 22 nm, about 21 nm, or about 20 nm. In some embodiments, the D10 of the nanoparticles in a population of nanoparticles is 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, 25 nm, 24 nm, 23 nm, 22 nm, 21 nm, or 20 nm. In some embodiments, the D10 of the nanoparticles in a population of nanoparticles is about 32 nm. In some embodiments, the D10 27 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) of the nanoparticles in a population of nanoparticles is 32 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0113] In some embodiments, the D90 of the nanoparticles in a population of nanoparticlesis less than about 200 nm, about 190 nm, about 180 nm, about 170 nm, about 160 nm, about 150 nm, about 140 nm, about 130 nm, about 120 nm, about 110 nm, about 100 nm, about 99 nm, about 98 nm, about 97 nm, about 96 nm, about 95 nm, about 94 nm, about 93 nm, about 92 nm, about 91 nm, about 90 nm, about 89 nm, about 88 nm, about 87 nm, about 86 nm, about 85 nm, about 84 nm, about 83 nm, about 82 nm, about 81 nm, about 80 nm, about 79 nm, about 78 nm, about 77 nm, about 76 nm, about 75 nm, about 74 nm, about 73 nm, about 72 nm, about 71 nm, or about 70 nm. In some embodiments, the D90 of the nanoparticles in a population of nanoparticles is less than 200 nm, 190 nm, 180 nm, 170 nm, 160 nm, 150 nm, 140 nm, 130 nm, 120 nm, 110 nm, 100 nm, 99 nm, 98 nm, 97 nm, 96 nm, 95 nm, 94 nm, 93 nm, 92 nm, 91 nm, 90 nm, 89 nm, 88 nm, 87 nm, 86 nm, 85 nm, 84 nm, 83 nm, 82 nm, 81 nm, 80 nm, 79 nm, 78 nm, 77 nm, 76 nm, 75 nm, 74 nm, 73 nm, 72 nm, 71 nm, or 70 nm. In some embodiments, the D90 of the nanoparticles in a population of nanoparticles is less than about 85 nm. In some embodiments, the D90 of the nanoparticles in a population of nanoparticles is less than 85 nm. In some embodiments, the D90 is D90(i), D90(v), or D90(n). In some embodiments, the D90 is D90(i).

[0114] In some embodiments, the D90 of the nanoparticles in a population of nanoparticlesis between about 70 nm and about 200 nm, between about 70 nm and about 150 nm, between about 75 nm and about 100 nm, or between about 80 nm and about 90 nm. In some embodiments, the D90 of the nanoparticles in a population of nanoparticles is between 70 nm and 200 nm, between 70 nm and 150 nm, between 75 nm and 100 nm, or between 80 nm and 90 nm. In some embodiments, the D90 is D90(i), D90(v), or D90(n). In some embodiments, the D90 is D90(i).

[0115] In some embodiments, the D90 of the nanoparticles in a population of nanoparticlesis about 200 nm, about 190 nm, about 180 nm, about 170 nm, about 160 nm, about 150 nm, about 140 nm, about 130 nm, about 120 nm, about 110 nm, about 100 nm, about 99 nm, about 98 nm, about 97 nm, about 96 nm, about 95 nm, about 94 nm, about 93 nm, about 92 nm, about 91 nm, about 90 nm, about 89 nm, about 88 nm, about 87 nm, about 86 nm, about 85 nm, about 84 nm, about 83 nm, about 82 nm, about 81 nm, about 80 nm, about 79 nm, about 78 nm, about 77 nm, about 76 nm, about 75 nm, about 74 nm, about 73 nm, about 72 nm, about 71 nm, or about 70 nm. In some embodiments, the D90 of the nanoparticles in a population of nanoparticles is 200 nm, 190 nm, 180 nm, 170 nm, 160 nm, 150 nm, 140 nm, 130 nm, 120 nm, 110 nm, 100 nm, 99 nm, 98 28 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) nm, 97 nm, 96 nm, 95 nm, 94 nm, 93 nm, 92 nm, 91 nm, 90 nm, 89 nm, 88 nm, 87 nm, 86 nm, 85 nm, 84 nm, 83 nm, 82 nm, 81 nm, 80 nm, 79 nm, 78 nm, 77 nm, 76 nm, 75 nm, 74 nm, 73 nm, 72 nm, 71 nm, or 70 nm. In some embodiments, the D90 of the nanoparticles in a population of nanoparticles is about 85 nm. In some embodiments, the D90 of the nanoparticles in a population of nanoparticles is 85 nm. In some embodiments, the D90 is D90(i), D90(v), or D90(n). In some embodiments, the D90 is D90(i).

[0116] In some embodiments, the nanoparticle is composed of an oxide of silicon, an oxideof aluminum, an oxide of a transition metal (e.g., titanium, zirconium, and the like), aluminosilicate, or combination thereof. Exemplary materials for the nanoparticle include, but are not limited to, silicon dioxide (e.g., silica), titanium dioxide, silicon-aluminum-oxide, aluminum oxide, iron oxide, polymers (e.g., polystyrene), metals (e.g., gold), and the like. In some instances, the nanoparticle is composed of other inorganic materials, such as, but not limited to, diatomaceous earth, calcium hydroxyapatite, and the like. Combinations of the above materials may also be included.

[0117] In some embodiments, the nanoparticle is composed of silica, e.g., amorphoussilica, colloidal silica, hydrophobic colloidal silica, non-crystalline silica, mesoporous silica, or a silica mixture (e.g., kaolin clay or diatomaceous earth). In some embodiments, the nanoparticle is composed of amorphous silica.

[0118] In some embodiments, the nanoparticle may have hemostatic activity, such that thenanoparticle promotes blood clotting (e.g., as compared to blood clotting in the absence of the hemostatic agent). As such, a nanoparticle with hemostatic activity may be described as being hemostatically effective. For example, without being limited to any particular theory, the nanoparticle may have a negative surface charge in body fluid (e.g., blood), which may facilitate activation of the coagulation cascade by activating Factor XII. The promotion of blood clotting may be described, e.g., by thromboelastography, a clotting test, by one or more of the following factors: (1) reduction in initial time for blood clot formation (R, min); (2) increase in the rate of clot formation (α, deg); (3) increase in clot strength or maximum amplitude (MA, m); and (4) reduction in time until clot reaches 20 mm (K, min).

[0119] In some embodiments, nanoparticles may be, e.g., sourced from an appropriatevendor or manufactured and / or purified by an appropriate method, e.g., as described in U.S. Patent No. 9,186,417, which is herein incorporated by reference in its entirety, or manufactured and / or purified by any other suitable method, e.g., any suitable method known in the art. 29 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) Polyphosphate Polymer

[0120] In some embodiments, a population of polyphosphate (e.g., sodium polyphosphate)polymers are attached to a nanoparticle to create an FNP. In some embodiments, a population of FNP are present in a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises polyphosphate polymers attached to the FNP and free polyphosphate. In some embodiments, the average chain length of the polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) is no more than about 70, no more than about 69, no more than about 68, no more than about 67, no more than about 66, no more than about 65, no more than about 64, no more than about 63, no more than about 62, no more than about 61, no more than about 60, no more than about 59, no more than about 58, no more than about 57, no more than about 56, no more than about 55, no more than about 54, no more than about 53, no more than about 52, no more than about 51, no more than about 50, no more than about 49, no more than about 48, no more than about 47, no more than about 46, no more than about 45, no more than about 44, no more than about 43, no more than about 42, no more than about 41, no more than about 40, no more than about 39, no more than about 38, no more than about 37, no more than about 36, no more than about 35, no more than about 34, no more than about 33, no more than about 32, no more than about 31, or no more than about 30 phosphate units.

[0121] In some embodiments, the average chain length of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) is no more than 70, no more than 69, no more than 68, no more than 67, no more than 66, no more than 65, no more than 64, no more than 63, no more than 62, no more than 61, no more than 60, no more than 59, no more than 58, no more than 57, no more than 56, no more than 55, no more than 54, no more than 53, no more than 52, no more than 51, no more than 50, no more than 49, no more than 48, no more than 47, no more than 46, no more than 45, no more than 44, no more than 43, no more than 42, no more than 41, no more than 40, no more than 39, no more than 38, no more than 37, no more than 36, no more than 35, no more than 34, no more than 33, no more than 32, no more than 31, or no more than 30 phosphate units.

[0122] In some embodiments, the average chain length of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) is between about 30 and about 60 30 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) phosphate units, between about 31 and about 60 phosphate units, between about 32 and about 60 phosphate units, between about 33 and about 60 phosphate units, between about 34 and about 60 phosphate units, between about 35 and about 60 phosphate units, between about 36 and about 60 phosphate units, between about 37 and about 60 phosphate units, between about 38 and about 60 phosphate units, between about 39 and about 60 phosphate units, between about 40 and about 60 phosphate units, between about 41 and about 60 phosphate units, between about 42 and about 60 phosphate units, between about 43 and about 60 phosphate units, between about 44 and about 60 phosphate units, between about 45 and about 60 phosphate units, between about 46 and about 60 phosphate units, between about 47 and about 60 phosphate units, between about 48 and about 60 phosphate units, between about 49 and about 60 phosphate units, between about 50 and about 60 phosphate units, between about 51 and about 60 phosphate units, between about 52 and about 60 phosphate units, between about 53 and about 60 phosphate units, between about 54 and about 60 phosphate units, or between about 55 and about 60 phosphate units.

[0123] In some embodiments, the average chain length of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) is between 30 and 60 phosphate units, between 31 and 60 phosphate units, between 32 and 60 phosphate units, between 33 and 60 phosphate units, between 34 and 60 phosphate units, between 35 and 60 phosphate units, between 36 and 60 phosphate units, between 37 and 60 phosphate units, between 38 and 60 phosphate units, between 39 and 60 phosphate units, between 40 and 60 phosphate units, between 41 and 60 phosphate units, between 42 and 60 phosphate units, between 43 and 60 phosphate units, between 44 and 60 phosphate units, between 45 and 60 phosphate units, between 46 and 60 phosphate units, between 47 and 60 phosphate units, between 48 and 60 phosphate units, between 49 and 60 phosphate units, between 50 and 60 phosphate units, between 51 and 60 phosphate units, between 52 and 60 phosphate units, between 53 and 60 phosphate units, between 54 and 60 phosphate units, or between 55 and 60 phosphate units.

[0124] In some embodiments, the average chain length of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) is between about 30 and about 59 phosphate units, between about 31 and about 59 phosphate units, between about 32 and about 59 phosphate units, between about 33 and about 59 phosphate units, between about 34 and about 59 phosphate units, between about 35 and about 59 phosphate units, between about 36 and about 59 31 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) phosphate units, between about 37 and about 59 phosphate units, between about 38 and about 59 phosphate units, between about 39 and about 59 phosphate units, between about 40 and about 59 phosphate units, between about 41 and about 59 phosphate units, between about 42 and about 59 phosphate units, between about 43 and about 59 phosphate units, between about 44 and about 59 phosphate units, between about 45 and about 59 phosphate units, between about 46 and about 59 phosphate units, between about 47 and about 59 phosphate units, between about 48 and about 59 phosphate units, between about 49 and about 59 phosphate units, between about 50 and about 59 phosphate units, between about 51 and about 59 phosphate units, between about 52 and about 59 phosphate units, between about 53 and about 59 phosphate units, between about 54 and about 59 phosphate units, or between about 55 and about 59 phosphate units.

[0125] In some embodiments, the average chain length of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) is between 30 and 59 phosphate units, between 31 and 59 phosphate units, between 32 and 59 phosphate units, between 33 and 59 phosphate units, between 34 and 59 phosphate units, between 35 and 59 phosphate units, between 36 and 59 phosphate units, between 37 and 59 phosphate units, between 38 and 59 phosphate units, between 39 and 59 phosphate units, between 40 and 59 phosphate units, between 41 and 59 phosphate units, between 42 and 59 phosphate units, between 43 and 59 phosphate units, between 44 and 59 phosphate units, between 45 and 59 phosphate units, between 46 and 59 phosphate units, between 47 and 59 phosphate units, between 48 and 59 phosphate units, between 49 and 59 phosphate units, between 50 and 59 phosphate units, between 51 and 59 phosphate units, between 52 and 59 phosphate units, between 53 and 59 phosphate units, between 54 and 59 phosphate units, or between 55 and 59 phosphate units.

[0126] In some embodiments, the average chain length of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) is between about 30 and about 58 phosphate units, between about 31 and about 58 phosphate units, between about 32 and about 58 phosphate units, between about 33 and about 58 phosphate units, between about 34 and about 58 phosphate units, between about 35 and about 58 phosphate units, between about 36 and about 58 phosphate units, between about 37 and about 58 phosphate units, between about 38 and about 58 phosphate units, between about 39 and about 58 phosphate units, between about 40 and about 58 phosphate units, between about 41 and about 58 phosphate units, between about 42 and about 58 32 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) phosphate units, between about 43 and about 58 phosphate units, between about 44 and about 58 phosphate units, between about 45 and about 58 phosphate units, between about 46 and about 58 phosphate units, between about 47 and about 58 phosphate units, between about 48 and about 58 phosphate units, between about 49 and about 58 phosphate units, between about 50 and about 58 phosphate units, between about 51 and about 58 phosphate units, between about 52 and about 58 phosphate units, between about 53 and about 58 phosphate units, between about 54 and about 58 phosphate units, or between about 55 and about 58 phosphate units.

[0127] In some embodiments, the average chain length of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) is between 30 and 58 phosphate units, between 31 and 58 phosphate units, between 32 and 58 phosphate units, between 33 and 58 phosphate units, between 34 and 58 phosphate units, between 35 and 58 phosphate units, between 36 and 58 phosphate units, between 37 and 58 phosphate units, between 38 and 58 phosphate units, between 39 and 58 phosphate units, between 40 and 58 phosphate units, between 41 and 58 phosphate units, between 42 and 58 phosphate units, between 43 and 58 phosphate units, between 44 and 58 phosphate units, between 45 and 58 phosphate units, between 46 and 58 phosphate units, between 47 and 58 phosphate units, between 48 and 58 phosphate units, between 49 and 58 phosphate units, between 50 and 58 phosphate units, between 51 and 58 phosphate units, between 52 and 58 phosphate units, between 53 and 58 phosphate units, between 54 and 58 phosphate units, or between 55 and 58 phosphate units.

[0128] In some embodiments, the shortest 10% of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) are no longer than about 40, no longer than about 39, no longer than about 38, no longer than about 37, no longer than about 36, no longer than about 35, no longer than about 34, no longer than about 33, no longer than about 32, no longer than about 31, no longer than about 30, no longer than about 29, no longer than about 28, no longer than about 27, no longer than about 26, no longer than about 25, no longer than about 24, no longer than about 23, no longer than about 22, no longer than about 21, no longer than about 20, no longer than about 19, no longer than about 18, no longer than about 17, no longer than about 16, no longer than about 15, no longer than about 14, no longer than about 13, no longer than about 12, no longer than about 11, or no longer than about 10 phosphate units. 33 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0129] In some embodiments, the shortest 10% of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) are no longer than 40, no longer than 39, no longer than 38, no longer than 37, no longer than 36, no longer than 35, no longer than 34, no longer than 33, no longer than 32, no longer than 31, no longer than 30, no longer than 29, no longer than 28, no longer than 27, no longer than 26, no longer than 25, no longer than 24, no longer than 23, no longer than 22, no longer than 21, no longer than 20, no longer than 19, no longer than 18, no longer than 17, no longer than 16, no longer than 15, no longer than 14, no longer than 13, no longer than 12, no longer than 11, or no longer than 10 phosphate units.

[0130] In some embodiments, the shortest 10% of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) are no longer than a length between about 10 and about 40, between about 10 and about 35, between about 10 and about 30, between about 15 and about 40, between about 15 and about 35, between about 15 and about 30, between about 20 and about 40, between about 20 and about 35, between about 20 and about 30, between about 25 and about 40, between about 25 and about 35, or between about 25 and about 30 phosphate units.

[0131] In some embodiments, the shortest 10% of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) are no longer than a length between 10 and 40, between 10 and 35, between 10 and 30, between 15 and 40, between 15 and 35, between 15 and 30, between 20 and 40, between 20 and 35, between 20 and 30, between 25 and 40, between 25 and 35, or between 25 and 30 phosphate units.

[0132] In some embodiments, the longest 90% of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) are no shorter than about 40, no shorter than about 39, no shorter than about 38, no shorter than about 37, no shorter than about 36, no shorter than about 35, no shorter than about 34, no shorter than about 33, no shorter than about 32, no shorter than about 31, no shorter than about 30, no shorter than about 29, no shorter than about 28, no shorter than about 27, no shorter than about 26, no shorter than about 25, no shorter than about 24, no shorter than about 23, no shorter than about 22, no shorter than about 21, no shorter than about 20, no shorter than about 19, no shorter than about 18, no shorter than about 17, 34 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) no shorter than about 16, no shorter than about 15, no shorter than about 14, no shorter than about 13, no shorter than about 12, no shorter than about 11, or no shorter than about 10 phosphate units.

[0133] In some embodiments, the longest 90% of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) are no shorter than 40, no shorter than 39, no shorter than 38, no shorter than 37, no shorter than 36, no shorter than 35, no shorter than 34, no shorter than 33, no shorter than 32, no shorter than 31, no shorter than 30, no shorter than 29, no shorter than 28, no shorter than 27, no shorter than 26, no shorter than 25, no shorter than 24, no shorter than 23, no shorter than 22, no shorter than 21, no shorter than 20, no shorter than 19, no shorter than 18, no shorter than 17, no shorter than 16, no shorter than 15, no shorter than 14, no shorter than 13, no shorter than 12, no shorter than 11, or no shorter than 10 phosphate units.

[0134] In some embodiments, the longest 90% of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) are no shorter than a length between about 10 and about 40, between about 10 and about 35, between about 10 and about 30, between about 15 and about 40, between about 15 and about 35, between about 15 and about 30, between about 20 and about 40, between about 20 and about 35, between about 20 and about 30, between about 25 and about 40, between about 25 and about 35, or between about 25 and about 30 phosphate units.

[0135] In some embodiments, the longest 90% of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) are no shorter than a length between 10 and 40, between 10 and 35, between 10 and 30, between 15 and 40, between 15 and 35, between 15 and 30, between 20 and 40, between 20 and 35, between 20 and 30, between 25 and 40, between 25 and 35, or between 25 and 30 phosphate units.

[0136] In some embodiments, the shortest 90% of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) are no longer than about 70, no longer than about 75, no longer than about 80, no longer than about 85, no longer than about 90, no longer than about 95, no longer than about 100, no longer than about 105, no longer than about 110, no longer than about 115, no longer than about 120, no longer than about 125, no longer than 35 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) about 130, no longer than about 135, or no longer than about 140 phosphate units. In some embodiments, the shortest 90% of the polyphosphate polymers in the population of polyphosphate polymers are no longer than 70, no longer than 75, no longer than 80, no longer than 85, no longer than 90, no longer than 95, no longer than 100, no longer than 105, no longer than 110, no longer than 115, no longer than 120, no longer than 125, no longer than 130, no longer than 135, or no longer than 140 phosphate units.

[0137] In some embodiments, the shortest 90% of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) are no longer than a length between about 70 and about 140, between about 75 and about 140, between about 80 and about 140, between about 70 and about 135, between about 75 and about 135, between about 80 and about 135, between about 70 and about 130, between about 75 and about 130, or between about 80 and about 130 phosphate units.

[0138] In some embodiments, the shortest 90% of the polyphosphate (e.g., sodiumpolyphosphate) polymers in the population of polyphosphate polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) are no longer than a length between 70 and 140, between 75 and 140, between 80 and 140, between 70 and 135, between 75 and 135, between 80 and 135, between 70 and 130, between 75 and 130, or between 80 and 130 phosphate units.

[0139] In some embodiments, 10% of the total mass of the population of polyphosphate(e.g., sodium polyphosphate) polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) are polyphosphate polymers with a chain length no longer than about 40, no longer than about 39, no longer than about 38, no longer than about 37, no longer than about 36, no longer than about 35, no longer than about 34, no longer than about 33, no longer than about 32, no longer than about 31, no longer than about 30, no longer than about 29, no longer than about 28, no longer than about 27, no longer than about 26, no longer than about 25, no longer than about 24, no longer than about 23, no longer than about 22, no longer than about 21, no longer than about 20, no longer than about 19, no longer than about 18, no longer than about 17, no longer than about 16, no longer than about 15, no longer than about 14, no longer than about 13, no longer than about 12, no longer than about 11, or no longer than about 10 phosphate units.

[0140] In some embodiments, 10% of the total mass of the population of polyphosphate(e.g., sodium polyphosphate) polymers in the population of FNP or in the pharmaceutical 36 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) composition (i.e. both bound and free) are polyphosphate polymers with a chain length no longer than 40, no longer than 39, no longer than 38, no longer than 37, no longer than 36, no longer than 35, no longer than 34, no longer than 33, no longer than 32, no longer than 31, no longer than 30, no longer than 29, no longer than 28, no longer than 27, no longer than 26, no longer than 25, no longer than 24, no longer than 23, no longer than 22, no longer than 21, no longer than 20, no longer than 19, no longer than 18, no longer than 17, no longer than 16, no longer than 15, no longer than 14, no longer than 13, no longer than 12, no longer than 11, or no longer than 10 phosphate units.

[0141] In some embodiments, 10% of the total mass of the population of polyphosphate(e.g., sodium polyphosphate) polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) are polyphosphate polymers no longer than a chain length no longer than a length between about 10 and about 40, between about 10 and about 35, between about 10 and about 30, between about 15 and about 40, between about 15 and about 35, between about 15 and about 30, between about 20 and about 40, between about 20 and about 35, between about 20 and about 30, between about 25 and about 40, between about 25 and about 35, or between about 25 and about 30 phosphate units.

[0142] In some embodiments, 10% of the total mass of the population of polyphosphate(e.g., sodium polyphosphate) polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) are polyphosphate polymers no longer than a chain length no longer than a length between 10 and 40, between 10 and 35, between 10 and 30, between 15 and 40, between 15 and 35, between 15 and 30, between 20 and 40, between 20 and 35, between 20 and 30, between 25 and 40, between 25 and 35, or between 25 and 30 phosphate units.

[0143] In some embodiments, 90% of the total mass of the population of polyphosphate(e.g., sodium polyphosphate) polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) are polyphosphate polymers with a chain length no longer than about 70, no longer than about 75, no longer than about 80, no longer than about 85, no longer than about 90, no longer than about 95, no longer than about 100, no longer than about 105, no longer than about 110, no longer than about 115, no longer than about 120, no longer than about 125, no longer than about 130, no longer than about 135, or no longer than about 140 phosphate units. In some embodiments, 90% of the total mass of the population of polyphosphate polymers are polyphosphate polymers with a chain length no longer than 70, no longer than 75, no longer than 80, no longer than 85, no longer than 90, no longer than 95, no longer than 100, no longer 37 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) than 105, no longer than 110, no longer than 115, no longer than 120, no longer than 125, no longer than 130, no longer than 135, or no longer than 140 phosphate units.

[0144] In some embodiments, 90% of the total mass of the population of polyphosphate(e.g., sodium polyphosphate) polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) are polyphosphate polymers no longer than a chain length no longer than a length between about 70 and about 140, between about 75 and about 140, between about 80 and about 140, between about 70 and about 135, between about 75 and about 135, between about 80 and about 135, between about 70 and about 130, between about 75 and about 130, or between about 80 and about 130 phosphate units.

[0145] In some embodiments, 90% of the total mass of the population of polyphosphate(e.g., sodium polyphosphate) polymers in the population of FNP or in the pharmaceutical composition (i.e. both bound and free) are polyphosphate polymers no longer than a chain length no longer than a length between 70 and 140, between 75 and 140, between 80 and 140, between 70 and 135, between 75 and 135, between 80 and 135, between 70 and 130, between 75 and 130, or between 80 and 130 phosphate units.

[0146] In some embodiments, the chain length of the polyphosphate polymer is measuredby GPC (gel filtration HPLC-RI), titration, or31P-NMR.

[0147] In some embodiments, polyphosphate polymers may be, e.g., sourced from anappropriate vendor or manufactured and / or purified by an appropriate method, e.g., as described in Momeni and Filiaggi (2013) J. Non-Cryst. Solids 382:11–17, or in U.S. Patent No.9,186,417, each of which is herein incorporated by reference in its entirety, or manufactured and / or purified by any other suitable method, e.g., any suitable method known in the art. For example, sodium phosphate monobasic monohydrate may be heated in an appropriate crucible (such as Pt) until it forms a melt. This melt may then be rapidly quenched in order to form a polyphosphate glass, which may then be ground and dissolved in deionized water. Chain lengths may be fractionated through methods such as alcohol precipitation or separation via retention time. The resulting fractions may then be dried in order to form a polyphosphate powder. Functionalized Nanoparticles (FNP) and Populations Thereof

[0148] As discussed above, polyphosphate polymers are attached to nanoparticles to createthe functionalized nanoparticles (FNP) of the instant disclosure. The FNP described herein are, e.g., optimized for safety by incorporating shorter polyphosphate polymers which effectively 38 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) promote acceleration of blood clotting via FXI and FV and thrombin while avoiding initiation of blood clotting via FXII or FVII and TF. Unexpectedly, use of shorter polyphosphate polymers as described herein was at least as effective in promoting blood clotting as longer endogenous polyphosphate polymers secreted by platelets in response to injury (see, e.g., Choi et al. (2011) Blood 118(26):6963-70; Choi et al. (2015) Thromb Haemost. 113(3):599–604; and Smith et al. (2010) Blood 116(20):4353-9, each of which are incorporated herein by reference in their entirety).

[0149] Each polyphosphate polymer may be attached to the nanoparticle by any suitablemeans. For example, the polyphosphate polymer may be adsorbed on the surface of the nanoparticle. In some embodiments, the polyphosphate polymers are attached to the nanoparticle by a binding interaction. The binding interaction can be based on one or more of a variety of binding interactions between the polyphosphate polymer and the nanoparticle, such as, but not limited to, hydrogen bonds, van der Waals forces (e.g., London dispersion forces), dipole-dipole interactions, hydrophobic interactions, ionic bonds, electrostatic interactions, covalent bonds, combinations thereof, and the like. The polyphosphate polymer may be attached to the nanoparticle through a linking group between the nanoparticle surface or pores and the polyphosphate polymer. The binding interactions may be substantially permanent (e.g., requiring a relatively large amount of energy to overcome the binding interaction, such as with covalent bonds) or may be reversible (e.g., requiring a relatively low amount of energy to disrupt the binding interaction, such as with dipole-dipole interactions). For example, the polyphosphate polymer may be attached to the nanoparticle via a phosphoramidate bond, ester linkage, carboxylic acid linkage, or another form of linkage. In certain embodiments, bonds may be altered in strength depending on factors present or arising in the body (e.g., enzymes, fibrin, etc.), or affected by externally applied fields (e.g., magnetic, etc.), or by injection of a modifier agent directed at the polyphosphate polymer, linkage, or nanoparticle.

[0150] In some embodiments, the polyphosphate polymer is attached to the nanoparticlethrough a non-covalent bond. This allows the polyphosphate polymer to dissociate from the nanoparticle in vivo. In some embodiments, the polyphosphate polymers are attached to the nanoparticle by hydrogen bonds, Van der Waals forces (e.g., London dispersion forces), or a combination thereof.

[0151] In some embodiments, the nanoparticle of an FNP has a size, e.g., hydrodynamicsize, or diameter, of about 200 nm or less. In some embodiments, the nanoparticle has a size, e.g., hydrodynamic size, or diameter, of about 190 nm or less, about 180 nm or less, about 170 nm or 39 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) less, about 160 nm or less, about 150 nm or less, about 140 nm or less, about 130 nm or less, about 120 nm or less, about 110 nm or less, about 100 nm or less, about 95 nm or less, about 90 nm or less, about 85 nm or less, about 80 nm or less, about 75 nm or less, about 70 nm or less, about 65 nm or less, about 60 nm or less, about 55 nm or less, about 50 nm or less, about 45 nm or less, about 40 nm or less, about 35 nm or less, about 30 nm or less, or about 25 nm or less.

[0152] In some embodiments, the nanoparticle of an FNP has a size, e.g., hydrodynamicsize, or diameter, of 200 nm or less. In some embodiments, the nanoparticle has a size, e.g., hydrodynamic size, or diameter, of 190 nm or less, 180 nm or less, 170 nm or less, 160 nm or less, 150 nm or less, 140 nm or less, 130 nm or less, 120 nm or less, 110 nm or less, 100 nm or less, 95 nm or less, 90 nm or less, 85 nm or less, 80 nm or less, 75 nm or less, 70 nm or less, 65 nm or less, 60 nm or less, 55 nm or less, 50 nm or less, 45 nm or less, 40 nm or less, 35 nm or less, 30 nm or less, or 25 nm or less.

[0153] In some embodiments, the nanoparticle of an FNP has a size, e.g., hydrodynamicsize, or diameter, between about 25 nm and about 30 nm, between about 25 nm and about 35 nm, between about 25 nm and about 40 nm, between about 25 nm and about 45 nm, between about 25 nm and about 50 nm, between about 25 nm and about 55 nm, between about 25 nm and about 60 nm, between about 25 nm and about 65 nm, between about 25 nm and about 70 nm, between about 25 nm and about 75 nm, between about 25 nm and about 80 nm, between about 25 nm and about 85 nm, between about 25 nm and about 90 nm, between about 25 nm and about 95 nm, between about 25 nm and about 100 nm, between about 25 nm and about 110 nm, between about 25 nm and about 120 nm, between about 25 nm and about 130 nm, between about 25 nm and about 140 nm, between about 25 nm and about 150 nm, between about 25 nm and about 160 nm, between about 25 nm and about 170 nm, between about 25 nm and about 180 nm, between about 25 nm and about 190 nm, or between about 25 nm and about 200 nm.

[0154] In some embodiments, the nanoparticle of an FNP has a size, e.g., hydrodynamicsize, or diameter, between 25 nm and 30 nm, between 25 nm and 35 nm, between 25 nm and 40 nm, between 25 nm and 45 nm, between 25 nm and 50 nm, between 25 nm and 55 nm, between 25 nm and 60 nm, between 25 nm and 65 nm, between 25 nm and 70 nm, between 25 nm and 75 nm, between 25 nm and 80 nm, between 25 nm and 85 nm, between 25 nm and 90 nm, between 25 nm and 95 nm, between 25 nm and 100 nm, between 25 nm and 110 nm, between 25 nm and 120 nm, between 25 nm and 130 nm, between 25 nm and 140 nm, between 25 nm and 150 nm, 40 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) between 25 nm and 160 nm, between 25 nm and 170 nm, between 25 nm and 180 nm, between 25 nm and 190 nm, or between 25 nm and 200 nm.

[0155] In some embodiments, the average chain length of the polyphosphate polymers perindividual FNP is no more than about 70, no more than about 69, no more than about 68, no more than about 67, no more than about 66, no more than about 65, no more than about 64, no more than about 63, no more than about 62, no more than about 61, no more than about 60, no more than about 59, no more than about 58, no more than about 57, no more than about 56, no more than about 55, no more than about 54, no more than about 53, no more than about 52, no more than about 51, no more than about 50, no more than about 49, no more than about 48, no more than about 47, no more than about 46, no more than about 45, no more than about 44, no more than about 43, no more than about 42, no more than about 41, no more than about 40, no more than about 39, no more than about 38, no more than about 37, no more than about 36, no more than about 35, no more than about 34, no more than about 33, no more than about 32, no more than about 31, or no more than about 30 phosphate units.

[0156] In some embodiments, the average chain length of the polyphosphate polymers perindividual FNP is no more than 70, no more than 69, no more than 68, no more than 67, no more than 66, no more than 65, no more than 64, no more than 63, no more than 62, no more than 61, no more than 60, no more than 59, no more than 58, no more than 57, no more than 56, no more than 55, no more than 54, no more than 53, no more than 52, no more than 51, no more than 50, no more than 49, no more than 48, no more than 47, no more than 46, no more than 45, no more than 44, no more than 43, no more than 42, no more than 41, no more than 40, no more than 39, no more than 38, no more than 37, no more than 36, no more than 35, no more than 34, no more than 33, no more than 32, no more than 31, or no more than 30 phosphate units.

[0157] In some embodiments, the average chain length of the polyphosphate polymers perindividual FNP is between about 30 and about 60 phosphate units, between about 31 and about 60 phosphate units, between about 32 and about 60 phosphate units, between about 33 and about 60 phosphate units, between about 34 and about 60 phosphate units, between about 35 and about 60 phosphate units, between about 36 and about 60 phosphate units, between about 37 and about 60 phosphate units, between about 38 and about 60 phosphate units, between about 39 and about 60 phosphate units, between about 40 and about 60 phosphate units, between about 41 and about 60 phosphate units, between about 42 and about 60 phosphate units, between about 43 and about 60 phosphate units, between about 44 and about 60 phosphate units, between about 45 and about 60 41 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) phosphate units, between about 46 and about 60 phosphate units, between about 47 and about 60 phosphate units, between about 48 and about 60 phosphate units, between about 49 and about 60 phosphate units, between about 50 and about 60 phosphate units, between about 51 and about 60 phosphate units, between about 52 and about 60 phosphate units, between about 53 and about 60 phosphate units, between about 54 and about 60 phosphate units, or between about 55 and about 60 phosphate units.

[0158] In some embodiments, the average chain length of the polyphosphate polymers perindividual FNP is between 30 and 60 phosphate units, between 31 and 60 phosphate units, between 32 and 60 phosphate units, between 33 and 60 phosphate units, between 34 and 60 phosphate units, between 35 and 60 phosphate units, between 36 and 60 phosphate units, between 37 and 60 phosphate units, between 38 and 60 phosphate units, between 39 and 60 phosphate units, between 40 and 60 phosphate units, between 41 and 60 phosphate units, between 42 and 60 phosphate units, between 43 and 60 phosphate units, between 44 and 60 phosphate units, between 45 and 60 phosphate units, between 46 and 60 phosphate units, between 47 and 60 phosphate units, between 48 and 60 phosphate units, between 49 and 60 phosphate units, between 50 and 60 phosphate units, between 51 and 60 phosphate units, between 52 and 60 phosphate units, between 53 and 60 phosphate units, between 54 and 60 phosphate units, or between 55 and 60 phosphate units.

[0159] In some embodiments, the average chain length of the polyphosphate polymers perindividual FNP is between about 30 and about 59 phosphate units, between about 31 and about 59 phosphate units, between about 32 and about 59 phosphate units, between about 33 and about 59 phosphate units, between about 34 and about 59 phosphate units, between about 35 and about 59 phosphate units, between about 36 and about 59 phosphate units, between about 37 and about 59 phosphate units, between about 38 and about 59 phosphate units, between about 39 and about 59 phosphate units, between about 40 and about 59 phosphate units, between about 41 and about 59 phosphate units, between about 42 and about 59 phosphate units, between about 43 and about 59 phosphate units, between about 44 and about 59 phosphate units, between about 45 and about 59 phosphate units, between about 46 and about 59 phosphate units, between about 47 and about 59 phosphate units, between about 48 and about 59 phosphate units, between about 49 and about 59 phosphate units, between about 50 and about 59 phosphate units, between about 51 and about 59 phosphate units, between about 52 and about 59 phosphate units, between about 53 and about 59 phosphate units, between about 54 and about 59 phosphate units, or between about 55 and about 59 phosphate units. 42 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0160] In some embodiments, the average chain length of the polyphosphate polymers perindividual FNP is between 30 and 59 phosphate units, between 31 and 59 phosphate units, between 32 and 59 phosphate units, between 33 and 59 phosphate units, between 34 and 59 phosphate units, between 35 and 59 phosphate units, between 36 and 59 phosphate units, between 37 and 59 phosphate units, between 38 and 59 phosphate units, between 39 and 59 phosphate units, between 40 and 59 phosphate units, between 41 and 59 phosphate units, between 42 and 59 phosphate units, between 43 and 59 phosphate units, between 44 and 59 phosphate units, between 45 and 59 phosphate units, between 46 and 59 phosphate units, between 47 and 59 phosphate units, between 48 and 59 phosphate units, between 49 and 59 phosphate units, between 50 and 59 phosphate units, between 51 and 59 phosphate units, between 52 and 59 phosphate units, between 53 and 59 phosphate units, between 54 and 59 phosphate units, or between 55 and 59 phosphate units.

[0161] In some embodiments, the average chain length of the polyphosphate polymers perindividual FNP is between about 30 and about 58 phosphate units, between about 31 and about 58 phosphate units, between about 32 and about 58 phosphate units, between about 33 and about 58 phosphate units, between about 34 and about 58 phosphate units, between about 35 and about 58 phosphate units, between about 36 and about 58 phosphate units, between about 37 and about 58 phosphate units, between about 38 and about 58 phosphate units, between about 39 and about 58 phosphate units, between about 40 and about 58 phosphate units, between about 41 and about 58 phosphate units, between about 42 and about 58 phosphate units, between about 43 and about 58 phosphate units, between about 44 and about 58 phosphate units, between about 45 and about 58 phosphate units, between about 46 and about 58 phosphate units, between about 47 and about 58 phosphate units, between about 48 and about 58 phosphate units, between about 49 and about 58 phosphate units, between about 50 and about 58 phosphate units, between about 51 and about 58 phosphate units, between about 52 and about 58 phosphate units, between about 53 and about 58 phosphate units, between about 54 and about 58 phosphate units, or between about 55 and about 58 phosphate units.

[0162] In some embodiments, the average chain length of the polyphosphate polymers perindividual FNP is between 30 and 58 phosphate units, between 31 and 58 phosphate units, between 32 and 58 phosphate units, between 33 and 58 phosphate units, between 34 and 58 phosphate units, between 35 and 58 phosphate units, between 36 and 58 phosphate units, between 37 and 58 phosphate units, between 38 and 58 phosphate units, between 39 and 58 phosphate units, between 40 and 58 phosphate units, between 41 and 58 phosphate units, between 42 and 58 phosphate units, 43 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) between 43 and 58 phosphate units, between 44 and 58 phosphate units, between 45 and 58 phosphate units, between 46 and 58 phosphate units, between 47 and 58 phosphate units, between 48 and 58 phosphate units, between 49 and 58 phosphate units, between 50 and 58 phosphate units, between 51 and 58 phosphate units, between 52 and 58 phosphate units, between 53 and 58 phosphate units, between 54 and 58 phosphate units, or between 55 and 58 phosphate units.

[0163] In some embodiments, the shortest 10% of the polyphosphate polymers perindividual FNP are no longer than about 40, no longer than about 39, no longer than about 38, no longer than about 37, no longer than about 36, no longer than about 35, no longer than about 34, no longer than about 33, no longer than about 32, no longer than about 31, no longer than about 30, no longer than about 29, no longer than about 28, no longer than about 27, no longer than about 26, no longer than about 25, no longer than about 24, no longer than about 23, no longer than about 22, no longer than about 21, no longer than about 20, no longer than about 19, no longer than about 18, no longer than about 17, no longer than about 16, no longer than about 15, no longer than about 14, no longer than about 13, no longer than about 12, no longer than about 11, or no longer than about 10 phosphate units.

[0164] In some embodiments, the shortest 10% of the polyphosphate polymers perindividual FNP are no longer than 40, no longer than 39, no longer than 38, no longer than 37, no longer than 36, no longer than 35, no longer than 34, no longer than 33, no longer than 32, no longer than 31, no longer than 30, no longer than 29, no longer than 28, no longer than 27, no longer than 26, no longer than 25, no longer than 24, no longer than 23, no longer than 22, no longer than 21, no longer than 20, no longer than 19, no longer than 18, no longer than 17, no longer than 16, no longer than 15, no longer than 14, no longer than 13, no longer than 12, no longer than 11, or no longer than 10 phosphate units.

[0165] In some embodiments, the shortest 10% of the polyphosphate polymers perindividual FNP are no longer than a length between about 10 and about 40, between about 10 and about 35, between about 10 and about 30, between about 15 and about 40, between about 15 and about 35, between about 15 and about 30, between about 20 and about 40, between about 20 and about 35, between about 20 and about 30, between about 25 and about 40, between about 25 and about 35, or between about 25 and about 30 phosphate units.

[0166] In some embodiments, the shortest 10% of the polyphosphate polymers perindividual FNP are no longer than a length between 10 and 40, between 10 and 35, between 10 and 30, between 15 and 40, between 15 and 35, between 15 and 30, between 20 and 40, between 44 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 20 and 35, between 20 and 30, between 25 and 40, between 25 and 35, or between 25 and 30 phosphate units.

[0167] In some embodiments, the shortest 10% of the polyphosphate polymers perindividual FNP are between 10 and 40, between 10 and 35, between 10 and 30, between 15 and 40, between 15 and 35, between 15 and 30, between 20 and 40, between 20 and 35, between 20 and 30, between 25 and 40, between 25 and 35, or between 25 and 30 phosphate units.

[0168] In some embodiments, the longest 90% of the polyphosphate polymers perindividual FNP are no shorter than about 40, no shorter than about 39, no shorter than about 38, no shorter than about 37, no shorter than about 36, no shorter than about 35, no shorter than about 34, no shorter than about 33, no shorter than about 32, no shorter than about 31, no shorter than about 30, no shorter than about 29, no shorter than about 28, no shorter than about 27, no shorter than about 26, no shorter than about 25, no shorter than about 24, no shorter than about 23, no shorter than about 22, no shorter than about 21, no shorter than about 20, no shorter than about 19, no shorter than about 18, no shorter than about 17, no shorter than about 16, no shorter than about 15, no shorter than about 14, no shorter than about 13, no shorter than about 12, no shorter than about 11, or no shorter than about 10 phosphate units.

[0169] In some embodiments, the longest 90% of the polyphosphate polymers perindividual FNP are no shorter than 40, no shorter than 39, no shorter than 38, no shorter than 37, no shorter than 36, no shorter than 35, no shorter than 34, no shorter than 33, no shorter than 32, no shorter than 31, no shorter than 30, no shorter than 29, no shorter than 28, no shorter than 27, no shorter than 26, no shorter than 25, no shorter than 24, no shorter than 23, no shorter than 22, no shorter than 21, no shorter than 20, no shorter than 19, no shorter than 18, no shorter than 17, no shorter than 16, no shorter than 15, no shorter than 14, no shorter than 13, no shorter than 12, no shorter than 11, or no shorter than 10 phosphate units.

[0170] In some embodiments, the longest 90% of the polyphosphate polymers perindividual FNP are no shorter than a length between about 10 and about 40, between about 10 and about 35, between about 10 and about 30, between about 15 and about 40, between about 15 and about 35, between about 15 and about 30, between about 20 and about 40, between about 20 and about 35, between about 20 and about 30, between about 25 and about 40, between about 25 and about 35, or between about 25 and about 30 phosphate units.

[0171] In some embodiments, the longest 90% of the polyphosphate polymers perindividual FNP are no shorter than a length between 10 and 40, between 10 and 35, between 10 45 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) and 30, between 15 and 40, between 15 and 35, between 15 and 30, between 20 and 40, between 20 and 35, between 20 and 30, between 25 and 40, between 25 and 35, or between 25 and 30 phosphate units.

[0172] In some embodiments, the shortest 90% of the polyphosphate polymers perindividual FNP are no longer than about 70, no longer than about 75, no longer than about 80, no longer than about 85, no longer than about 90, no longer than about 95, no longer than about 100, no longer than about 105, no longer than about 110, no longer than about 115, no longer than about 120, no longer than about 125, no longer than about 130, no longer than about 135, or no longer than about 140 phosphate units. In some embodiments, the shortest 90% of the polyphosphate polymers in the population of polyphosphate polymers are no longer than 70, no longer than 75, no longer than 80, no longer than 85, no longer than 90, no longer than 95, no longer than 100, no longer than 105, no longer than 110, no longer than 115, no longer than 120, no longer than 125, no longer than 130, no longer than 135, or no longer than 140 phosphate units.

[0173] In some embodiments, the shortest 90% of the polyphosphate polymers perindividual FNP are no longer than a length between about 70 and about 140, between about 75 and about 140, between about 80 and about 140, between about 70 and about 135, between about 75 and about 135, between about 80 and about 135, between about 70 and about 130, between about 75 and about 130, or between about 80 and about 130 phosphate units.

[0174] In some embodiments, the shortest 90% of the polyphosphate per individual FNPare no longer than a length between 70 and 140, between 75 and 140, between 80 and 140, between 70 and 135, between 75 and 135, between 80 and 135, between 70 and 130, between 75 and 130, or between 80 and 130 phosphate units.

[0175] In some embodiments, 10% of the total mass of the polyphosphate polymers perindividual FNP are polyphosphate polymers with a chain length no longer than about 40, no longer than about 39, no longer than about 38, no longer than about 37, no longer than about 36, no longer than about 35, no longer than about 34, no longer than about 33, no longer than about 32, no longer than about 31, no longer than about 30, no longer than about 29, no longer than about 28, no longer than about 27, no longer than about 26, no longer than about 25, no longer than about 24, no longer than about 23, no longer than about 22, no longer than about 21, no longer than about 20, no longer than about 19, no longer than about 18, no longer than about 17, no longer than about 16, no longer than about 15, no longer than about 14, no longer than about 13, no longer than about 12, no longer than about 11, or no longer than about 10 phosphate units. 46 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0176] In some embodiments, 10% of the total mass of the polyphosphate polymers perindividual FNP are polyphosphate polymers with a chain length no longer than 40, no longer than 39, no longer than 38, no longer than 37, no longer than 36, no longer than 35, no longer than 34, no longer than 33, no longer than 32, no longer than 31, no longer than 30, no longer than 29, no longer than 28, no longer than 27, no longer than 26, no longer than 25, no longer than 24, no longer than 23, no longer than 22, no longer than 21, no longer than 20, no longer than 19, no longer than 18, no longer than 17, no longer than 16, no longer than 15, no longer than 14, no longer than 13, no longer than 12, no longer than 11, or no longer than 10 phosphate units.

[0177] In some embodiments, 10% of the total mass of the polyphosphate polymers perindividual FNP are polyphosphate polymers no longer than a chain length between about 10 and about 40, between about 10 and about 35, between about 10 and about 30, between about 15 and about 40, between about 15 and about 35, between about 15 and about 30, between about 20 and about 40, between about 20 and about 35, between about 20 and about 30, between about 25 and about 40, between about 25 and about 35, or between about 25 and about 30 phosphate units.

[0178] In some embodiments, 10% of the total mass of the polyphosphate polymers perindividual FNP are polyphosphate polymers no longer than a chain length between 10 and 40, between 10 and 35, between 10 and 30, between 15 and 40, between 15 and 35, between 15 and 30, between 20 and 40, between 20 and 35, between 20 and 30, between 25 and 40, between 25 and 35, or between 25 and 30 phosphate units.

[0179] In some embodiments, 90% of the total mass of the polyphosphate polymers perindividual FNP are polyphosphate polymers with a chain length no longer than about 70, no longer than about 75, no longer than about 80, no longer than about 85, no longer than about 90, no longer than about 95, no longer than about 100, no longer than about 105, no longer than about 110, no longer than about 115, no longer than about 120, no longer than about 125, no longer than about 130, no longer than about 135, or no longer than about 140 phosphate units. In some embodiments, 90% of the total mass of the polyphosphate polymers per individual FNP are polyphosphate polymers with a chain length no longer than 70, no longer than 75, no longer than 80, no longer than 85, no longer than 90, no longer than 95, no longer than 100, no longer than 105, no longer than 110, no longer than 115, no longer than 120, no longer than 125, no longer than 130, no longer than 135, or no longer than 140 phosphate units.

[0180] In some embodiments, 90% of the total mass of the polyphosphate polymers perindividual FNP are polyphosphate polymers no longer than a chain length between about 70 and 47 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) about 140, between about 75 and about 140, between about 80 and about 140, between about 70 and about 135, between about 75 and about 135, between about 80 and about 135, between about 70 and about 130, between about 75 and about 130, or between about 80 and about 130 phosphate units.

[0181] In some embodiments, 90% of the total mass of the polyphosphate polymers perindividual FNP are polyphosphate polymers no longer than a chain length between 70 and 140, between 75 and 140, between 80 and 140, between 70 and 135, between 75 and 135, between 80 and 135, between 70 and 130, between 75 and 130, or between 80 and 130 phosphate units.

[0182] In some embodiments, the chain length of the polyphosphate polymer is measuredby GPC (gel filtration HPLC-RI), titration, or31P-NMR.

[0183] In some embodiments, the total mass of polyphosphate polymers is no more thanabout 24%, about 23%, about 22%, about 21%, about 20%, about 19%, about 18%, about 17%, or about 16% of the total mass of an FNP. In some embodiments, the total mass of polyphosphate polymers constitutes no more than 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, or 15% of the total mass of an FNP.

[0184] In some embodiments, the total mass of polyphosphate polymers is between about15% and about 24%, between about 15% and about 23%, between about 15% and about 22%, between about 15% and about 21%, between about 15% and about 20%, about 16% and about 24%, between about 16% and about 23%, between about 16% and about 22%, between about 16% and about 21%, between about 16% and about 20%, between about 17% and about 24%, between about 17% and about 23%, between about 17% and about 22%, between about 17% and about 21%, between about 17% and about 20%, between about 18% and about 24%, between about 18% and about 23%, between about 18% and about 22%, between about 18% and about 21%, or between about 18% and about 20% of the total mass of an FNP.

[0185] In some embodiments, the total mass of polyphosphate polymers is between 15%and 24%, between 15% and 23%, between 15% and 22%, between 15% and 21%, between 15% and 20%, 16% and 24%, between 16% and 23%, between 16% and 22%, between 16% and 21%, between 16% and 20%, between 17% and 24%, between 17% and 23%, between 17% and 22%, between 17% and 21%, between 17% and 20%, between 18% and 24%, between 18% and 23%, between 18% and 22%, between 18% and 21%, or between 18% and 20% of the total mass of an FNP. 48 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0186] In some embodiments, the total mass of polyphosphate polymers is about 24%,about 23%, about 22%, about 21%, about 20%, about 19%, about 18%, about 17%, or about 16% of the total mass of an FNP. In some embodiments, the total mass of polyphosphate polymers is 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, or 16% of the total mass of an FNP.

[0187] In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP isabout 200 nm or less. In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP is about 190 nm or less, about 180 nm or less, about 170 nm or less, about 160 nm or less, about 150 nm or less, about 140 nm or less, about 130 nm or less, about 120 nm or less, about 110 nm or less, about 100 nm or less, about 95 nm or less, about 90 nm or less, about 85 nm or less, about 80 nm or less, about 75 nm or less, about 70 nm or less, about 65 nm or less, about 60 nm or less, about 55 nm or less, about 50 nm or less, about 45 nm or less, about 40 nm or less, about 35 nm or less, about 30 nm or less, or about 25 nm or less.

[0188] In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP is200 nm or less. In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP is 190 nm or less, 180 nm or less, 170 nm or less, 160 nm or less, 150 nm or less, 140 nm or less, 130 nm or less, 120 nm or less, 110 nm or less, 100 nm or less, 95 nm or less, 90 nm or less, 85 nm or less, 80 nm or less, 75 nm or less, 70 nm or less, 65 nm or less, 60 nm or less, 55 nm or less, 50 nm or less, 45 nm or less, 40 nm or less, 35 nm or less, 30 nm or less, or 25 nm or less.

[0189] In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP isabout 200 nm, about 190 nm, about 180 nm, about 170 nm, about 160 nm, about 150 nm, about 140 nm, about 130 nm, about 120 nm, about 110 nm, about 100 nm, about 99 nm, about 98 nm, about 97 nm, about 96 nm, about 95 nm, about 94 nm, about 93 nm, about 92 nm, about 91 nm, about 90 nm, about 89 nm, about 88 nm, about 87 nm, about 86 nm, about 85 nm, about 84 nm, about 83 nm, about 82 nm, about 81 nm, about 80 nm, about 79 nm, about 78 nm, about 77 nm, about 76 nm, about 75 nm, about 74 nm, about 73 nm, about 72 nm, about 71 nm, about 70 nm, about 69 nm, about 68 nm, about 67 nm, about 66 nm, about 65 nm, about 64 nm, about 63 nm, about 62 nm, about 61 nm, about 60 nm, about 59 nm, about 58 nm, about 57 nm, about 56 nm, about 55 nm, about 54 nm, about 53 nm, about 52 nm, about 51 nm, about 50 nm, about 49 nm, about 48 nm, about 47 nm, about 46 nm, about 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, or about 25 nm. 49 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0190] In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP is200 nm, 190 nm, 180 nm, 170 nm, 160 nm, 150 nm, 140 nm, 130 nm, 120 nm, 110 nm, 100 nm, 99 nm, 98 nm, 97 nm, 96 nm, 95 nm, 94 nm, 93 nm, 92 nm, 91 nm, 90 nm, 89 nm, 88 nm, 87 nm, 86 nm, 85 nm, 84 nm, 83 nm, 82 nm, 81 nm, 80 nm, 79 nm, 78 nm, 77 nm, 76 nm, 75 nm, 74 nm, 73 nm, 72 nm, 71 nm, 70 nm, 69 nm, 68 nm, 67 nm, 66 nm, 65 nm, 64 nm, 63 nm, 62 nm, 61 nm, 60 nm, 59 nm, 58 nm, 57 nm, 56 nm, 55 nm, 54 nm, 53 nm, 52 nm, 51 nm, 50 nm, 49 nm, 48 nm, 47 nm, 46 nm, 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, or 25 nm.

[0191] In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP isbetween about 30 nm and about 200 nm, between about 30 nm and about 190 nm, between about 30 nm and about 180 nm, between about 30 nm and about 170 nm, between about 30 nm and about 160 nm, between about 30 nm and about 150 nm, between about 30 nm and about 140 nm, between about 30 nm and about 130 nm, between about 30 nm and about 120 nm, between about 30 nm and about 110 nm, between about 30 nm and about 100 nm, between about 30 nm and about 95 nm, between about 30 nm and about 90 nm, between about 30 nm and about 85 nm, between about 30 nm and about 80 nm, between about 30 nm and about 75 nm, between about 30 nm and about 70 nm, or between about 30 nm and about 65 nm.

[0192] In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP isbetween about 40 nm and about 200 nm, between about 40 nm and about 190 nm, between about 40 nm and about 180 nm, between about 40 nm and about 170 nm, between about 40 nm and about 160 nm, between about 40 nm and about 150 nm, between about 40 nm and about 140 nm, between about 40 nm and about 130 nm, between about 40 nm and about 120 nm, between about 40 nm and about 110 nm, between about 40 nm and about 100 nm, between about 40 nm and about 95 nm, between about 40 nm and about 90 nm, between about 40 nm and about 85 nm, between about 40 nm and about 80 nm, between about 40 nm and about 75 nm, between about 40 nm and about 70 nm, or between about 40 nm and about 65 nm.

[0193] In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP isbetween about 50 nm and about 200 nm, between about 50 nm and about 190 nm, between about 50 nm and about 180 nm, between about 50 nm and about 170 nm, between about 50 nm and about 160 nm, between about 50 nm and about 150 nm, between about 50 nm and about 140 nm, between about 50 nm and about 130 nm, between about 50 nm and about 120 nm, between about 50 nm and about 110 nm, between about 50 nm and about 100 nm, between about 50 nm and about 95 50 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) nm, between about 50 nm and about 90 nm, between about 50 nm and about 85 nm, between about 50 nm and about 80 nm, between about 50 nm and about 75 nm, between about 50 nm and about 70 nm, or between about 50 nm and about 65 nm.

[0194] In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP isbetween about 55 nm and about 200 nm, between about 55 nm and about 190 nm, between about 55 nm and about 180 nm, between about 55 nm and about 170 nm, between about 55 nm and about 160 nm, between about 55 nm and about 150 nm, between about 55 nm and about 140 nm, between about 55 nm and about 130 nm, between about 55 nm and about 120 nm, between about 55 nm and about 110 nm, between about 55 nm and about 100 nm, between about 55 nm and about 95 nm, between about 55 nm and about 90 nm, between about 55 nm and about 85 nm, between about 55 nm and about 80 nm, between about 55 nm and about 75 nm, between about 55 nm and about 70 nm, or between about 55 nm and about 65 nm.

[0195] In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP isbetween about 60 nm and about 200 nm, between about 60 nm and about 190 nm, between about 60 nm and about 180 nm, between about 60 nm and about 170 nm, between about 60 nm and about 160 nm, between about 60 nm and about 150 nm, between about 60 nm and about 140 nm, between about 60 nm and about 130 nm, between about 60 nm and about 120 nm, between about 60 nm and about 110 nm, between about 60 nm and about 100 nm, between about 60 nm and about 95 nm, between about 60 nm and about 90 nm, between about 60 nm and about 85 nm, between about 60 nm and about 80 nm, between about 60 nm and about 75 nm, between about 60 nm and about 70 nm, or between about 60 nm and about 65 nm.

[0196] In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP isbetween about 65 nm and about 200 nm, between about 65 nm and about 190 nm, between about 65 nm and about 180 nm, between about 65 nm and about 170 nm, between about 65 nm and about 160 nm, between about 65 nm and about 150 nm, between about 65 nm and about 140 nm, between about 65 nm and about 130 nm, between about 65 nm and about 120 nm, between about 65 nm and about 110 nm, between about 65 nm and about 100 nm, between about 65 nm and about 95 nm, between about 65 nm and about 90 nm, between about 65 nm and about 85 nm, between about 65 nm and about 80 nm, between about 65 nm and about 75 nm, or between about 65 nm and about 70 nm.

[0197] In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP isbetween 30 nm and 200 nm, between 30 nm and 190 nm, between 30 nm and 180 nm, between 30 51 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) nm and 170 nm, between 30 nm and 160 nm, between 30 nm and 150 nm, between 30 nm and 140 nm, between 30 nm and 130 nm, between 30 nm and 120 nm, between 30 nm and 110 nm, between 30 nm and 100 nm, between 30 nm and 95 nm, between 30 nm and 90 nm, between 30 nm and 85 nm, between 30 nm and 80 nm, between 30 nm and 75 nm, between 30 nm and 70 nm, or between 30 nm and 65 nm.

[0198] In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP isbetween 40 nm and 200 nm, between 40 nm and 190 nm, between 40 nm and 180 nm, between 40 nm and 170 nm, between 40 nm and 160 nm, between 40 nm and 150 nm, between 40 nm and 140 nm, between 40 nm and 130 nm, between 40 nm and 120 nm, between 40 nm and 110 nm, between 40 nm and 100 nm, between 40 nm and 95 nm, between 40 nm and 90 nm, between 40 nm and 85 nm, between 40 nm and 80 nm, between 40 nm and 75 nm, between 40 nm and 70 nm, or between 40 nm and 65 nm.

[0199] In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP isbetween 50 nm and 200 nm, between 50 nm and 190 nm, between 50 nm and 180 nm, between 50 nm and 170 nm, between 50 nm and 160 nm, between 50 nm and 150 nm, between 50 nm and 140 nm, between 50 nm and 130 nm, between 50 nm and 120 nm, between 50 nm and 110 nm, between 50 nm and 100 nm, between 50 nm and 95 nm, between 50 nm and 90 nm, between 50 nm and 85 nm, between 50 nm and 80 nm, between 50 nm and 75 nm, between 50 nm and 70 nm, or between 50 nm and 65 nm.

[0200] In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP isbetween 55 nm and 200 nm, between 55 nm and 190 nm, between 55 nm and 180 nm, between 55 nm and 170 nm, between 55 nm and 160 nm, between 55 nm and 150 nm, between 55 nm and 140 nm, between 55 nm and 130 nm, between 55 nm and 120 nm, between 55 nm and 110 nm, between 55 nm and 100 nm, between 55 nm and 95 nm, between 55 nm and 90 nm, between 55 nm and 85 nm, between 55 nm and 80 nm, between 55 nm and 75 nm, between 55 nm and 70 nm, or between 55 nm and 65 nm.

[0201] In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP isbetween 60 nm and 200 nm, between 60 nm and 190 nm, between 60 nm and 180 nm, between 60 nm and 170 nm, between 60 nm and 160 nm, between 60 nm and 150 nm, between 60 nm and 140 nm, between 60 nm and 130 nm, between 60 nm and 120 nm, between 60 nm and 110 nm, between 60 nm and 100 nm, between 60 nm and 95 nm, between 60 nm and 90 nm, between 60 nm and 85 52 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) nm, between 60 nm and 80 nm, between 60 nm and 75 nm, between 60 nm and 70 nm, or between 60 nm and 65 nm.

[0202] In some embodiments, the size, e.g., hydrodynamic size, or diameter of an FNP isbetween 65 nm and 200 nm, between 65 nm and 190 nm, between 65 nm and 180 nm, between 65 nm and 170 nm, between 65 nm and 160 nm, between 65 nm and 150 nm, between 65 nm and 140 nm, between 65 nm and 130 nm, between 65 nm and 120 nm, between 65 nm and 110 nm, between 65 nm and 100 nm, between 65 nm and 95 nm, between 65 nm and 90 nm, between 65 nm and 85 nm, between 65 nm and 80 nm, between 65 nm and 75 nm, or between 65 nm and 70 nm.

[0203] In an aspect, a population of FNP is provided by the instant disclosure. An FNP inthe population of FNP may be any FNP described above or elsewhere herein. The population of polyphosphate polymers attached to the nanoparticle to produce an FNP may be any population of polyphosphate polymers described above or elsewhere herein. Similarly, the nanoparticle may be any nanoparticle described above or elsewhere herein.

[0204] In some embodiments, the concentration of FNP in a population of FNP asdescribed herein is at least 0.01% w / v. In some embodiments, the distribution of FNP in a population of FNP is a normal distribution. In some embodiments, the median FNP size and the mean FNP size are the same or similar.

[0205] In some embodiments, the average chain length of the polyphosphate polymers inthe population of FNP refers to the average chain length of polyphosphate polymers within the entire population of FNP, not the average chain length of the polyphosphate polymers per individual FNP.

[0206] In some embodiments, the average chain length of the polyphosphate polymers inthe population of FNP is no more than about 70, no more than about 69, no more than about 68, no more than about 67, no more than about 66, no more than about 65, no more than about 64, no more than about 63, no more than about 62, no more than about 61, no more than about 60, no more than about 59, no more than about 58, no more than about 57, no more than about 56, no more than about 55, no more than about 54, no more than about 53, no more than about 52, no more than about 51, no more than about 50, no more than about 49, no more than about 48, no more than about 47, no more than about 46, no more than about 45, no more than about 44, no more than about 43, no more than about 42, no more than about 41, no more than about 40, no more than about 39, no more than about 38, no more than about 37, no more than about 36, no 53 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) more than about 35, no more than about 34, no more than about 33, no more than about 32, no more than about 31, or no more than about 30 phosphate units.

[0207] In some embodiments, the average chain length of the polyphosphate polymers inthe population of FNP is no more than 70, no more than 69, no more than 68, no more than 67, no more than 66, no more than 65, no more than 64, no more than 63, no more than 62, no more than 61, no more than 60, no more than 59, no more than 58, no more than 57, no more than 56, no more than 55, no more than 54, no more than 53, no more than 52, no more than 51, no more than 50, no more than 49, no more than 48, no more than 47, no more than 46, no more than 45, no more than 44, no more than 43, no more than 42, no more than 41, no more than 40, no more than 39, no more than 38, no more than 37, no more than 36, no more than 35, no more than 34, no more than 33, no more than 32, no more than 31, or no more than 30 phosphate units.

[0208] In some embodiments, the average chain length of the polyphosphate polymers inthe population of FNP is between about 30 and about 60 phosphate units, between about 31 and about 60 phosphate units, between about 32 and about 60 phosphate units, between about 33 and about 60 phosphate units, between about 34 and about 60 phosphate units, between about 35 and about 60 phosphate units, between about 36 and about 60 phosphate units, between about 37 and about 60 phosphate units, between about 38 and about 60 phosphate units, between about 39 and about 60 phosphate units, between about 40 and about 60 phosphate units, between about 41 and about 60 phosphate units, between about 42 and about 60 phosphate units, between about 43 and about 60 phosphate units, between about 44 and about 60 phosphate units, between about 45 and about 60 phosphate units, between about 46 and about 60 phosphate units, between about 47 and about 60 phosphate units, between about 48 and about 60 phosphate units, between about 49 and about 60 phosphate units, between about 50 and about 60 phosphate units, between about 51 and about 60 phosphate units, between about 52 and about 60 phosphate units, between about 53 and about 60 phosphate units, between about 54 and about 60 phosphate units, or between about 55 and about 60 phosphate units.

[0209] In some embodiments, the average chain length of the polyphosphate polymers inthe population of FNP is between 30 and 60 phosphate units, between 31 and 60 phosphate units, between 32 and 60 phosphate units, between 33 and 60 phosphate units, between 34 and 60 phosphate units, between 35 and 60 phosphate units, between 36 and 60 phosphate units, between 37 and 60 phosphate units, between 38 and 60 phosphate units, between 39 and 60 phosphate units, between 40 and 60 phosphate units, between 41 and 60 phosphate units, between 42 and 60 54 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) phosphate units, between 43 and 60 phosphate units, between 44 and 60 phosphate units, between 45 and 60 phosphate units, between 46 and 60 phosphate units, between 47 and 60 phosphate units, between 48 and 60 phosphate units, between 49 and 60 phosphate units, between 50 and 60 phosphate units, between 51 and 60 phosphate units, between 52 and 60 phosphate units, between 53 and 60 phosphate units, between 54 and 60 phosphate units, or between 55 and 60 phosphate units.

[0210] In some embodiments, the average chain length of the polyphosphate polymers inthe population of FNP is between about 30 and about 59 phosphate units, between about 31 and about 59 phosphate units, between about 32 and about 59 phosphate units, between about 33 and about 59 phosphate units, between about 34 and about 59 phosphate units, between about 35 and about 59 phosphate units, between about 36 and about 59 phosphate units, between about 37 and about 59 phosphate units, between about 38 and about 59 phosphate units, between about 39 and about 59 phosphate units, between about 40 and about 59 phosphate units, between about 41 and about 59 phosphate units, between about 42 and about 59 phosphate units, between about 43 and about 59 phosphate units, between about 44 and about 59 phosphate units, between about 45 and about 59 phosphate units, between about 46 and about 59 phosphate units, between about 47 and about 59 phosphate units, between about 48 and about 59 phosphate units, between about 49 and about 59 phosphate units, between about 50 and about 59 phosphate units, between about 51 and about 59 phosphate units, between about 52 and about 59 phosphate units, between about 53 and about 59 phosphate units, between about 54 and about 59 phosphate units, or between about 55 and about 59 phosphate units.

[0211] In some embodiments, the average chain length of the polyphosphate polymers inthe population of FNP is between 30 and 59 phosphate units, between 31 and 59 phosphate units, between 32 and 59 phosphate units, between 33 and 59 phosphate units, between 34 and 59 phosphate units, between 35 and 59 phosphate units, between 36 and 59 phosphate units, between 37 and 59 phosphate units, between 38 and 59 phosphate units, between 39 and 59 phosphate units, between 40 and 59 phosphate units, between 41 and 59 phosphate units, between 42 and 59 phosphate units, between 43 and 59 phosphate units, between 44 and 59 phosphate units, between 45 and 59 phosphate units, between 46 and 59 phosphate units, between 47 and 59 phosphate units, between 48 and 59 phosphate units, between 49 and 59 phosphate units, between 50 and 59 phosphate units, between 51 and 59 phosphate units, between 52 and 59 phosphate units, between 55 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 53 and 59 phosphate units, between 54 and 59 phosphate units, or between 55 and 59 phosphate units.

[0212] In some embodiments, the average chain length of the polyphosphate polymers inthe population of FNP is between about 30 and about 58 phosphate units, between about 31 and about 58 phosphate units, between about 32 and about 58 phosphate units, between about 33 and about 58 phosphate units, between about 34 and about 58 phosphate units, between about 35 and about 58 phosphate units, between about 36 and about 58 phosphate units, between about 37 and about 58 phosphate units, between about 38 and about 58 phosphate units, between about 39 and about 58 phosphate units, between about 40 and about 58 phosphate units, between about 41 and about 58 phosphate units, between about 42 and about 58 phosphate units, between about 43 and about 58 phosphate units, between about 44 and about 58 phosphate units, between about 45 and about 58 phosphate units, between about 46 and about 58 phosphate units, between about 47 and about 58 phosphate units, between about 48 and about 58 phosphate units, between about 49 and about 58 phosphate units, between about 50 and about 58 phosphate units, between about 51 and about 58 phosphate units, between about 52 and about 58 phosphate units, between about 53 and about 58 phosphate units, between about 54 and about 58 phosphate units, or between about 55 and about 58 phosphate units.

[0213] In some embodiments, the average chain length of the polyphosphate polymers inthe population of FNP is between 30 and 58 phosphate units, between 31 and 58 phosphate units, between 32 and 58 phosphate units, between 33 and 58 phosphate units, between 34 and 58 phosphate units, between 35 and 58 phosphate units, between 36 and 58 phosphate units, between 37 and 58 phosphate units, between 38 and 58 phosphate units, between 39 and 58 phosphate units, between 40 and 58 phosphate units, between 41 and 58 phosphate units, between 42 and 58 phosphate units, between 43 and 58 phosphate units, between 44 and 58 phosphate units, between 45 and 58 phosphate units, between 46 and 58 phosphate units, between 47 and 58 phosphate units, between 48 and 58 phosphate units, between 49 and 58 phosphate units, between 50 and 58 phosphate units, between 51 and 58 phosphate units, between 52 and 58 phosphate units, between 53 and 58 phosphate units, between 54 and 58 phosphate units, or between 55 and 58 phosphate units.

[0214] In some embodiments, the shortest 10% of the polyphosphate polymers in thepopulation of FNP are no longer than about 40, no longer than about 39, no longer than about 38, no longer than about 37, no longer than about 36, no longer than about 35, no longer than about 56 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 34, no longer than about 33, no longer than about 32, no longer than about 31, no longer than about 30, no longer than about 29, no longer than about 28, no longer than about 27, no longer than about 26, no longer than about 25, no longer than about 24, no longer than about 23, no longer than about 22, no longer than about 21, no longer than about 20, no longer than about 19, no longer than about 18, no longer than about 17, no longer than about 16, no longer than about 15, no longer than about 14, no longer than about 13, no longer than about 12, no longer than about 11, or no longer than about 10 phosphate units.

[0215] In some embodiments, the shortest 10% of the polyphosphate polymers in thepopulation of FNP are no longer than 40, no longer than 39, no longer than 38, no longer than 37, no longer than 36, no longer than 35, no longer than 34, no longer than 33, no longer than 32, no longer than 31, no longer than 30, no longer than 29, no longer than 28, no longer than 27, no longer than 26, no longer than 25, no longer than 24, no longer than 23, no longer than 22, no longer than 21, no longer than 20, no longer than 19, no longer than 18, no longer than 17, no longer than 16, no longer than 15, no longer than 14, no longer than 13, no longer than 12, no longer than 11, or no longer than 10 phosphate units.

[0216] In some embodiments, the shortest 10% of the polyphosphate polymers in thepopulation of FNP are no longer than a length between about 10 and about 40, between about 10 and about 35, between about 10 and about 30, between about 15 and about 40, between about 15 and about 35, between about 15 and about 30, between about 20 and about 40, between about 20 and about 35, between about 20 and about 30, between about 25 and about 40, between about 25 and about 35, or between about 25 and about 30 phosphate units.

[0217] In some embodiments, the shortest 10% of the polyphosphate polymers in thepopulation of FNP are no longer than a length between 10 and 40, between 10 and 35, between 10 and 30, between 15 and 40, between 15 and 35, between 15 and 30, between 20 and 40, between 20 and 35, between 20 and 30, between 25 and 40, between 25 and 35, or between 25 and 30 phosphate units.

[0218] In some embodiments, the longest 90% of the polyphosphate polymers in thepopulation of FNP are no shorter than about 40, no shorter than about 39, no shorter than about 38, no shorter than about 37, no shorter than about 36, no shorter than about 35, no shorter than about 34, no shorter than about 33, no shorter than about 32, no shorter than about 31, no shorter than about 30, no shorter than about 29, no shorter than about 28, no shorter than about 27, no shorter than about 26, no shorter than about 25, no shorter than about 24, no shorter than about 23, 57 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) no shorter than about 22, no shorter than about 21, no shorter than about 20, no shorter than about 19, no shorter than about 18, no shorter than about 17, no shorter than about 16, no shorter than about 15, no shorter than about 14, no shorter than about 13, no shorter than about 12, no shorter than about 11, or no shorter than about 10 phosphate units.

[0219] In some embodiments, the longest 90% of the polyphosphate polymers in thepopulation of FNP are no shorter than 40, no shorter than 39, no shorter than 38, no shorter than 37, no shorter than 36, no shorter than 35, no shorter than 34, no shorter than 33, no shorter than 32, no shorter than 31, no shorter than 30, no shorter than 29, no shorter than 28, no shorter than 27, no shorter than 26, no shorter than 25, no shorter than 24, no shorter than 23, no shorter than 22, no shorter than 21, no shorter than 20, no shorter than 19, no shorter than 18, no shorter than 17, no shorter than 16, no shorter than 15, no shorter than 14, no shorter than 13, no shorter than 12, no shorter than 11, or no shorter than 10 phosphate units.

[0220] In some embodiments, the longest 90% of the polyphosphate polymers in thepopulation of FNP are no shorter than a length between about 10 and about 40, between about 10 and about 35, between about 10 and about 30, between about 15 and about 40, between about 15 and about 35, between about 15 and about 30, between about 20 and about 40, between about 20 and about 35, between about 20 and about 30, between about 25 and about 40, between about 25 and about 35, or between about 25 and about 30 phosphate units.

[0221] In some embodiments, the longest 90% of the polyphosphate polymers in thepopulation of FNP are no shorter than a length between 10 and 40, between 10 and 35, between 10 and 30, between 15 and 40, between 15 and 35, between 15 and 30, between 20 and 40, between 20 and 35, between 20 and 30, between 25 and 40, between 25 and 35, or between 25 and 30 phosphate units.

[0222] In some embodiments, the shortest 90% of the polyphosphate polymers in thepopulation of FNP are no longer than about 70, no longer than about 75, no longer than about 80, no longer than about 85, no longer than about 90, no longer than about 95, no longer than about 100, no longer than about 105, no longer than about 110, no longer than about 115, no longer than about 120, no longer than about 125, no longer than about 130, no longer than about 135, or no longer than about 140 phosphate units. In some embodiments, the shortest 90% of the polyphosphate polymers in the population of polyphosphate polymers are no longer than 70, no longer than 75, no longer than 80, no longer than 85, no longer than 90, no longer than 95, no 58 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) longer than 100, no longer than 105, no longer than 110, no longer than 115, no longer than 120, no longer than 125, no longer than 130, no longer than 135, or no longer than 140 phosphate units.

[0223] In some embodiments, the shortest 90% of the polyphosphate polymers in thepopulation of FNP are no longer than a length between about 70 and about 140, between about 75 and about 140, between about 80 and about 140, between about 70 and about 135, between about 75 and about 135, between about 80 and about 135, between about 70 and about 130, between about 75 and about 130, or between about 80 and about 130 phosphate units.

[0224] In some embodiments, the shortest 90% of the polyphosphate polymers in thepopulation of FNP are no longer than a length between 70 and 140, between 75 and 140, between 80 and 140, between 70 and 135, between 75 and 135, between 80 and 135, between 70 and 130, between 75 and 130, or between 80 and 130 phosphate units.

[0225] In some embodiments, 10% of the total mass of the polyphosphate polymers in thepopulation of FNP are polyphosphate polymers with a chain length no longer than about 40, no longer than about 39, no longer than about 38, no longer than about 37, no longer than about 36, no longer than about 35, no longer than about 34, no longer than about 33, no longer than about 32, no longer than about 31, no longer than about 30, no longer than about 29, no longer than about 28, no longer than about 27, no longer than about 26, no longer than about 25, no longer than about 24, no longer than about 23, no longer than about 22, no longer than about 21, no longer than about 20, no longer than about 19, no longer than about 18, no longer than about 17, no longer than about 16, no longer than about 15, no longer than about 14, no longer than about 13, no longer than about 12, no longer than about 11, or no longer than about 10 phosphate units.

[0226] In some embodiments, 10% of the total mass of the polyphosphate polymers in thepopulation of FNP are polyphosphate polymers with a chain length no longer than 40, no longer than 39, no longer than 38, no longer than 37, no longer than 36, no longer than 35, no longer than 34, no longer than 33, no longer than 32, no longer than 31, no longer than 30, no longer than 29, no longer than 28, no longer than 27, no longer than 26, no longer than 25, no longer than 24, no longer than 23, no longer than 22, no longer than 21, no longer than 20, no longer than 19, no longer than 18, no longer than 17, no longer than 16, no longer than 15, no longer than 14, no longer than 13, no longer than 12, no longer than 11, or no longer than 10 phosphate units.

[0227] In some embodiments, 10% of the total mass of the polyphosphate polymers in thepopulation of FNP are polyphosphate polymers no longer than a chain length between about 10 and about 40, between about 10 and about 35, between about 10 and about 30, between about 15 59 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) and about 40, between about 15 and about 35, between about 15 and about 30, between about 20 and about 40, between about 20 and about 35, between about 20 and about 30, between about 25 and about 40, between about 25 and about 35, or between about 25 and about 30 phosphate units.

[0228] In some embodiments, 10% of the total mass of the polyphosphate polymers in thepopulation of FNP are polyphosphate polymers no longer than a chain length between 10 and 40, between 10 and 35, between 10 and 30, between 15 and 40, between 15 and 35, between 15 and 30, between 20 and 40, between 20 and 35, between 20 and 30, between 25 and 40, between 25 and 35, or between 25 and 30 phosphate units.

[0229] In some embodiments, 90% of the total mass of the polyphosphate polymers in thepopulation of FNP are polyphosphate polymers with a chain length no longer than about 70, no longer than about 75, no longer than about 80, no longer than about 85, no longer than about 90, no longer than about 95, no longer than about 100, no longer than about 105, no longer than about 110, no longer than about 115, no longer than about 120, no longer than about 125, no longer than about 130, no longer than about 135, or no longer than about 140 phosphate units. In some embodiments, 90% of the total mass of the polyphosphate polymers in the population of FNP are polyphosphate polymers with a chain length no longer than 70, no longer than 75, no longer than 80, no longer than 85, no longer than 90, no longer than 95, no longer than 100, no longer than 105, no longer than 110, no longer than 115, no longer than 120, no longer than 125, no longer than 130, no longer than 135, or no longer than 140 phosphate units.

[0230] In some embodiments, 90% of the total mass of the polyphosphate polymers in thepopulation of FNP are polyphosphate polymers no longer than a chain length between about 70 and about 140, between about 75 and about 140, between about 80 and about 140, between about 70 and about 135, between about 75 and about 135, between about 80 and about 135, between about 70 and about 130, between about 75 and about 130, or between about 80 and about 130 phosphate units.

[0231] In some embodiments, 90% of the total mass of the polyphosphate polymers in thepopulation of FNP are polyphosphate polymers no longer than a chain length between 70 and 140, between 75 and 140, between 80 and 140, between 70 and 135, between 75 and 135, between 80 and 135, between 70 and 130, between 75 and 130, or between 80 and 130 phosphate units.

[0232] In some embodiments, the total mass of polyphosphate polymers is no more thanabout 24%, about 23%, about 22%, about 21%, about 20%, about 19%, about 18%, about 17%, or about 16% of the total mass of the population of FNP. In some embodiments, the total mass of 60 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) polyphosphate polymers is no more than 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, or 16% of the total mass of the population of FNP.

[0233] In some embodiments, the total mass of polyphosphate polymers is between about16% and about 24%, between about 16% and about 23%, between about 16% and about 22%, between about 16% and about 21%, between about 16% and about 20%, between about 17% and about 24%, between about 17% and about 23%, between about 17% and about 22%, between about 17% and about 21%, between about 17% and about 20%, between about 18% and about 24%, between about 18% and about 23%, between about 18% and about 22%, between about 18% and about 21%, or between about 18% and about 20% of the total mass of the population of FNP.

[0234] In some embodiments, the total mass of polyphosphate polymers is between 16%and 24%, between 16% and 23%, between 16% and 22%, between 16% and 21%, between 16% and 20%, between 17% and 24%, between 17% and 23%, between 17% and 22%, between 17% and 21%, between 17% and 20%, between 18% and 24%, between 18% and 23%, between 18% and 22%, between 18% and 21%, or between 18% and 20% of the total mass of the population of FNP.

[0235] In some embodiments, the total mass of polyphosphate polymers is about 24%,about 23%, about 22%, about 21%, about 20%, about 19%, about 18%, about 17%, or about 16% of the total mass of the population of FNP. In some embodiments, the total mass of polyphosphate polymers is 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, or 16% of the total mass of the population of FNP.

[0236] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP is about 200 nm or less. In some embodiments, the Z-average size of the nanoparticles in the population of FNP is about 190 nm or less, about 180 nm or less, about 170 nm or less, about 160 nm or less, about 150 nm or less, about 140 nm or less, about 130 nm or less, about 120 nm or less, about 110 nm or less, about 100 nm or less, about 95 nm or less, about 90 nm or less, about 85 nm or less, about 80 nm or less, about 75 nm or less, about 70 nm or less, about 65 nm or less, about 60 nm or less, about 55 nm or less, about 50 nm or less, about 45 nm or less, about 40 nm or less, about 35 nm or less, about 30 nm or less, or about 25 nm or less.

[0237] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP is 200 nm or less. In some embodiments, the Z-average size of the nanoparticles in the population of FNP is 190 nm or less, 180 nm or less, 170 nm or less, 160 nm or less, 150 nm or less, 140 nm or less, 130 nm or less, 120 nm or less, 110 nm or less, 100 nm or less, 95 nm or less, 61 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 90 nm or less, 85 nm or less, 80 nm or less, 75 nm or less, 70 nm or less, 65 nm or less, 60 nm or less, 55 nm or less, 50 nm or less, 45 nm or less, 40 nm or less, 35 nm or less, 30 nm or less, or 25 nm or less.

[0238] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP is about 200 nm, about 190 nm, about 180 nm, about 170 nm, about 160 nm, about 150 nm, about 140 nm, about 130 nm, about 120 nm, about 110 nm, about 100 nm, about 99 nm, about 98 nm, about 97 nm, about 96 nm, about 95 nm, about 94 nm, about 93 nm, about 92 nm, about 91 nm, about 90 nm, about 89 nm, about 88 nm, about 87 nm, about 86 nm, about 85 nm, about 84 nm, about 83 nm, about 82 nm, about 81 nm, about 80 nm, about 79 nm, about 78 nm, about 77 nm, about 76 nm, about 75 nm, about 74 nm, about 73 nm, about 72 nm, about 71 nm, about 70 nm, about 69 nm, about 68 nm, about 67 nm, about 66 nm, about 65 nm, about 64 nm, about 63 nm, about 62 nm, about 61 nm, about 60 nm, about 59 nm, about 58 nm, about 57 nm, about 56 nm, about 55 nm, about 54 nm, about 53 nm, about 52 nm, about 51 nm, about 50 nm, about 49 nm, about 48 nm, about 47 nm, about 46 nm, about 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, or about 25 nm.

[0239] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP is 200 nm, 190 nm, 180 nm, 170 nm, 160 nm, 150 nm, 140 nm, 130 nm, 120 nm, 110 nm, 100 nm, 99 nm, 98 nm, 97 nm, 96 nm, 95 nm, 94 nm, 93 nm, 92 nm, 91 nm, 90 nm, 89 nm, 88 nm, 87 nm, 86 nm, 85 nm, 84 nm, 83 nm, 82 nm, 81 nm, 80 nm, 79 nm, 78 nm, 77 nm, 76 nm, 75 nm, 74 nm, 73 nm, 72 nm, 71 nm, 70 nm, 69 nm, 68 nm, 67 nm, 66 nm, 65 nm, 64 nm, 63 nm, 62 nm, 61 nm, 60 nm, 59 nm, 58 nm, 57 nm, 56 nm, 55 nm, 54 nm, 53 nm, 52 nm, 51 nm, 50 nm, 49 nm, 48 nm, 47 nm, 46 nm, 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, or 25 nm.

[0240] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP is between about 30 nm and about 200 nm, between about 30 nm and about 190 nm, between about 30 nm and about 180 nm, between about 30 nm and about 170 nm, between about 30 nm and about 160 nm, between about 30 nm and about 150 nm, between about 30 nm and about 140 nm, between about 30 nm and about 130 nm, between about 30 nm and about 120 nm, between about 30 nm and about 110 nm, between about 30 nm and about 100 nm, between about 30 nm and about 95 nm, between about 30 nm and about 90 nm, between about 30 nm and about 85 nm, 62 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) between about 30 nm and about 80 nm, between about 30 nm and about 75 nm, between about 30 nm and about 70 nm, or between about 30 nm and about 65 nm.

[0241] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP is between about 40 nm and about 200 nm, between about 40 nm and about 190 nm, between about 40 nm and about 180 nm, between about 40 nm and about 170 nm, between about 40 nm and about 160 nm, between about 40 nm and about 150 nm, between about 40 nm and about 140 nm, between about 40 nm and about 130 nm, between about 40 nm and about 120 nm, between about 40 nm and about 110 nm, between about 40 nm and about 100 nm, between about 40 nm and about 95 nm, between about 40 nm and about 90 nm, between about 40 nm and about 85 nm, between about 40 nm and about 80 nm, between about 40 nm and about 75 nm, between about 40 nm and about 70 nm, or between about 40 nm and about 65 nm.

[0242] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP is between about 50 nm and about 200 nm, between about 50 nm and about 190 nm, between about 50 nm and about 180 nm, between about 50 nm and about 170 nm, between about 50 nm and about 160 nm, between about 50 nm and about 150 nm, between about 50 nm and about 140 nm, between about 50 nm and about 130 nm, between about 50 nm and about 120 nm, between about 50 nm and about 110 nm, between about 50 nm and about 100 nm, between about 50 nm and about 95 nm, between about 50 nm and about 90 nm, between about 50 nm and about 85 nm, between about 50 nm and about 80 nm, between about 50 nm and about 75 nm, between about 50 nm and about 70 nm, or between about 50 nm and about 65 nm.

[0243] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP is between about 55 nm and about 200 nm, between about 55 nm and about 190 nm, between about 55 nm and about 180 nm, between about 55 nm and about 170 nm, between about 55 nm and about 160 nm, between about 55 nm and about 150 nm, between about 55 nm and about 140 nm, between about 55 nm and about 130 nm, between about 55 nm and about 120 nm, between about 55 nm and about 110 nm, between about 55 nm and about 100 nm, between about 55 nm and about 95 nm, between about 55 nm and about 90 nm, between about 55 nm and about 85 nm, between about 55 nm and about 80 nm, between about 55 nm and about 75 nm, between about 55 nm and about 70 nm, or between about 55 nm and about 65 nm.

[0244] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP is between about 60 nm and about 200 nm, between about 60 nm and about 190 nm, between about 60 nm and about 180 nm, between about 60 nm and about 170 nm, between about 60 nm 63 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) and about 160 nm, between about 60 nm and about 150 nm, between about 60 nm and about 140 nm, between about 60 nm and about 130 nm, between about 60 nm and about 120 nm, between about 60 nm and about 110 nm, between about 60 nm and about 100 nm, between about 60 nm and about 95 nm, between about 60 nm and about 90 nm, between about 60 nm and about 85 nm, between about 60 nm and about 80 nm, between about 60 nm and about 75 nm, between about 60 nm and about 70 nm, or between about 60 nm and about 65 nm.

[0245] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP is between about 65 nm and about 200 nm, between about 65 nm and about 190 nm, between about 65 nm and about 180 nm, between about 65 nm and about 170 nm, between about 65 nm and about 160 nm, between about 65 nm and about 150 nm, between about 65 nm and about 140 nm, between about 65 nm and about 130 nm, between about 65 nm and about 120 nm, between about 65 nm and about 110 nm, between about 65 nm and about 100 nm, between about 65 nm and about 95 nm, between about 65 nm and about 90 nm, between about 65 nm and about 85 nm, between about 65 nm and about 80 nm, between about 65 nm and about 75 nm, or between about 65 nm and about 70 nm.

[0246] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP is between 30 nm and 200 nm, between 30 nm and 190 nm, between 30 nm and 180 nm, between 30 nm and 170 nm, between 30 nm and 160 nm, between 30 nm and 150 nm, between 30 nm and 140 nm, between 30 nm and 130 nm, between 30 nm and 120 nm, between 30 nm and 110 nm, between 30 nm and 100 nm, between 30 nm and 95 nm, between 30 nm and 90 nm, between 30 nm and 85 nm, between 30 nm and 80 nm, between 30 nm and 75 nm, between 30 nm and 70 nm, or between 30 nm and 65 nm.

[0247] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP is between 40 nm and 200 nm, between 40 nm and 190 nm, between 40 nm and 180 nm, between 40 nm and 170 nm, between 40 nm and 160 nm, between 40 nm and 150 nm, between 40 nm and 140 nm, between 40 nm and 130 nm, between 40 nm and 120 nm, between 40 nm and 110 nm, between 40 nm and 100 nm, between 40 nm and 95 nm, between 40 nm and 90 nm, between 40 nm and 85 nm, between 40 nm and 80 nm, between 40 nm and 75 nm, between 40 nm and 70 nm, or between 40 nm and 65 nm.

[0248] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP is between 50 nm and 200 nm, between 50 nm and 190 nm, between 50 nm and 180 nm, between 50 nm and 170 nm, between 50 nm and 160 nm, between 50 nm and 150 nm, between 50 64 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) nm and 140 nm, between 50 nm and 130 nm, between 50 nm and 120 nm, between 50 nm and 110 nm, between 50 nm and 100 nm, between 50 nm and 95 nm, between 50 nm and 90 nm, between 50 nm and 85 nm, between 50 nm and 80 nm, between 50 nm and 75 nm, between 50 nm and 70 nm, or between 50 nm and 65 nm.

[0249] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP is between 55 nm and 200 nm, between 55 nm and 190 nm, between 55 nm and 180 nm, between 55 nm and 170 nm, between 55 nm and 160 nm, between 55 nm and 150 nm, between 55 nm and 140 nm, between 55 nm and 130 nm, between 55 nm and 120 nm, between 55 nm and 110 nm, between 55 nm and 100 nm, between 55 nm and 95 nm, between 55 nm and 90 nm, between 55 nm and 85 nm, between 55 nm and 80 nm, between 55 nm and 75 nm, between 55 nm and 70 nm, or between 55 nm and 65 nm.

[0250] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP is between 60 nm and 200 nm, between 60 nm and 190 nm, between 60 nm and 180 nm, between 60 nm and 170 nm, between 60 nm and 160 nm, between 60 nm and 150 nm, between 60 nm and 140 nm, between 60 nm and 130 nm, between 60 nm and 120 nm, between 60 nm and 110 nm, between 60 nm and 100 nm, between 60 nm and 95 nm, between 60 nm and 90 nm, between 60 nm and 85 nm, between 60 nm and 80 nm, between 60 nm and 75 nm, between 60 nm and 70 nm, or between 60 nm and 65 nm.

[0251] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP is between 65 nm and 200 nm, between 65 nm and 190 nm, between 65 nm and 180 nm, between 65 nm and 170 nm, between 65 nm and 160 nm, between 65 nm and 150 nm, between 65 nm and 140 nm, between 65 nm and 130 nm, between 65 nm and 120 nm, between 65 nm and 110 nm, between 65 nm and 100 nm, between 65 nm and 95 nm, between 65 nm and 90 nm, between 65 nm and 85 nm, between 65 nm and 80 nm, between 65 nm and 75 nm, or between 65 nm and 70 nm.

[0252] In some embodiments, the D10 of the nanoparticles in the population of FNP is lessthan about 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, about 25 nm, about 24 nm, about 23 nm, about 22 nm, about 21 nm, or about 20 nm. In some embodiments, the D10 of the nanoparticles in the population of FNP is less than 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 65 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 28 nm, 27 nm, 26 nm, 25 nm, 24 nm, 23 nm, 22 nm, 21 nm, or 20 nm. In some embodiments, the D10 of the nanoparticles in the population of FNP is less than about 32 nm. In some embodiments, the D10 of the nanoparticles in the population of FNP is less than 32 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0253] In some embodiments, the D10 of the nanoparticles in the population of FNP isgreater than about 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, about 25 nm, about 24 nm, about 23 nm, about 22 nm, about 21 nm, or about 20 nm. In some embodiments, the D10 of the nanoparticles in the population of FNP is greater than 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, 25 nm, 24 nm, 23 nm, 22 nm, 21 nm, or 20 nm. In some embodiments, the D10 of the nanoparticles in the population of FNP is greater than about 32 nm. In some embodiments, the D10 of the nanoparticles in the population of FNP is greater than 32 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0254] In some embodiments, the D10 of the nanoparticles in a population of FNP isbetween about 20 nm and about 45 nm, between about 25 nm and about 40 nm, or between about 30 nm and about 35 nm. In some embodiments, the D10 of the nanoparticles in a population of FNP is between 20 nm and 45 nm, between 25 nm and 40 nm, or between 30 nm and 35 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0255] In some embodiments, the D10 of the nanoparticles in the population of FNP isabout 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, about 25 nm, about 24 nm, about 23 nm, about 22 nm, about 21 nm, or about 20 nm. In some embodiments, the D10 of the nanoparticles in the population of FNP is 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, 25 nm, 24 nm, 23 nm, 22 nm, 21 nm, or 20 nm. In some embodiments, the D10 of the nanoparticles in the population of FNP is about 32 nm. In some embodiments, the D10 of the 66 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) nanoparticles in the population of FNP is 32 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0256] In some embodiments, the D90 of the nanoparticles in the population of FNP is lessthan about 200 nm, about 190 nm, about 180 nm, about 170 nm, about 160 nm, about 150 nm, about 149 nm, about 148 nm, about 147 nm, about 146 nm, about 145 nm, about 144 nm, about 143 nm, about 142 nm, about 141 nm, about 140 nm, about 139 nm, about 138 nm, about 137 nm, about 136 nm, about 135 nm, about 134 nm, about 133 nm, about 132 nm, about 131 nm, about 130 nm, about 129 nm, about 128 nm, about 127 nm, about 126 nm, about 125 nm, about 124 nm, about 123 nm, about 122 nm, about 121 nm, about 120 nm, about 119 nm, about 118 nm, about 117 nm, about 116 nm, about 115 nm, about 114 nm, about 113 nm, about 112 nm, about 111 nm, about 110 nm, about 109 nm, about 108 nm, about 107 nm, about 106 nm, about 105 nm, about 104 nm, about 103 nm, about 102 nm, about 101 nm, about 100 nm, about 99 nm, about 98 nm, about 97 nm, about 96 nm, about 95 nm, about 94 nm, about 93 nm, about 92 nm, about 91 nm, about 90 nm, about 89 nm, about 88 nm, about 87 nm, about 86 nm, about 85 nm, about 84 nm, about 83 nm, about 82 nm, about 81 nm, about 80 nm, about 79 nm, about 78 nm, about 77 nm, about 76 nm, about 75 nm, about 74 nm, about 73 nm, about 72 nm, about 71 nm, or about 70 nm. In some embodiments, the D90 of the nanoparticles in the population of FNP is less than 200 nm, 190 nm, 180 nm, 170 nm, 160 nm, 150 nm, 149 nm, 148 nm, 147 nm, 146 nm, 145 nm, 144 nm, 143 nm, 142 nm, 141 nm, 140 nm, 139 nm, 138 nm, 137 nm, 136 nm, 135 nm, 134 nm, 133 nm, 132 nm, 131 nm, 130 nm, 129 nm, 128 nm, 127 nm, 126 nm, 125 nm, 124 nm, 123 nm, 122 nm, 121 nm, 120 nm, 119 nm, 118 nm, 117 nm, 116 nm, 115 nm, 114 nm, 113 nm, 112 nm, 111 nm, 110 nm, 109 nm, 108 nm, 107 nm, 106 nm, 105 nm, 104 nm, 103 nm, 102 nm, 101 nm, 100 nm, 99 nm, 98 nm, 97 nm, 96 nm, 95 nm, 94 nm, 93 nm, 92 nm, 91 nm, 90 nm, 89 nm, 88 nm, 87 nm, 86 nm, 85 nm, 84 nm, 83 nm, 82 nm, 81 nm, 80 nm, 79 nm, 78 nm, 77 nm, 76 nm, 75 nm, 74 nm, 73 nm, 72 nm, 71 nm, or 70 nm. In some embodiments, the D90 of the nanoparticles in the population of FNP is less than about 85 nm. In some embodiments, the D90 of the nanoparticles in the population of FNP is less than 85 nm. In some embodiments, the D90 is D90(i), D90(v), or D90(n). In some embodiments, the D90 is D90(i).

[0257] In some embodiments, the D90 of the nanoparticles in a population of FNP isbetween about 70 nm and about 200 nm, between about 70 nm and about 150 nm, between about 75 nm and about 100 nm, or between about 80 nm and about 90 nm. In some embodiments, the D90 of the nanoparticles in a population of FNP is between 70 nm and 200 nm, between 70 nm 67 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) and 150 nm, between 75 nm and 100 nm, or between 80 nm and 90 nm. In some embodiments, the D90 is D90(i), D90(v), or D90(n). In some embodiments, the D90 is D90(i).

[0258] In some embodiments, the D90 of the nanoparticles in the population of FNP isabout 200 nm, about 190 nm, about 180 nm, about 170 nm, about 160 nm, about 150 nm, about 149 nm, about 148 nm, about 147 nm, about 146 nm, about 145 nm, about 144 nm, about 143 nm, about 142 nm, about 141 nm, about 140 nm, about 139 nm, about 138 nm, about 137 nm, about 136 nm, about 135 nm, about 134 nm, about 133 nm, about 132 nm, about 131 nm, about 130 nm, about 129 nm, about 128 nm, about 127 nm, about 126 nm, about 125 nm, about 124 nm, about 123 nm, about 122 nm, about 121 nm, about 120 nm, about 119 nm, about 118 nm, about 117 nm, about 116 nm, about 115 nm, about 114 nm, about 113 nm, about 112 nm, about 111 nm, about 110 nm, about 109 nm, about 108 nm, about 107 nm, about 106 nm, about 105 nm, about 104 nm, about 103 nm, about 102 nm, about 101 nm, about 100 nm, about 99 nm, about 98 nm, about 97 nm, about 96 nm, about 95 nm, about 94 nm, about 93 nm, about 92 nm, about 91 nm, about 90 nm, about 89 nm, about 88 nm, about 87 nm, about 86 nm, about 85 nm, about 84 nm, about 83 nm, about 82 nm, about 81 nm, about 80 nm, about 79 nm, about 78 nm, about 77 nm, about 76 nm, about 75 nm, about 74 nm, about 73 nm, about 72 nm, about 71 nm, or about 70 nm. In some embodiments, the D90 of the nanoparticles in the population of FNP is 200 nm, 190 nm, 180 nm, 170 nm, 160 nm, 150 nm, 149 nm, 148 nm, 147 nm, 146 nm, 145 nm, 144 nm, 143 nm, 142 nm, 141 nm, 140 nm, 139 nm, 138 nm, 137 nm, 136 nm, 135 nm, 134 nm, 133 nm, 132 nm, 131 nm, 130 nm, 129 nm, 128 nm, 127 nm, 126 nm, 125 nm, 124 nm, 123 nm, 122 nm, 121 nm, 120 nm, 119 nm, 118 nm, 117 nm, 116 nm, 115 nm, 114 nm, 113 nm, 112 nm, 111 nm, 110 nm, 109 nm, 108 nm, 107 nm, 106 nm, 105 nm, 104 nm, 103 nm, 102 nm, 101 nm, 100 nm, 99 nm, 98 nm, 97 nm, 96 nm, 95 nm, 94 nm, 93 nm, 92 nm, 91 nm, 90 nm, 89 nm, 88 nm, 87 nm, 86 nm, 85 nm, 84 nm, 83 nm, 82 nm, 81 nm, 80 nm, 79 nm, 78 nm, 77 nm, 76 nm, 75 nm, 74 nm, 73 nm, 72 nm, 71 nm, or 70 nm. In some embodiments, the D90 of the nanoparticles in the population of FNP is about 85 nm. In some embodiments, the D90 of the nanoparticles in the population of FNP is 85 nm. In some embodiments, the D90 is D90(i), D90(v), or D90(n). In some embodiments, the D90 is D90(i).

[0259] In some embodiments, the Z-average size of the FNP in the population of FNP isabout 200 nm or less. In some embodiments, the Z-average size of the FNP in the population of FNP is about 190 nm or less, about 180 nm or less, about 170 nm or less, about 160 nm or less, about 150 nm or less, about 140 nm or less, about 130 nm or less, about 120 nm or less, about 110 68 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) nm or less, about 100 nm or less, about 95 nm or less, about 90 nm or less, about 85 nm or less, about 80 nm or less, about 75 nm or less, about 70 nm or less, about 65 nm or less, about 60 nm or less, about 55 nm or less, about 50 nm or less, about 45 nm or less, about 40 nm or less, about 35 nm or less, about 30 nm or less, or about 25 nm or less.

[0260] In some embodiments, the Z-average size of the FNP in the population of FNP is200 nm or less. In some embodiments, the Z-average size of the FNP in the population of FNP is 190 nm or less, 180 nm or less, 170 nm or less, 160 nm or less, 150 nm or less, 140 nm or less, 130 nm or less, 120 nm or less, 110 nm or less, 100 nm or less, 95 nm or less, 90 nm or less, 85 nm or less, 80 nm or less, 75 nm or less, 70 nm or less, 65 nm or less, 60 nm or less, 55 nm or less, 50 nm or less, 45 nm or less, 40 nm or less, 35 nm or less, 30 nm or less, or 25 nm or less.

[0261] In some embodiments, the Z-average size of the FNP in the population of FNP isabout 200 nm, about 190 nm, about 180 nm, about 170 nm, about 160 nm, about 150 nm, about 140 nm, about 130 nm, about 120 nm, about 110 nm, about 100 nm, about 99 nm, about 98 nm, about 97 nm, about 96 nm, about 95 nm, about 94 nm, about 93 nm, about 92 nm, about 91 nm, about 90 nm, about 89 nm, about 88 nm, about 87 nm, about 86 nm, about 85 nm, about 84 nm, about 83 nm, about 82 nm, about 81 nm, about 80 nm, about 79 nm, about 78 nm, about 77 nm, about 76 nm, about 75 nm, about 74 nm, about 73 nm, about 72 nm, about 71 nm, about 70 nm, about 69 nm, about 68 nm, about 67 nm, about 66 nm, about 65 nm, about 64 nm, about 63 nm, about 62 nm, about 61 nm, about 60 nm, about 59 nm, about 58 nm, about 57 nm, about 56 nm, about 55 nm, about 54 nm, about 53 nm, about 52 nm, about 51 nm, about 50 nm, about 49 nm, about 48 nm, about 47 nm, about 46 nm, about 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, or about 25 nm.

[0262] In some embodiments, the Z-average size of the FNP in the population of FNP is200 nm, 190 nm, 180 nm, 170 nm, 160 nm, 150 nm, 140 nm, 130 nm, 120 nm, 110 nm, 100 nm, 99 nm, 98 nm, 97 nm, 96 nm, 95 nm, 94 nm, 93 nm, 92 nm, 91 nm, 90 nm, 89 nm, 88 nm, 87 nm, 86 nm, 85 nm, 84 nm, 83 nm, 82 nm, 81 nm, 80 nm, 79 nm, 78 nm, 77 nm, 76 nm, 75 nm, 74 nm, 73 nm, 72 nm, 71 nm, 70 nm, 69 nm, 68 nm, 67 nm, 66 nm, 65 nm, 64 nm, 63 nm, 62 nm, 61 nm, 60 nm, 59 nm, 58 nm, 57 nm, 56 nm, 55 nm, 54 nm, 53 nm, 52 nm, 51 nm, 50 nm, 49 nm, 48 nm, 47 nm, 46 nm, 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, or 25 nm. 69 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0263] In some embodiments, the Z-average size of the FNP in the population of FNP isbetween about 30 nm and about 200 nm, between about 30 nm and about 190 nm, between about 30 nm and about 180 nm, between about 30 nm and about 170 nm, between about 30 nm and about 160 nm, between about 30 nm and about 150 nm, between about 30 nm and about 140 nm, between about 30 nm and about 130 nm, between about 30 nm and about 120 nm, between about 30 nm and about 110 nm, between about 30 nm and about 100 nm, between about 30 nm and about 95 nm, between about 30 nm and about 90 nm, between about 30 nm and about 85 nm, between about 30 nm and about 80 nm, between about 30 nm and about 75 nm, between about 30 nm and about 70 nm, or between about 30 nm and about 65 nm.

[0264] In some embodiments, the Z-average size of the FNP in the population of FNP isbetween about 40 nm and about 200 nm, between about 40 nm and about 190 nm, between about 40 nm and about 180 nm, between about 40 nm and about 170 nm, between about 40 nm and about 160 nm, between about 40 nm and about 150 nm, between about 40 nm and about 140 nm, between about 40 nm and about 130 nm, between about 40 nm and about 120 nm, between about 40 nm and about 110 nm, between about 40 nm and about 100 nm, between about 40 nm and about 95 nm, between about 40 nm and about 90 nm, between about 40 nm and about 85 nm, between about 40 nm and about 80 nm, between about 40 nm and about 75 nm, between about 40 nm and about 70 nm, or between about 40 nm and about 65 nm.

[0265] In some embodiments, the Z-average size of the FNP in the population of FNP isbetween about 50 nm and about 200 nm, between about 50 nm and about 190 nm, between about 50 nm and about 180 nm, between about 50 nm and about 170 nm, between about 50 nm and about 160 nm, between about 50 nm and about 150 nm, between about 50 nm and about 140 nm, between about 50 nm and about 130 nm, between about 50 nm and about 120 nm, between about 50 nm and about 110 nm, between about 50 nm and about 100 nm, between about 50 nm and about 95 nm, between about 50 nm and about 90 nm, between about 50 nm and about 85 nm, between about 50 nm and about 80 nm, between about 50 nm and about 75 nm, between about 50 nm and about 70 nm, or between about 50 nm and about 65 nm.

[0266] In some embodiments, the Z-average size of the FNP in the population of FNP isbetween about 55 nm and about 200 nm, between about 55 nm and about 190 nm, between about 55 nm and about 180 nm, between about 55 nm and about 170 nm, between about 55 nm and about 160 nm, between about 55 nm and about 150 nm, between about 55 nm and about 140 nm, between about 55 nm and about 130 nm, between about 55 nm and about 120 nm, between about 55 nm 70 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) and about 110 nm, between about 55 nm and about 100 nm, between about 55 nm and about 95 nm, between about 55 nm and about 90 nm, between about 55 nm and about 85 nm, between about 55 nm and about 80 nm, between about 55 nm and about 75 nm, between about 55 nm and about 70 nm, or between about 55 nm and about 65 nm.

[0267] In some embodiments, the Z-average size of the FNP in the population of FNP isbetween about 60 nm and about 200 nm, between about 60 nm and about 190 nm, between about 60 nm and about 180 nm, between about 60 nm and about 170 nm, between about 60 nm and about 160 nm, between about 60 nm and about 150 nm, between about 60 nm and about 140 nm, between about 60 nm and about 130 nm, between about 60 nm and about 120 nm, between about 60 nm and about 110 nm, between about 60 nm and about 100 nm, between about 60 nm and about 95 nm, between about 60 nm and about 90 nm, between about 60 nm and about 85 nm, between about 60 nm and about 80 nm, between about 60 nm and about 75 nm, between about 60 nm and about 70 nm, or between about 60 nm and about 65 nm.

[0268] In some embodiments, the Z-average size of the FNP in the population of FNP isbetween about 65 nm and about 200 nm, between about 65 nm and about 190 nm, between about 65 nm and about 180 nm, between about 65 nm and about 170 nm, between about 65 nm and about 160 nm, between about 65 nm and about 150 nm, between about 65 nm and about 140 nm, between about 65 nm and about 130 nm, between about 65 nm and about 120 nm, between about 65 nm and about 110 nm, between about 65 nm and about 100 nm, between about 65 nm and about 95 nm, between about 65 nm and about 90 nm, between about 65 nm and about 85 nm, between about 65 nm and about 80 nm, between about 65 nm and about 75 nm, or between about 65 nm and about 70 nm.

[0269] In some embodiments, the Z-average size of the FNP in the population of FNP isbetween 30 nm and 200 nm, between 30 nm and 190 nm, between 30 nm and 180 nm, between 30 nm and 170 nm, between 30 nm and 160 nm, between 30 nm and 150 nm, between 30 nm and 140 nm, between 30 nm and 130 nm, between 30 nm and 120 nm, between 30 nm and 110 nm, between 30 nm and 100 nm, between 30 nm and 95 nm, between 30 nm and 90 nm, between 30 nm and 85 nm, between 30 nm and 80 nm, between 30 nm and 75 nm, between 30 nm and 70 nm, or between 30 nm and 65 nm.

[0270] In some embodiments, the Z-average size of the FNP in the population of FNP isbetween 40 nm and 200 nm, between 40 nm and 190 nm, between 40 nm and 180 nm, between 40 nm and 170 nm, between 40 nm and 160 nm, between 40 nm and 150 nm, between 40 nm and 140 71 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) nm, between 40 nm and 130 nm, between 40 nm and 120 nm, between 40 nm and 110 nm, between 40 nm and 100 nm, between 40 nm and 95 nm, between 40 nm and 90 nm, between 40 nm and 85 nm, between 40 nm and 80 nm, between 40 nm and 75 nm, between 40 nm and 70 nm, or between 40 nm and 65 nm.

[0271] In some embodiments, the Z-average size of the FNP in the population of FNP isbetween 50 nm and 200 nm, between 50 nm and 190 nm, between 50 nm and 180 nm, between 50 nm and 170 nm, between 50 nm and 160 nm, between 50 nm and 150 nm, between 50 nm and 140 nm, between 50 nm and 130 nm, between 50 nm and 120 nm, between 50 nm and 110 nm, between 50 nm and 100 nm, between 50 nm and 95 nm, between 50 nm and 90 nm, between 50 nm and 85 nm, between 50 nm and 80 nm, between 50 nm and 75 nm, between 50 nm and 70 nm, or between 50 nm and 65 nm.

[0272] In some embodiments, the Z-average size of the FNP in the population of FNP isbetween 55 nm and 200 nm, between 55 nm and 190 nm, between 55 nm and 180 nm, between 55 nm and 170 nm, between 55 nm and 160 nm, between 55 nm and 150 nm, between 55 nm and 140 nm, between 55 nm and 130 nm, between 55 nm and 120 nm, between 55 nm and 110 nm, between 55 nm and 100 nm, between 55 nm and 95 nm, between 55 nm and 90 nm, between 55 nm and 85 nm, between 55 nm and 80 nm, between 55 nm and 75 nm, between 55 nm and 70 nm, or between 55 nm and 65 nm.

[0273] In some embodiments, the Z-average size of the FNP in the population of FNP isbetween 60 nm and 200 nm, between 60 nm and 190 nm, between 60 nm and 180 nm, between 60 nm and 170 nm, between 60 nm and 160 nm, between 60 nm and 150 nm, between 60 nm and 140 nm, between 60 nm and 130 nm, between 60 nm and 120 nm, between 60 nm and 110 nm, between 60 nm and 100 nm, between 60 nm and 95 nm, between 60 nm and 90 nm, between 60 nm and 85 nm, between 60 nm and 80 nm, between 60 nm and 75 nm, between 60 nm and 70 nm, or between 60 nm and 65 nm.

[0274] In some embodiments, the Z-average size of the FNP in the population of FNP isbetween 65 nm and 200 nm, between 65 nm and 190 nm, between 65 nm and 180 nm, between 65 nm and 170 nm, between 65 nm and 160 nm, between 65 nm and 150 nm, between 65 nm and 140 nm, between 65 nm and 130 nm, between 65 nm and 120 nm, between 65 nm and 110 nm, between 65 nm and 100 nm, between 65 nm and 95 nm, between 65 nm and 90 nm, between 65 nm and 85 nm, between 65 nm and 80 nm, between 65 nm and 75 nm, or between 65 nm and 70 nm. 72 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0275] In some embodiments, the D10 of the FNP in the population of FNP is less thanabout 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, about 25 nm, about 24 nm, about 23 nm, about 22 nm, about 21 nm, or about 20 nm. In some embodiments, the D10 of the FNP in the population of FNP is less than 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, 25 nm, 24 nm, 23 nm, 22 nm, 21 nm, or 20 nm. In some embodiments, the D10 of the FNP in the population of FNP is less than about 39 nm. In some embodiments, the D10 of the FNP in the population of FNP is less than 39 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0276] In some embodiments, the D10 of the FNP in the population of FNP is greater thanabout 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, about 25 nm, about 24 nm, about 23 nm, about 22 nm, about 21 nm, or about 20 nm. In some embodiments, the D10 of the FNP in the population of FNP is greater than 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, 25 nm, 24 nm, 23 nm, 22 nm, 21 nm, or 20 nm. In some embodiments, the D10 of the FNP in the population of FNP is greater than about 39 nm. In some embodiments, the D10 of the FNP in the population of FNP is greater than 39 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0277] In some embodiments, the D10 of the FNP in a population of FNP is between about20 nm and about 45 nm, between about 25 nm and about 40 nm, or between about 35 nm and about 40 nm. In some embodiments, the D10 of the FNP in a population of FNP is between 20 nm and 45 nm, between 25 nm and 40 nm, or between 35 nm and 40 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0278] In some embodiments, the D10 of the FNP in the population of FNP is about 45nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, about 25 nm, about 24 nm, about 23 nm, about 22 nm, about 21 nm, or about 20 nm. In some embodiments, the D10 of 73 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) the FNP in the population of FNP is 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, 25 nm, 24 nm, 23 nm, 22 nm, 21 nm, or 20 nm. In some embodiments, the D10 of the FNP in the population of FNP is about 39 nm. In some embodiments, the D10 of the FNP in the population of FNP is 39 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0279] In some embodiments, the D90 of the FNP in the population of FNP is less thanabout 200 nm, about 190 nm, about 180 nm, about 170 nm, about 160 nm, about 150 nm, about 149 nm, about 148 nm, about 147 nm, about 146 nm, about 145 nm, about 144 nm, about 143 nm, about 142 nm, about 141 nm, about 140 nm, about 139 nm, about 138 nm, about 137 nm, about 136 nm, about 135 nm, about 134 nm, about 133 nm, about 132 nm, about 131 nm, about 130 nm, about 129 nm, about 128 nm, about 127 nm, about 126 nm, about 125 nm, about 124 nm, about 123 nm, about 122 nm, about 121 nm, about 120 nm, about 119 nm, about 118 nm, about 117 nm, about 116 nm, about 115 nm, about 114 nm, about 113 nm, about 112 nm, about 111 nm, about 110 nm, about 109 nm, about 108 nm, about 107 nm, about 106 nm, about 105 nm, about 104 nm, about 103 nm, about 102 nm, about 101 nm, about 100 nm, about 99 nm, about 98 nm, about 97 nm, about 96 nm, about 95 nm, about 94 nm, about 93 nm, about 92 nm, about 91 nm, about 90 nm, about 89 nm, about 88 nm, about 87 nm, about 86 nm, about 85 nm, about 84 nm, about 83 nm, about 82 nm, about 81 nm, about 80 nm, about 79 nm, about 78 nm, about 77 nm, about 76 nm, about 75 nm, about 74 nm, about 73 nm, about 72 nm, about 71 nm, or about 70 nm. In some embodiments, the D90 of the FNP in the population of FNP is less than 200 nm, 190 nm, 180 nm, 170 nm, 160 nm, 150 nm, 149 nm, 148 nm, 147 nm, 146 nm, 145 nm, 144 nm, 143 nm, 142 nm, 141 nm, 140 nm, 139 nm, 138 nm, 137 nm, 136 nm, 135 nm, 134 nm, 133 nm, 132 nm, 131 nm, 130 nm, 129 nm, 128 nm, 127 nm, 126 nm, 125 nm, 124 nm, 123 nm, 122 nm, 121 nm, 120 nm, 119 nm, 118 nm, 117 nm, 116 nm, 115 nm, 114 nm, 113 nm, 112 nm, 111 nm, 110 nm, 109 nm, 108 nm, 107 nm, 106 nm, 105 nm, 104 nm, 103 nm, 102 nm, 101 nm, 100 nm, 99 nm, 98 nm, 97 nm, 96 nm, 95 nm, 94 nm, 93 nm, 92 nm, 91 nm, 90 nm, 89 nm, 88 nm, 87 nm, 86 nm, 85 nm, 84 nm, 83 nm, 82 nm, 81 nm, 80 nm, 79 nm, 78 nm, 77 nm, 76 nm, 75 nm, 74 nm, 73 nm, 72 nm, 71 nm, or 70 nm. In some embodiments, the D90 of the FNP in the population of FNP is less than about 113 nm. In some embodiments, the D90 of the FNP in the population of FNP is less than 113 nm. In some embodiments, the D90 is D90(i), D90(v), or D90(n). In some embodiments, the D90 is D90(i). 74 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0280] In some embodiments, the D90 of the FNP in a population of FNP is between about70 nm and about 200 nm, between about 75 nm and about 150 nm, between about 80 nm and about 130 nm, between about 90 nm and about 125 nm, or between about 110 nm and about 120 nm. In some embodiments, the D90 of the FNP in a population of FNP is between 70 nm and 200 nm, between 75 nm and 150 nm, between 80 nm and 130 nm, between 90 nm and 125 nm, or between 110 nm and 120 nm. In some embodiments, the D90 is D90(i), D90(v), or D90(n). In some embodiments, the D90 is D90(i).

[0281] In some embodiments, the D90 of the FNP in the population of FNP is about 200nm, about 190 nm, about 180 nm, about 170 nm, about 160 nm, about 150 nm, about 149 nm, about 148 nm, about 147 nm, about 146 nm, about 145 nm, about 144 nm, about 143 nm, about 142 nm, about 141 nm, about 140 nm, about 139 nm, about 138 nm, about 137 nm, about 136 nm, about 135 nm, about 134 nm, about 133 nm, about 132 nm, about 131 nm, about 130 nm, about 129 nm, about 128 nm, about 127 nm, about 126 nm, about 125 nm, about 124 nm, about 123 nm, about 122 nm, about 121 nm, about 120 nm, about 119 nm, about 118 nm, about 117 nm, about 116 nm, about 115 nm, about 114 nm, about 113 nm, about 112 nm, about 111 nm, about 110 nm, about 109 nm, about 108 nm, about 107 nm, about 106 nm, about 105 nm, about 104 nm, about 103 nm, about 102 nm, about 101 nm, about 100 nm, about 99 nm, about 98 nm, about 97 nm, about 96 nm, about 95 nm, about 94 nm, about 93 nm, about 92 nm, about 91 nm, about 90 nm, about 89 nm, about 88 nm, about 87 nm, about 86 nm, about 85 nm, about 84 nm, about 83 nm, about 82 nm, about 81 nm, about 80 nm, about 79 nm, about 78 nm, about 77 nm, about 76 nm, about 75 nm, about 74 nm, about 73 nm, about 72 nm, about 71 nm, or about 70 nm. In some embodiments, the D90 of the FNP in the population of FNP is 200 nm, 190 nm, 180 nm, 170 nm, 160 nm, 150 nm, 149 nm, 148 nm, 147 nm, 146 nm, 145 nm, 144 nm, 143 nm, 142 nm, 141 nm, 140 nm, 139 nm, 138 nm, 137 nm, 136 nm, 135 nm, 134 nm, 133 nm, 132 nm, 131 nm, 130 nm, 129 nm, 128 nm, 127 nm, 126 nm, 125 nm, 124 nm, 123 nm, 122 nm, 121 nm, 120 nm, 119 nm, 118 nm, 117 nm, 116 nm, 115 nm, 114 nm, 113 nm, 112 nm, 111 nm, 110 nm, 109 nm, 108 nm, 107 nm, 106 nm, 105 nm, 104 nm, 103 nm, 102 nm, 101 nm, 100 nm, 99 nm, 98 nm, 97 nm, 96 nm, 95 nm, 94 nm, 93 nm, 92 nm, 91 nm, 90 nm, 89 nm, 88 nm, 87 nm, 86 nm, 85 nm, 84 nm, 83 nm, 82 nm, 81 nm, 80 nm, 79 nm, 78 nm, 77 nm, 76 nm, 75 nm, 74 nm, 73 nm, 72 nm, 71 nm, or 70 nm. In some embodiments, the D90 of the FNP in the population of FNP is about 113 nm. In some embodiments, the D90 of the FNP in the population of FNP is 113 nm. In some embodiments, the D90 is D90(i), D90(v), or D90(n). In some embodiments, the D90 is D90(i). 75 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0282] In some embodiments, FNP may be, e.g., sourced from an appropriate vendor ormanufactured and / or purified by an appropriate method, e.g., as described in U.S. Patent No. 9,186,417, which is herein incorporated by reference in its entirety, or manufactured and / or purified by any other suitable method, e.g., any suitable method known in the art. Pharmaceutical Compositions

[0283] In an aspect, the instant disclosure provides pharmaceutical compositionscomprising a population of FNP for use e.g., in methods of promoting blood clotting, preventing bleeding, controlling bleeding, reducing blood loss, and / or promoting hemostasis in a subject in need thereof. In particular, the pharmaceutical compositions provided herein have improved safety, improved efficacy, increased stability, and / or extended shelf life.

[0284] In some embodiments, the pharmaceutical compositions are suspensions, e.g.,aqueous suspensions. In some embodiments, the pharmaceutical compositions are characterized as containing low concentrations of free polyphosphate polymers (i.e., polyphosphate polymers not bound to nanoparticles) or low percentages of free polyphosphate polymer mass relative to total polyphosphate polymer mass present. Polyphosphate polymers promote blood clotting. However, free polyphosphate polymers are poorly soluble, and in some cases, administration to animals has been shown to result in fatal thrombi.

[0285] Thus, in some embodiments, the percentage of the total polyphosphate polymermass in the pharmaceutical composition that exists as free polyphosphate polymers (i.e., (mass of free polyphosphate polymers in the pharmaceutical composition / mass of total polyphosphate polymers in the pharmaceutical composition) × 100%) is no more than about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, or about 0.5%. In some embodiments, the percentage of the total polyphosphate polymers in the pharmaceutical composition that exist as free polyphosphate polymers is no more than 55%, 50%, 45%, 40%, 45%, 30%, 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9% 0.8%, 0.7%, 0.6%, or 0.5%.

[0286] In some embodiments, the polydispersity index (PDI) of the pharmaceuticalcomposition is no more than about 0.30, about 0.29, about 0.28, about 0.27, about 0.26, about 0.25, 76 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) about 0.24, about 0.23, about 0.22, about 0.21, about 0.20, about 0.19, about 0.18, about 0.17, about 0.16, about 0.15, about 0.14, about 0.13, about 0.12, about 0.11, or about 0.10. In some embodiments, the polydispersity index of the pharmaceutical composition is no more than 0.30, 0.29, 0.28, 0.27, 0.26, 0.25, 0.24, 0.23, 0.22, 0.21, 0.20, 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13. 0.12, 0.11, or 0.10.

[0287] In some embodiments, the PDI of the pharmaceutical composition is between about0.1 and about 0.3, between about 0.15 and about 0.3, between about 0.2 and about 0.3, between about 0.25 and about 0.3, between about 0.1 and about 0.25, between about 0.15 and about 0.25, between about 0.2 and about 0.25, between about 0.1 and about 0.2, or between about 0.15 and about 0.2.

[0288] In some embodiments, the PDI of the pharmaceutical composition is between 0.1and 0.3, between 0.15 and 0.3, between 0.2 and 0.3, between 0.25 and 0.3, between 0.1 and 0.25, between 0.15 and 0.25, between 0.2 and 0.25, between 0.1 and 0.2, or between 0.15 and 0.2.

[0289] In some embodiments, the PDI of the pharmaceutical composition is about 0.30,about 0.29, about 0.28, about 0.27, about 0.26, about 0.25, about 0.24, about 0.23, about 0.22, about 0.21, about 0.20, about 0.19, about 0.18, about 0.17, about 0.16, about 0.15, about 0.14, about 0.13, about 0.12, about 0.11, or about 0.10. In some embodiments, the polydispersity index of the pharmaceutical composition is 0.30, 0.29, 0.28, 0.27, 0.26, 0.25, 0.24, 0.23, 0.22, 0.21, 0.20, 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13.0.12, 0.11, or 0.10.

[0290] In some embodiments, the PDI of the pharmaceutical composition is measured,e.g., using a Malvern Zetasizer Nano ZS90 or similar instrument.

[0291] In some embodiments, the pH of the pharmaceutical composition is between about4.0 and about 8.0, between about 4.0 and about 7.5, between about 4.0 and about 7.0, between about 4.0 and about 6.5, between about 4.0 and about 6.0, between about 4.5 and about 8.0, between about 4.5 and about 7.5, between about 4.5 and about 7.0, between about 4.5 and about 6.5, between about 4.5 and about 6.0, between about 5.0 and about 8.0, between about 5.0 and about 7.5, between about 5.0 and about 7.0, between about 5.0 and about 6.5, between about 5.0 and about 6.0, between about 5.5 and about 8.0, between about 5.5 and about 7.5, between about 5.5 and about 7.0, between about 5.5 and about 6.5, and between about 5.5 and about 6.0. In some embodiments, the pH of the pharmaceutical composition is between about 5.75 and about 5.95 or between about 5.81 and about 5.91. 77 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0292] In some embodiments, the pH of the pharmaceutical composition is between 4.0and 8.0, between 4.0 and 7.5, between 4.0 and 7.0, between 4.0 and 6.5, between 4.0 and 6.0, between 4.5 and 8.0, between 4.5 and 7.5, between 4.5 and 7.0, between 4.5 and 6.5, between 4.5 and 6.0, between 5.0 and 8.0, between 5.0 and 7.5, between 5.0 and 7.0, between 5.0 and 6.5, between 5.0 and 6.0, between 5.5 and 8.0, between 5.5 and 7.5, between 5.5 and 7.0, between 5.5 and 6.5, and between 5.5 and 6.0. In some embodiments, the pH of the pharmaceutical composition is between 5.75 and 5.95 or between 5.81 and 5.91.

[0293] In some embodiments, the pH of the pharmaceutical composition is about 5.0, about5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, or about 6.0. In some embodiments, the pH of the pharmaceutical composition is about 5.75, about 5.76, about 5.77, about 5.78, about 5.79, about 5.80, about 5.81, about 5.82, about 5.83, about 5.84, about 5.85, about 5.86, about 5.87, about 5.88, about 5.89, about 5.90, about 5.91, about 5.92, about 5.93, about 5.94, or about 5.95.

[0294] In some embodiments, the pH of the pharmaceutical composition is 5.0, 5.1, 5.2,5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0. In some embodiments, the pH of the pharmaceutical composition is 5.75, 5.76, 5.77, 5.78, 5.79, 5.80, 5.81, 5.82, 5.83, 5.84, 5.85, 5.86, 5.87, 5.88, 5.89, 5.90, 5.91, 5.92, 5.93, 5.94, or 5.95.

[0295] In some embodiments, the zeta potential of the pharmaceutical composition isbetween about -60 mV and about -25 mV, between about -60 mV and about -30 mV, between about -60 mV and about -35 mV, between about -60 mV and about -40 mV, between about -60 mV and about -45 mV, between about -60 mV and about -50 mV, between about -55 mV and about -25 mV, between about -55 mV and about -30 mV, between about -55 mV and about -35 mV, between about -55 mV and about -40 mV, between about -55 mV and about -45 mV, between about -55 mV and about -50 mV, between about -50 mV and about -25 mV, between about -50 mV and about -30 mV, between about -50 mV and about -35 mV, between about -50 mV and about -40 mV, between about -50 mV and about -45 mV. In some embodiments, the zeta potential of the pharmaceutical composition is between about -50 mV to about -41 mV, between about -50 mV to about -42 mV, between about -50 mV to about -43 mV, between about -50 mV to about - 44 mV, between about -50 mV to about -45 mV, between about -49 mV to about -41 mV, between about -49 mV to about -42 mV, between about -49 mV to about -43 mV, between about -49 mV to about -44 mV, between about -49 mV to about -45 mV, between about -48 mV to about -41 78 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) mV, between about -48 mV to about -42 mV, between about -48 mV to about -43 mV, between about -48 mV to about -44 mV, or between about -48 mV to about -45 mV.

[0296] In some embodiments, the zeta potential of the pharmaceutical composition isbetween -60 mV and -25 mV, between -60 mV and -30 mV, between -60 mV and -35 mV, between -60 mV and -40 mV, between -60 mV and -45 mV, between -60 mV and -50 mV, between -55 mV and -25 mV, between -55 mV and -30 mV, between -55 mV and -35 mV, between -55 mV and -40 mV, between -55 mV and -45 mV, between -55 mV and -50 mV, between -50 mV and - 25 mV, between -50 mV and -30 mV, between -50 mV and -35 mV, between -50 mV and -40 mV, between -50 mV and -45 mV. In some embodiments, the zeta potential of the pharmaceutical composition is between -50 mV to -41 mV, between -50 mV to -42 mV, between -50 mV to -43 mV, between -50 mV to -44 mV, between -50 mV to -45 mV, between -49 mV to -41 mV, between -49 mV to -42 mV, between -49 mV to -43 mV, between -49 mV to -44 mV, between -49 mV to -45 mV, between -48 mV to -41 mV, between -48 mV to -42 mV, between -48 mV to -43 mV, between -48 mV to -44 mV, or between -48 mV to -45 mV.

[0297] In some embodiments, the pharmaceutical composition is stable as an aqueoussuspension or as a lyophilized material, e.g., a cake or a powder. Stability of the aqueous suspension or reconstituted lyophilized material can be determined by measuring one or more of particle size, PDI, and % free polyphosphate polymer mass to total polyphosphate polymer mass, at multiple time points. In some embodiments, the aqueous suspension or reconstituted lyophilized material is considered stable if there are no visible particles. In some embodiments, the aqueous suspension or reconstituted suspension is considered stable if the PDI is no more than about 0.30, about 0.29, about 0.28, about 0.27, about 0.26, about 0.25, about 0.24, about 0.23, about 0.22, about 0.21, about 0.20, about 0.19, about 0.18, about 0.17, about 0.16, about 0.15, about 0.14, about 0.13, about 0.12, about 0.11, or about 0.10, e.g., for a set period of time at a set temperature. In some embodiments, the aqueous suspension or reconstituted suspension is considered stable if the PDI is no more than 0.30, 0.29, 0.28, 0.27, 0.26, 0.25, 0.24, 0.23, 0.22, 0.21, 0.20, 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13.0.12, 0.11, or 0.10, e.g., for a set period of time at a set temperature. For the above embodiments, the set period of time may be at least about 12 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, about 15 days, about 20 days, about 25 days, about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 55 days, about 60 days, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 79 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 2 years, about 3 years, about 4 years, or about 5 years. For the above embodiments, the set period of time may be at least 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days, 45 days, 50 days, 55 days, or 60 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, 4 years, or 5 years. For the above embodiments, the set temperature may be about -20°C, -20°C, about 5°C, 5°C, about 25°C, 25°C, about 40°C, or 40°C.

[0298] In some embodiments, the aqueous suspension or reconstituted lyophilized materialis considered stable if the percentage of the total polyphosphate polymer mass in the pharmaceutical composition that exist as free polyphosphate polymers is no more than about 30%, about 29%, about 28%, about 27%, about 26%, about 25%, about 24%, about 23%, about 22%, about 21%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, or about 5%, e.g., for a set period of time at a set temperature. In some embodiments, the aqueous suspension or reconstituted lyophilized material is considered stable if the percentage of the total polyphosphate polymer mass in the pharmaceutical composition that exist as free polyphosphate polymers is no more than 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%, e.g., for a set period of time at a set temperature. For the above embodiments, the set period of time may be at least about 12 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, about 15 days, about 20 days, about 25 days, about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 55 days, about 60 days, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 2 years, about 3 years, about 4 years, or about 5 years. For the above embodiments, the set period of time may be at least 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days, 45 days, 50 days, 55 days, or 60 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, 4 years, or 5 80 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) years. For the above embodiments, the set temperature may be about -20°C, -20°C, about 5°C, 5°C, about 25°C, 25°C, about 40°C, or 40°C.

[0299] In some embodiments, the pharmaceutical composition is stable for at least about12 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, about 15 days, about 20 days, about 25 days, about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 55 days, about 60 days, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 2 years, about 3 years, about 4 years, or about 5 years at room temperature. In some embodiments, room temperature is about 22℃ to about 27℃. In some embodiments, room temperature is about 22℃, about 23℃, about 24℃, about 25℃, about 26℃, or 27℃.

[0300] In some embodiments, the pharmaceutical composition is stable for at least 12hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days, 45 days, 50 days, 55 days, or 60 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, 4 years, or 5 years at room temperature. In some embodiments, room temperature is 22℃ to 27℃. In some embodiments, room temperature is 22℃, 23℃, 24℃, 25℃, 26℃, or 27℃.

[0301] In some embodiments, the pharmaceutical composition is stable for at least about12 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, about 15 days, about 20 days, about 25 days, about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 55 days, about 60 days, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 2 years, about 3 years, about 4 years, or about 5 years when refrigerated. In some embodiments, refrigerated refers to a temperature from about 3℃ to about 8℃ or from about 2℃ to about 8℃. In some embodiments, refrigerated refers to a temperature of about 2℃, about 3℃, about 4℃, about 5℃, about 6℃, about 7℃, or about 8℃.

[0302] In some embodiments, the pharmaceutical composition is stable for at least 12hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 15 days, 20 days, 25 days, 81 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 30 days, 35 days, 40 days, 45 days, 50 days, 55 days, or 60 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, 4 years, or 5 years when refrigerated. In some embodiments, refrigerated refers to a temperature from 3℃ to 8℃ or from 2℃ to 8℃. In some embodiments, refrigerated refers to a temperature of 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, or 8℃.

[0303] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP in the pharmaceutical composition is about 200 nm or less. In some embodiments, the Z- average size of the nanoparticles in the population of FNP in the pharmaceutical composition is about 190 nm or less, about 180 nm or less, about 170 nm or less, about 160 nm or less, about 150 nm or less, about 140 nm or less, about 130 nm or less, about 120 nm or less, about 110 nm or less, about 100 nm or less, about 95 nm or less, about 90 nm or less, about 85 nm or less, about 80 nm or less, about 75 nm or less, about 70 nm or less, about 65 nm or less, about 60 nm or less, about 55 nm or less, about 50 nm or less, about 45 nm or less, about 40 nm or less, about 35 nm or less, about 30 nm or less, or about 25 nm or less.

[0304] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP in the pharmaceutical composition is 200 nm or less. In some embodiments, the Z-average size of the nanoparticles in the population of FNP in the pharmaceutical composition is 190 nm or less, 180 nm or less, 170 nm or less, 160 nm or less, 150 nm or less, 140 nm or less, 130 nm or less, 120 nm or less, 110 nm or less, 100 nm or less, 95 nm or less, 90 nm or less, 85 nm or less, 80 nm or less, 75 nm or less, 70 nm or less, 65 nm or less, 60 nm or less, 55 nm or less, 50 nm or less, 45 nm or less, 40 nm or less, 35 nm or less, 30 nm or less, or 25 nm or less.

[0305] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP in the pharmaceutical composition is about 200 nm, about 190 nm, about 180 nm, about 170 nm, about 160 nm, about 150 nm, about 140 nm, about 130 nm, about 120 nm, about 110 nm, about 100 nm, about 99 nm, about 98 nm, about 97 nm, about 96 nm, about 95 nm, about 94 nm, about 93 nm, about 92 nm, about 91 nm, about 90 nm, about 89 nm, about 88 nm, about 87 nm, about 86 nm, about 85 nm, about 84 nm, about 83 nm, about 82 nm, about 81 nm, about 80 nm, about 79 nm, about 78 nm, about 77 nm, about 76 nm, about 75 nm, about 74 nm, about 73 nm, about 72 nm, about 71 nm, about 70 nm, about 69 nm, about 68 nm, about 67 nm, about 66 nm, about 65 nm, about 64 nm, about 63 nm, about 62 nm, about 61 nm, about 60 nm, about 59 nm, about 58 nm, about 57 nm, about 56 nm, about 55 nm, about 54 nm, about 53 nm, about 52 nm, 82 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) about 51 nm, about 50 nm, about 49 nm, about 48 nm, about 47 nm, about 46 nm, about 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, or about 25 nm.

[0306] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP in the pharmaceutical composition is 200 nm, 190 nm, 180 nm, 170 nm, 160 nm, 150 nm, 140 nm, 130 nm, 120 nm, 110 nm, 100 nm, 99 nm, 98 nm, 97 nm, 96 nm, 95 nm, 94 nm, 93 nm, 92 nm, 91 nm, 90 nm, 89 nm, 88 nm, 87 nm, 86 nm, 85 nm, 84 nm, 83 nm, 82 nm, 81 nm, 80 nm, 79 nm, 78 nm, 77 nm, 76 nm, 75 nm, 74 nm, 73 nm, 72 nm, 71 nm, 70 nm, 69 nm, 68 nm, 67 nm, 66 nm, 65 nm, 64 nm, 63 nm, 62 nm, 61 nm, 60 nm, 59 nm, 58 nm, 57 nm, 56 nm, 55 nm, 54 nm, 53 nm, 52 nm, 51 nm, 50 nm, 49 nm, 48 nm, 47 nm, 46 nm, 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, or 25 nm.

[0307] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP in the pharmaceutical composition is between about 30 nm and about 200 nm, between about 30 nm and about 190 nm, between about 30 nm and about 180 nm, between about 30 nm and about 170 nm, between about 30 nm and about 160 nm, between about 30 nm and about 150 nm, between about 30 nm and about 140 nm, between about 30 nm and about 130 nm, between about 30 nm and about 120 nm, between about 30 nm and about 110 nm, between about 30 nm and about 100 nm, between about 30 nm and about 95 nm, between about 30 nm and about 90 nm, between about 30 nm and about 85 nm, between about 30 nm and about 80 nm, between about 30 nm and about 75 nm, between about 30 nm and about 70 nm, or between about 30 nm and about 65 nm.

[0308] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP in the pharmaceutical composition is between about 40 nm and about 200 nm, between about 40 nm and about 190 nm, between about 40 nm and about 180 nm, between about 40 nm and about 170 nm, between about 40 nm and about 160 nm, between about 40 nm and about 150 nm, between about 40 nm and about 140 nm, between about 40 nm and about 130 nm, between about 40 nm and about 120 nm, between about 40 nm and about 110 nm, between about 40 nm and about 100 nm, between about 40 nm and about 95 nm, between about 40 nm and about 90 nm, between about 40 nm and about 85 nm, between about 40 nm and about 80 nm, between about 40 nm and about 75 nm, between about 40 nm and about 70 nm, or between about 40 nm and about 65 nm. 83 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0309] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP in the pharmaceutical composition is between about 50 nm and about 200 nm, between about 50 nm and about 190 nm, between about 50 nm and about 180 nm, between about 50 nm and about 170 nm, between about 50 nm and about 160 nm, between about 50 nm and about 150 nm, between about 50 nm and about 140 nm, between about 50 nm and about 130 nm, between about 50 nm and about 120 nm, between about 50 nm and about 110 nm, between about 50 nm and about 100 nm, between about 50 nm and about 95 nm, between about 50 nm and about 90 nm, between about 50 nm and about 85 nm, between about 50 nm and about 80 nm, between about 50 nm and about 75 nm, between about 50 nm and about 70 nm, or between about 50 nm and about 65 nm.

[0310] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP in the pharmaceutical composition is between about 55 nm and about 200 nm, between about 55 nm and about 190 nm, between about 55 nm and about 180 nm, between about 55 nm and about 170 nm, between about 55 nm and about 160 nm, between about 55 nm and about 150 nm, between about 55 nm and about 140 nm, between about 55 nm and about 130 nm, between about 55 nm and about 120 nm, between about 55 nm and about 110 nm, between about 55 nm and about 100 nm, between about 55 nm and about 95 nm, between about 55 nm and about 90 nm, between about 55 nm and about 85 nm, between about 55 nm and about 80 nm, between about 55 nm and about 75 nm, between about 55 nm and about 70 nm, or between about 55 nm and about 65 nm.

[0311] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP in the pharmaceutical composition is between about 60 nm and about 200 nm, between about 60 nm and about 190 nm, between about 60 nm and about 180 nm, between about 60 nm and about 170 nm, between about 60 nm and about 160 nm, between about 60 nm and about 150 nm, between about 60 nm and about 140 nm, between about 60 nm and about 130 nm, between about 60 nm and about 120 nm, between about 60 nm and about 110 nm, between about 60 nm and about 100 nm, between about 60 nm and about 95 nm, between about 60 nm and about 90 nm, between about 60 nm and about 85 nm, between about 60 nm and about 80 nm, between about 60 nm and about 75 nm, between about 60 nm and about 70 nm, or between about 60 nm and about 65 nm.

[0312] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP in the pharmaceutical composition is between about 65 nm and about 200 nm, between about 65 nm and about 190 nm, between about 65 nm and about 180 nm, between about 65 nm and about 170 nm, between about 65 nm and about 160 nm, between about 65 nm and about 150 nm, between about 65 nm and about 140 nm, between about 65 nm and about 130 nm, between about 65 nm 84 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) and about 120 nm, between about 65 nm and about 110 nm, between about 65 nm and about 100 nm, between about 65 nm and about 95 nm, between about 65 nm and about 90 nm, between about 65 nm and about 85 nm, between about 65 nm and about 80 nm, between about 65 nm and about 75 nm, or between about 65 nm and about 70 nm.

[0313] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP in the pharmaceutical composition is between 30 nm and 200 nm, between 30 nm and 190 nm, between 30 nm and 180 nm, between 30 nm and 170 nm, between 30 nm and 160 nm, between 30 nm and 150 nm, between 30 nm and 140 nm, between 30 nm and 130 nm, between 30 nm and 120 nm, between 30 nm and 110 nm, between 30 nm and 100 nm, between 30 nm and 95 nm, between 30 nm and 90 nm, between 30 nm and 85 nm, between 30 nm and 80 nm, between 30 nm and 75 nm, between 30 nm and 70 nm, or between 30 nm and 65 nm.

[0314] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP in the pharmaceutical composition is between 40 nm and 200 nm, between 40 nm and 190 nm, between 40 nm and 180 nm, between 40 nm and 170 nm, between 40 nm and 160 nm, between 40 nm and 150 nm, between 40 nm and 140 nm, between 40 nm and 130 nm, between 40 nm and 120 nm, between 40 nm and 110 nm, between 40 nm and 100 nm, between 40 nm and 95 nm, between 40 nm and 90 nm, between 40 nm and 85 nm, between 40 nm and 80 nm, between 40 nm and 75 nm, between 40 nm and 70 nm, or between 40 nm and 65 nm.

[0315] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP in the pharmaceutical composition is between 50 nm and 200 nm, between 50 nm and 190 nm, between 50 nm and 180 nm, between 50 nm and 170 nm, between 50 nm and 160 nm, between 50 nm and 150 nm, between 50 nm and 140 nm, between 50 nm and 130 nm, between 50 nm and 120 nm, between 50 nm and 110 nm, between 50 nm and 100 nm, between 50 nm and 95 nm, between 50 nm and 90 nm, between 50 nm and 85 nm, between 50 nm and 80 nm, between 50 nm and 75 nm, between 50 nm and 70 nm, or between 50 nm and 65 nm.

[0316] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP in the pharmaceutical composition is between 55 nm and 200 nm, between 55 nm and 190 nm, between 55 nm and 180 nm, between 55 nm and 170 nm, between 55 nm and 160 nm, between 55 nm and 150 nm, between 55 nm and 140 nm, between 55 nm and 130 nm, between 55 nm and 120 nm, between 55 nm and 110 nm, between 55 nm and 100 nm, between 55 nm and 95 nm, between 55 nm and 90 nm, between 55 nm and 85 nm, between 55 nm and 80 nm, between 55 nm and 75 nm, between 55 nm and 70 nm, or between 55 nm and 65 nm. 85 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0317] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP in the pharmaceutical composition is between 60 nm and 200 nm, between 60 nm and 190 nm, between 60 nm and 180 nm, between 60 nm and 170 nm, between 60 nm and 160 nm, between 60 nm and 150 nm, between 60 nm and 140 nm, between 60 nm and 130 nm, between 60 nm and 120 nm, between 60 nm and 110 nm, between 60 nm and 100 nm, between 60 nm and 95 nm, between 60 nm and 90 nm, between 60 nm and 85 nm, between 60 nm and 80 nm, between 60 nm and 75 nm, between 60 nm and 70 nm, or between 60 nm and 65 nm.

[0318] In some embodiments, the Z-average size of the nanoparticles in the population ofFNP in the pharmaceutical composition is between 65 nm and 200 nm, between 65 nm and 190 nm, between 65 nm and 180 nm, between 65 nm and 170 nm, between 65 nm and 160 nm, between 65 nm and 150 nm, between 65 nm and 140 nm, between 65 nm and 130 nm, between 65 nm and 120 nm, between 65 nm and 110 nm, between 65 nm and 100 nm, between 65 nm and 95 nm, between 65 nm and 90 nm, between 65 nm and 85 nm, between 65 nm and 80 nm, between 65 nm and 75 nm, or between 65 nm and 70 nm.

[0319] In some embodiments, the D10 of the nanoparticles in the population of FNP in thepharmaceutical composition is less than about 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, about 25 nm, about 24 nm, about 23 nm, about 22 nm, about 21 nm, or about 20 nm. In some embodiments, the D10 of the nanoparticles in the population of FNP in the pharmaceutical composition is less than 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, 25 nm, 24 nm, 23 nm, 22 nm, 21 nm, or 20 nm. In some embodiments, the D10 of the nanoparticles in the population of FNP in the pharmaceutical composition is less than about 32 nm. In some embodiments, the D10 of the nanoparticles in the population of FNP in the pharmaceutical composition is less than 32 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0320] In some embodiments, the D10 of the nanoparticles in the population of FNP in thepharmaceutical composition is greater than about 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, about 25 nm, about 24 nm, about 23 nm, about 22 nm, about 21 nm, or 86 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) about 20 nm. In some embodiments, the D10 of the nanoparticles in the population of FNP in the pharmaceutical composition is greater than 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, 25 nm, 24 nm, 23 nm, 22 nm, 21 nm, or 20 nm. In some embodiments, the D10 of the nanoparticles in the population of FNP in the pharmaceutical composition is greater than about 32 nm. In some embodiments, the D10 of the nanoparticles in the population of FNP in the pharmaceutical composition is greater than 32 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0321] In some embodiments, the D10 of the nanoparticles in a population of FNP in thepharmaceutical composition is between about 20 nm and about 45 nm, between about 25 nm and about 40 nm, or between about 30 nm and about 35 nm. In some embodiments, the D10 of the nanoparticles in a population of FNP in the pharmaceutical composition is between 20 nm and 45 nm, between 25 nm and 40 nm, or between 30 nm and 35 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0322] In some embodiments, the D10 of the nanoparticles in the population of FNP in thepharmaceutical composition is about 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, about 25 nm, about 24 nm, about 23 nm, about 22 nm, about 21 nm, or about 20 nm. In some embodiments, the D10 of the nanoparticles in the population of FNP in the pharmaceutical composition is 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, 25 nm, 24 nm, 23 nm, 22 nm, 21 nm, or 20 nm. In some embodiments, the D10 of the nanoparticles in the population of FNP in the pharmaceutical composition is about 32 nm. In some embodiments, the D10 of the nanoparticles in the population of FNP in the pharmaceutical composition is 32 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0323] In some embodiments, the D90 of the nanoparticles in the population of FNP in thepharmaceutical composition is less than about 200 nm, about 190 nm, about 180 nm, about 170 nm, about 160 nm, about 150 nm, about 149 nm, about 148 nm, about 147 nm, about 146 nm, about 145 nm, about 144 nm, about 143 nm, about 142 nm, about 141 nm, about 140 nm, about 139 nm, about 138 nm, about 137 nm, about 136 nm, about 135 nm, about 134 nm, about 133 nm, 87 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) about 132 nm, about 131 nm, about 130 nm, about 129 nm, about 128 nm, about 127 nm, about 126 nm, about 125 nm, about 124 nm, about 123 nm, about 122 nm, about 121 nm, about 120 nm, about 119 nm, about 118 nm, about 117 nm, about 116 nm, about 115 nm, about 114 nm, about 113 nm, about 112 nm, about 111 nm, about 110 nm, about 109 nm, about 108 nm, about 107 nm, about 106 nm, about 105 nm, about 104 nm, about 103 nm, about 102 nm, about 101 nm, about 100 nm, about 99 nm, about 98 nm, about 97 nm, about 96 nm, about 95 nm, about 94 nm, about 93 nm, about 92 nm, about 91 nm, about 90 nm, about 89 nm, about 88 nm, about 87 nm, about 86 nm, about 85 nm, about 84 nm, about 83 nm, about 82 nm, about 81 nm, about 80 nm, about 79 nm, about 78 nm, about 77 nm, about 76 nm, about 75 nm, about 74 nm, about 73 nm, about 72 nm, about 71 nm, or about 70 nm. In some embodiments, the D90 of the nanoparticles in the population of FNP in the pharmaceutical composition is less than 200 nm, 190 nm, 180 nm, 170 nm, 160 nm, 150 nm, 149 nm, 148 nm, 147 nm, 146 nm, 145 nm, 144 nm, 143 nm, 142 nm, 141 nm, 140 nm, 139 nm, 138 nm, 137 nm, 136 nm, 135 nm, 134 nm, 133 nm, 132 nm, 131 nm, 130 nm, 129 nm, 128 nm, 127 nm, 126 nm, 125 nm, 124 nm, 123 nm, 122 nm, 121 nm, 120 nm, 119 nm, 118 nm, 117 nm, 116 nm, 115 nm, 114 nm, 113 nm, 112 nm, 111 nm, 110 nm, 109 nm, 108 nm, 107 nm, 106 nm, 105 nm, 104 nm, 103 nm, 102 nm, 101 nm, 100 nm, 99 nm, 98 nm, 97 nm, 96 nm, 95 nm, 94 nm, 93 nm, 92 nm, 91 nm, 90 nm, 89 nm, 88 nm, 87 nm, 86 nm, 85 nm, 84 nm, 83 nm, 82 nm, 81 nm, 80 nm, 79 nm, 78 nm, 77 nm, 76 nm, 75 nm, 74 nm, 73 nm, 72 nm, 71 nm, or 70 nm. In some embodiments, the D90 of the nanoparticles in the population of FNP in the pharmaceutical composition is less than about 85 nm. In some embodiments, the D90 of the nanoparticles in the population of FNP in the pharmaceutical composition is less than 85 nm. In some embodiments, the D90 is D90(i), D90(v), or D90(n). In some embodiments, the D90 is D90(i).

[0324] In some embodiments, the D90 of the nanoparticles in a population of FNP in thepharmaceutical composition is between about 70 nm and about 200 nm, between about 70 nm and about 150 nm, between about 75 nm and about 100 nm, or between about 80 nm and about 90 nm. In some embodiments, the D90 of the nanoparticles in a population of FNP in the pharmaceutical composition is between 70 nm and 200 nm, between 70 nm and 150 nm, between 75 nm and 100 nm, or between 80 nm and 90 nm. In some embodiments, the D90 is D90(i), D90(v), or D90(n). In some embodiments, the D90 is D90(i).

[0325] In some embodiments, the D90 of the nanoparticles in the population of FNP in thepharmaceutical composition is about 200 nm, about 190 nm, about 180 nm, about 170 nm, about 88 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 160 nm, about 150 nm, about 149 nm, about 148 nm, about 147 nm, about 146 nm, about 145 nm, about 144 nm, about 143 nm, about 142 nm, about 141 nm, about 140 nm, about 139 nm, about 138 nm, about 137 nm, about 136 nm, about 135 nm, about 134 nm, about 133 nm, about 132 nm, about 131 nm, about 130 nm, about 129 nm, about 128 nm, about 127 nm, about 126 nm, about 125 nm, about 124 nm, about 123 nm, about 122 nm, about 121 nm, about 120 nm, about 119 nm, about 118 nm, about 117 nm, about 116 nm, about 115 nm, about 114 nm, about 113 nm, about 112 nm, about 111 nm, about 110 nm, about 109 nm, about 108 nm, about 107 nm, about 106 nm, about 105 nm, about 104 nm, about 103 nm, about 102 nm, about 101 nm, about 100 nm, about 99 nm, about 98 nm, about 97 nm, about 96 nm, about 95 nm, about 94 nm, about 93 nm, about 92 nm, about 91 nm, about 90 nm, about 89 nm, about 88 nm, about 87 nm, about 86 nm, about 85 nm, about 84 nm, about 83 nm, about 82 nm, about 81 nm, about 80 nm, about 79 nm, about 78 nm, about 77 nm, about 76 nm, about 75 nm, about 74 nm, about 73 nm, about 72 nm, about 71 nm, or about 70 nm. In some embodiments, the D90 of the nanoparticles in the population of FNP in the pharmaceutical composition is 200 nm, 190 nm, 180 nm, 170 nm, 160 nm, 150 nm, 149 nm, 148 nm, 147 nm, 146 nm, 145 nm, 144 nm, 143 nm, 142 nm, 141 nm, 140 nm, 139 nm, 138 nm, 137 nm, 136 nm, 135 nm, 134 nm, 133 nm, 132 nm, 131 nm, 130 nm, 129 nm, 128 nm, 127 nm, 126 nm, 125 nm, 124 nm, 123 nm, 122 nm, 121 nm, 120 nm, 119 nm, 118 nm, 117 nm, 116 nm, 115 nm, 114 nm, 113 nm, 112 nm, 111 nm, 110 nm, 109 nm, 108 nm, 107 nm, 106 nm, 105 nm, 104 nm, 103 nm, 102 nm, 101 nm, 100 nm, 99 nm, 98 nm, 97 nm, 96 nm, 95 nm, 94 nm, 93 nm, 92 nm, 91 nm, 90 nm, 89 nm, 88 nm, 87 nm, 86 nm, 85 nm, 84 nm, 83 nm, 82 nm, 81 nm, 80 nm, 79 nm, 78 nm, 77 nm, 76 nm, 75 nm, 74 nm, 73 nm, 72 nm, 71 nm, or 70 nm. In some embodiments, the D90 of the nanoparticles in the population of FNP in the pharmaceutical composition is about 85 nm. In some embodiments, the D90 of the nanoparticles in the population of FNP in the pharmaceutical composition is 85 nm. In some embodiments, the D90 is D90(i), D90(v), or D90(n). In some embodiments, the D90 is D90(i).

[0326] In some embodiments, the Z-average size of the FNP in the population of FNP inthe pharmaceutical composition is about 200 nm or less. In some embodiments, the Z-average size of the FNP in the population of FNP in the pharmaceutical composition is about 190 nm or less, about 180 nm or less, about 170 nm or less, about 160 nm or less, about 150 nm or less, about 140 nm or less, about 130 nm or less, about 120 nm or less, about 110 nm or less, about 100 nm or less, about 95 nm or less, about 90 nm or less, about 85 nm or less, about 80 nm or less, about 75 nm or less, about 70 nm or less, about 65 nm or less, about 60 nm or less, about 55 nm or less, 89 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) about 50 nm or less, about 45 nm or less, about 40 nm or less, about 35 nm or less, about 30 nm or less, or about 25 nm or less.

[0327] In some embodiments, the Z-average size of the FNP in the population of FNP inthe pharmaceutical composition is 200 nm or less. In some embodiments, the Z-average size of the FNP in the population of FNP in the pharmaceutical composition is 190 nm or less, 180 nm or less, 170 nm or less, 160 nm or less, 150 nm or less, 140 nm or less, 130 nm or less, 120 nm or less, 110 nm or less, 100 nm or less, 95 nm or less, 90 nm or less, 85 nm or less, 80 nm or less, 75 nm or less, 70 nm or less, 65 nm or less, 60 nm or less, 55 nm or less, 50 nm or less, 45 nm or less, 40 nm or less, 35 nm or less, 30 nm or less, or 25 nm or less.

[0328] In some embodiments, the Z-average size of the FNP in the population of FNP inthe pharmaceutical composition is about 200 nm, about 190 nm, about 180 nm, about 170 nm, about 160 nm, about 150 nm, about 140 nm, about 130 nm, about 120 nm, about 110 nm, about 100 nm, about 99 nm, about 98 nm, about 97 nm, about 96 nm, about 95 nm, about 94 nm, about 93 nm, about 92 nm, about 91 nm, about 90 nm, about 89 nm, about 88 nm, about 87 nm, about 86 nm, about 85 nm, about 84 nm, about 83 nm, about 82 nm, about 81 nm, about 80 nm, about 79 nm, about 78 nm, about 77 nm, about 76 nm, about 75 nm, about 74 nm, about 73 nm, about 72 nm, about 71 nm, about 70 nm, about 69 nm, about 68 nm, about 67 nm, about 66 nm, about 65 nm, about 64 nm, about 63 nm, about 62 nm, about 61 nm, about 60 nm, about 59 nm, about 58 nm, about 57 nm, about 56 nm, about 55 nm, about 54 nm, about 53 nm, about 52 nm, about 51 nm, about 50 nm, about 49 nm, about 48 nm, about 47 nm, about 46 nm, about 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, or about 25 nm.

[0329] In some embodiments, the Z-average size of the FNP in the population of FNP inthe pharmaceutical composition is 200 nm, 190 nm, 180 nm, 170 nm, 160 nm, 150 nm, 140 nm, 130 nm, 120 nm, 110 nm, 100 nm, 99 nm, 98 nm, 97 nm, 96 nm, 95 nm, 94 nm, 93 nm, 92 nm, 91 nm, 90 nm, 89 nm, 88 nm, 87 nm, 86 nm, 85 nm, 84 nm, 83 nm, 82 nm, 81 nm, 80 nm, 79 nm, 78 nm, 77 nm, 76 nm, 75 nm, 74 nm, 73 nm, 72 nm, 71 nm, 70 nm, 69 nm, 68 nm, 67 nm, 66 nm, 65 nm, 64 nm, 63 nm, 62 nm, 61 nm, 60 nm, 59 nm, 58 nm, 57 nm, 56 nm, 55 nm, 54 nm, 53 nm, 52 nm, 51 nm, 50 nm, 49 nm, 48 nm, 47 nm, 46 nm, 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, or 25 nm. 90 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0330] In some embodiments, the Z-average size of the FNP in the population of FNP inthe pharmaceutical composition is between about 30 nm and about 200 nm, between about 30 nm and about 190 nm, between about 30 nm and about 180 nm, between about 30 nm and about 170 nm, between about 30 nm and about 160 nm, between about 30 nm and about 150 nm, between about 30 nm and about 140 nm, between about 30 nm and about 130 nm, between about 30 nm and about 120 nm, between about 30 nm and about 110 nm, between about 30 nm and about 100 nm, between about 30 nm and about 95 nm, between about 30 nm and about 90 nm, between about 30 nm and about 85 nm, between about 30 nm and about 80 nm, between about 30 nm and about 75 nm, between about 30 nm and about 70 nm, or between about 30 nm and about 65 nm.

[0331] In some embodiments, the Z-average size of the FNP in the population of FNP inthe pharmaceutical composition is between about 40 nm and about 200 nm, between about 40 nm and about 190 nm, between about 40 nm and about 180 nm, between about 40 nm and about 170 nm, between about 40 nm and about 160 nm, between about 40 nm and about 150 nm, between about 40 nm and about 140 nm, between about 40 nm and about 130 nm, between about 40 nm and about 120 nm, between about 40 nm and about 110 nm, between about 40 nm and about 100 nm, between about 40 nm and about 95 nm, between about 40 nm and about 90 nm, between about 40 nm and about 85 nm, between about 40 nm and about 80 nm, between about 40 nm and about 75 nm, between about 40 nm and about 70 nm, or between about 40 nm and about 65 nm.

[0332] In some embodiments, the Z-average size of the FNP in the population of FNP inthe pharmaceutical composition is between about 50 nm and about 200 nm, between about 50 nm and about 190 nm, between about 50 nm and about 180 nm, between about 50 nm and about 170 nm, between about 50 nm and about 160 nm, between about 50 nm and about 150 nm, between about 50 nm and about 140 nm, between about 50 nm and about 130 nm, between about 50 nm and about 120 nm, between about 50 nm and about 110 nm, between about 50 nm and about 100 nm, between about 50 nm and about 95 nm, between about 50 nm and about 90 nm, between about 50 nm and about 85 nm, between about 50 nm and about 80 nm, between about 50 nm and about 75 nm, between about 50 nm and about 70 nm, or between about 50 nm and about 65 nm.

[0333] In some embodiments, the Z-average size of the FNP in the population of FNP inthe pharmaceutical composition is between about 55 nm and about 200 nm, between about 55 nm and about 190 nm, between about 55 nm and about 180 nm, between about 55 nm and about 170 nm, between about 55 nm and about 160 nm, between about 55 nm and about 150 nm, between about 55 nm and about 140 nm, between about 55 nm and about 130 nm, between about 55 nm 91 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) and about 120 nm, between about 55 nm and about 110 nm, between about 55 nm and about 100 nm, between about 55 nm and about 95 nm, between about 55 nm and about 90 nm, between about 55 nm and about 85 nm, between about 55 nm and about 80 nm, between about 55 nm and about 75 nm, between about 55 nm and about 70 nm, or between about 55 nm and about 65 nm.

[0334] In some embodiments, the Z-average size of the FNP in the population of FNP inthe pharmaceutical composition is between about 60 nm and about 200 nm, between about 60 nm and about 190 nm, between about 60 nm and about 180 nm, between about 60 nm and about 170 nm, between about 60 nm and about 160 nm, between about 60 nm and about 150 nm, between about 60 nm and about 140 nm, between about 60 nm and about 130 nm, between about 60 nm and about 120 nm, between about 60 nm and about 110 nm, between about 60 nm and about 100 nm, between about 60 nm and about 95 nm, between about 60 nm and about 90 nm, between about 60 nm and about 85 nm, between about 60 nm and about 80 nm, between about 60 nm and about 75 nm, between about 60 nm and about 70 nm, or between about 60 nm and about 65 nm.

[0335] In some embodiments, the Z-average size of the FNP in the population of FNP inthe pharmaceutical composition is between about 65 nm and about 200 nm, between about 65 nm and about 190 nm, between about 65 nm and about 180 nm, between about 65 nm and about 170 nm, between about 65 nm and about 160 nm, between about 65 nm and about 150 nm, between about 65 nm and about 140 nm, between about 65 nm and about 130 nm, between about 65 nm and about 120 nm, between about 65 nm and about 110 nm, between about 65 nm and about 100 nm, between about 65 nm and about 95 nm, between about 65 nm and about 90 nm, between about 65 nm and about 85 nm, between about 65 nm and about 80 nm, between about 65 nm and about 75 nm, or between about 65 nm and about 70 nm.

[0336] In some embodiments, the Z-average size of the FNP in the population of FNP inthe pharmaceutical composition is between 30 nm and 200 nm, between 30 nm and 190 nm, between 30 nm and 180 nm, between 30 nm and 170 nm, between 30 nm and 160 nm, between 30 nm and 150 nm, between 30 nm and 140 nm, between 30 nm and 130 nm, between 30 nm and 120 nm, between 30 nm and 110 nm, between 30 nm and 100 nm, between 30 nm and 95 nm, between 30 nm and 90 nm, between 30 nm and 85 nm, between 30 nm and 80 nm, between 30 nm and 75 nm, between 30 nm and 70 nm, or between 30 nm and 65 nm.

[0337] In some embodiments, the Z-average size of the FNP in the population of FNP inthe pharmaceutical composition is between 40 nm and 200 nm, between 40 nm and 190 nm, between 40 nm and 180 nm, between 40 nm and 170 nm, between 40 nm and 160 nm, between 40 92 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) nm and 150 nm, between 40 nm and 140 nm, between 40 nm and 130 nm, between 40 nm and 120 nm, between 40 nm and 110 nm, between 40 nm and 100 nm, between 40 nm and 95 nm, between 40 nm and 90 nm, between 40 nm and 85 nm, between 40 nm and 80 nm, between 40 nm and 75 nm, between 40 nm and 70 nm, or between 40 nm and 65 nm.

[0338] In some embodiments, the Z-average size of the FNP in the population of FNP inthe pharmaceutical composition is between 50 nm and 200 nm, between 50 nm and 190 nm, between 50 nm and 180 nm, between 50 nm and 170 nm, between 50 nm and 160 nm, between 50 nm and 150 nm, between 50 nm and 140 nm, between 50 nm and 130 nm, between 50 nm and 120 nm, between 50 nm and 110 nm, between 50 nm and 100 nm, between 50 nm and 95 nm, between 50 nm and 90 nm, between 50 nm and 85 nm, between 50 nm and 80 nm, between 50 nm and 75 nm, between 50 nm and 70 nm, or between 50 nm and 65 nm.

[0339] In some embodiments, the Z-average size of the FNP in the population of FNP inthe pharmaceutical composition is between 55 nm and 200 nm, between 55 nm and 190 nm, between 55 nm and 180 nm, between 55 nm and 170 nm, between 55 nm and 160 nm, between 55 nm and 150 nm, between 55 nm and 140 nm, between 55 nm and 130 nm, between 55 nm and 120 nm, between 55 nm and 110 nm, between 55 nm and 100 nm, between 55 nm and 95 nm, between 55 nm and 90 nm, between 55 nm and 85 nm, between 55 nm and 80 nm, between 55 nm and 75 nm, between 55 nm and 70 nm, or between 55 nm and 65 nm.

[0340] In some embodiments, the Z-average size of the FNP in the population of FNP inthe pharmaceutical composition is between 60 nm and 200 nm, between 60 nm and 190 nm, between 60 nm and 180 nm, between 60 nm and 170 nm, between 60 nm and 160 nm, between 60 nm and 150 nm, between 60 nm and 140 nm, between 60 nm and 130 nm, between 60 nm and 120 nm, between 60 nm and 110 nm, between 60 nm and 100 nm, between 60 nm and 95 nm, between 60 nm and 90 nm, between 60 nm and 85 nm, between 60 nm and 80 nm, between 60 nm and 75 nm, between 60 nm and 70 nm, or between 60 nm and 65 nm.

[0341] In some embodiments, the Z-average size of the FNP in the population of FNP inthe pharmaceutical composition is between 65 nm and 200 nm, between 65 nm and 190 nm, between 65 nm and 180 nm, between 65 nm and 170 nm, between 65 nm and 160 nm, between 65 nm and 150 nm, between 65 nm and 140 nm, between 65 nm and 130 nm, between 65 nm and 120 nm, between 65 nm and 110 nm, between 65 nm and 100 nm, between 65 nm and 95 nm, between 65 nm and 90 nm, between 65 nm and 85 nm, between 65 nm and 80 nm, between 65 nm and 75 nm, or between 65 nm and 70 nm. 93 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0342] In some embodiments, the D10 of the FNP in the population of FNP in thepharmaceutical composition is less than about 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, about 25 nm, about 24 nm, about 23 nm, about 22 nm, about 21 nm, or about 20 nm. In some embodiments, the D10 of the FNP in the population of FNP in the pharmaceutical composition is less than 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, 25 nm, 24 nm, 23 nm, 22 nm, 21 nm, or 20 nm. In some embodiments, the D10 of the FNP in the population of FNP in the pharmaceutical composition is less than about 39 nm. In some embodiments, the D10 of the FNP in the population of FNP in the pharmaceutical composition is less than 39 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0343] In some embodiments, the D10 of the FNP in the population of FNP in thepharmaceutical composition is greater than about 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, about 25 nm, about 24 nm, about 23 nm, about 22 nm, about 21 nm, or about 20 nm. In some embodiments, the D10 of the FNP in the population of FNP in the pharmaceutical composition is greater than 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, 25 nm, 24 nm, 23 nm, 22 nm, 21 nm, or 20 nm. In some embodiments, the D10 of the FNP in the population of FNP in the pharmaceutical composition is greater than about 39 nm. In some embodiments, the D10 of the FNP in the population of FNP in the pharmaceutical composition is greater than 39 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0344] In some embodiments, the D10 of the FNP in a population of FNP in thepharmaceutical composition is between about 20 nm and about 45 nm, between about 25 nm and about 40 nm, or between about 35 nm and about 40 nm. In some embodiments, the D10 of the FNP in a population of FNP in the pharmaceutical composition is between 20 nm and 45 nm, between 25 nm and 40 nm, or between 35 nm and 40 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i). BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0345] In some embodiments, the D10 of the FNP in the population of FNP in thepharmaceutical composition is about 45 nm, about 44 nm, about 43 nm, about 42 nm, about 41 nm, about 40 nm, about 39 nm, about 38 nm, about 37 nm, about 36 nm, about 35 nm, about 34 nm, about 33 nm, about 32 nm, about 31 nm, about 30 nm, about 29 nm, about 28 nm, about 27 nm, about 26 nm, about 25 nm, about 24 nm, about 23 nm, about 22 nm, about 21 nm, or about 20 nm. In some embodiments, the D10 of the FNP in the population of FNP in the pharmaceutical composition is 45 nm, 44 nm, 43 nm, 42 nm, 41 nm, 40 nm, 39 nm, 38 nm, 37 nm, 36 nm, 35 nm, 34 nm, 33 nm, 32 nm, 31 nm, 30 nm, 29 nm, 28 nm, 27 nm, 26 nm, 25 nm, 24 nm, 23 nm, 22 nm, 21 nm, or 20 nm. In some embodiments, the D10 of the FNP in the population of FNP in the pharmaceutical composition is about 39 nm. In some embodiments, the D10 of the FNP in the population of FNP in the pharmaceutical composition is 39 nm. In some embodiments, the D10 is D10(i), D10(v), or D10(n). In some embodiments, the D10 is D10(i).

[0346] In some embodiments, the D90 of the FNP in the population of FNP in thepharmaceutical composition is less than about 200 nm, about 190 nm, about 180 nm, about 170 nm, about 160 nm, about 150 nm, about 149 nm, about 148 nm, about 147 nm, about 146 nm, about 145 nm, about 144 nm, about 143 nm, about 142 nm, about 141 nm, about 140 nm, about 139 nm, about 138 nm, about 137 nm, about 136 nm, about 135 nm, about 134 nm, about 133 nm, about 132 nm, about 131 nm, about 130 nm, about 129 nm, about 128 nm, about 127 nm, about 126 nm, about 125 nm, about 124 nm, about 123 nm, about 122 nm, about 121 nm, about 120 nm, about 119 nm, about 118 nm, about 117 nm, about 116 nm, about 115 nm, about 114 nm, about 113 nm, about 112 nm, about 111 nm, about 110 nm, about 109 nm, about 108 nm, about 107 nm, about 106 nm, about 105 nm, about 104 nm, about 103 nm, about 102 nm, about 101 nm, about 100 nm, about 99 nm, about 98 nm, about 97 nm, about 96 nm, about 95 nm, about 94 nm, about 93 nm, about 92 nm, about 91 nm, about 90 nm, about 89 nm, about 88 nm, about 87 nm, about 86 nm, about 85 nm, about 84 nm, about 83 nm, about 82 nm, about 81 nm, about 80 nm, about 79 nm, about 78 nm, about 77 nm, about 76 nm, about 75 nm, about 74 nm, about 73 nm, about 72 nm, about 71 nm, or about 70 nm. In some embodiments, the D90 of the FNP in the population of FNP in the pharmaceutical composition is less than 200 nm, 190 nm, 180 nm, 170 nm, 160 nm, 150 nm, 149 nm, 148 nm, 147 nm, 146 nm, 145 nm, 144 nm, 143 nm, 142 nm, 141 nm, 140 nm, 139 nm, 138 nm, 137 nm, 136 nm, 135 nm, 134 nm, 133 nm, 132 nm, 131 nm, 130 nm, 129 nm, 128 nm, 127 nm, 126 nm, 125 nm, 124 nm, 123 nm, 122 nm, 121 nm, 120 nm, 119 nm, 118 nm, 117 nm, 116 nm, 115 nm, 114 nm, 113 nm, 112 nm, 111 nm, 110 nm, 109 nm, 108 nm, 107 nm, 95 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 106 nm, 105 nm, 104 nm, 103 nm, 102 nm, 101 nm, 100 nm, 99 nm, 98 nm, 97 nm, 96 nm, 95 nm, 94 nm, 93 nm, 92 nm, 91 nm, 90 nm, 89 nm, 88 nm, 87 nm, 86 nm, 85 nm, 84 nm, 83 nm, 82 nm, 81 nm, 80 nm, 79 nm, 78 nm, 77 nm, 76 nm, 75 nm, 74 nm, 73 nm, 72 nm, 71 nm, or 70 nm. In some embodiments, the D90 of the FNP in the population of FNP in the pharmaceutical composition is less than about 113 nm. In some embodiments, the D90 of the FNP in the population of FNP in the pharmaceutical composition is less than 113 nm. In some embodiments, the D90 is D90(i), D90(v), or D90(n). In some embodiments, the D90 is D90(i).

[0347] In some embodiments, the D90 of the FNP in a population of FNP in thepharmaceutical composition is between about 70 nm and about 200 nm, between about 75 nm and about 150 nm, between about 80 nm and about 130 nm, between about 90 nm and about 125 nm, or between about 110 nm and about 120 nm. In some embodiments, the D90 of the FNP in a population of FNP in the pharmaceutical composition is between 70 nm and 200 nm, between 75 nm and 150 nm, between 80 nm and 130 nm, between 90 nm and 125 nm, or between 110 nm and 120 nm. In some embodiments, the D90 is D90(i), D90(v), or D90(n). In some embodiments, the D90 is D90(i).

[0348] In some embodiments, the D90 of the FNP in the population of FNP in thepharmaceutical composition is about 200 nm, about 190 nm, about 180 nm, about 170 nm, about 160 nm, about 150 nm, about 149 nm, about 148 nm, about 147 nm, about 146 nm, about 145 nm, about 144 nm, about 143 nm, about 142 nm, about 141 nm, about 140 nm, about 139 nm, about 138 nm, about 137 nm, about 136 nm, about 135 nm, about 134 nm, about 133 nm, about 132 nm, about 131 nm, about 130 nm, about 129 nm, about 128 nm, about 127 nm, about 126 nm, about 125 nm, about 124 nm, about 123 nm, about 122 nm, about 121 nm, about 120 nm, about 119 nm, about 118 nm, about 117 nm, about 116 nm, about 115 nm, about 114 nm, about 113 nm, about 112 nm, about 111 nm, about 110 nm, about 109 nm, about 108 nm, about 107 nm, about 106 nm, about 105 nm, about 104 nm, about 103 nm, about 102 nm, about 101 nm, about 100 nm, about 99 nm, about 98 nm, about 97 nm, about 96 nm, about 95 nm, about 94 nm, about 93 nm, about 92 nm, about 91 nm, about 90 nm, about 89 nm, about 88 nm, about 87 nm, about 86 nm, about 85 nm, about 84 nm, about 83 nm, about 82 nm, about 81 nm, about 80 nm, about 79 nm, about 78 nm, about 77 nm, about 76 nm, about 75 nm, about 74 nm, about 73 nm, about 72 nm, about 71 nm, or about 70 nm. In some embodiments, the D90 of the FNP in the population of FNP in the pharmaceutical composition is 200 nm, 190 nm, 180 nm, 170 nm, 160 nm, 150 nm, 149 nm, 148 nm, 147 nm, 146 nm, 145 nm, 144 nm, 143 nm, 142 nm, 141 nm, 140 nm, 139 nm, 138 nm, 137 96 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) nm, 136 nm, 135 nm, 134 nm, 133 nm, 132 nm, 131 nm, 130 nm, 129 nm, 128 nm, 127 nm, 126 nm, 125 nm, 124 nm, 123 nm, 122 nm, 121 nm, 120 nm, 119 nm, 118 nm, 117 nm, 116 nm, 115 nm, 114 nm, 113 nm, 112 nm, 111 nm, 110 nm, 109 nm, 108 nm, 107 nm, 106 nm, 105 nm, 104 nm, 103 nm, 102 nm, 101 nm, 100 nm, 99 nm, 98 nm, 97 nm, 96 nm, 95 nm, 94 nm, 93 nm, 92 nm, 91 nm, 90 nm, 89 nm, 88 nm, 87 nm, 86 nm, 85 nm, 84 nm, 83 nm, 82 nm, 81 nm, 80 nm, 79 nm, 78 nm, 77 nm, 76 nm, 75 nm, 74 nm, 73 nm, 72 nm, 71 nm, or 70 nm. In some embodiments, the D90 of the FNP in the population of FNP in the pharmaceutical composition is about 113 nm. In some embodiments, the D90 of the FNP in the population of FNP in the pharmaceutical composition is 113 nm. In some embodiments, the D90 is D90(i), D90(v), or D90(n). In some embodiments, the D90 is D90(i).

[0349] In some embodiments, the pharmaceutical composition comprises a population ofFNP and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as dextrose, sucrose, mannitol, trehalose (e.g., trehalose dihydrate) or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEENTM, PLURONICSTM, or polyethylene glycol (PEG).

[0350] Pharmaceutically acceptable excipients include carriers used in parenteralpreparations such as aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents, and other pharmaceutically acceptable substances. Examples of aqueous vehicles include Sodium Chloride Injection, Ringer’s Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose, and Lactated Ringer’s Injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations can be added to 97 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) parenteral preparations packaged in multiple-dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN® 80). A sequestering or chelating agent of metal ions includes EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol, and propylene glycol for water miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0351] A pharmaceutical composition may be formulated for any route of administrationto a subject. Specific examples of routes of administration include intranasal, oral, pulmonary, transdermal, intradermal, and parenteral (e.g., intravenous injection). Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. The injectables, solutions, and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol, or ethanol. In addition, if desired, the pharmaceutical compositions to be administered can also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins.

[0352] Preparations for parenteral administration include sterile solutions ready forinjection, sterile dry soluble products, such as lyophilized materials, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use, and sterile emulsions. The solutions may be either aqueous or nonaqueous.

[0353] If administered intravenously, suitable carriers include physiological saline orphosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, polypropylene glycol, and mixtures thereof.

[0354] In some embodiments, the pharmaceutically acceptable excipient is acryoprotectant.

[0355] For each concentration or range of concentrations provided in % w / v herein, thecorresponding concentration in mg / mL is also encompassed by the disclosure. Similarly, for each 98 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) concentration or range of concentrations provided in mg / mL herein, the corresponding concentration in % w / v is also encompassed by the disclosure. The % w / v can be calculated as g of solute / 100 mL of solution.

[0356] In some embodiments, the pharmaceutical composition comprises a population ofFNP at a concentration from about 0.1% to about 10%, from about 0.5% to about 5%, from about 1% to about 3%, from about 1.5% to about 2.5%, or from about 1.6% to about 2.2% w / v. In some embodiments, the pharmaceutical composition comprises a population of FNP at a concentration from 0.1% to 10%, from 0.5% to 5%, from 1% to 3%, from 1.5% to 2.5% w / v, or from 1.6% to 2.2% w / v.

[0357] In some embodiments, the pharmaceutical composition comprises a population ofFNP at a concentration of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7% about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.2%, about 3.4%, about 3.6%, about 3.8%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% w / v.

[0358] In some embodiments, the pharmaceutical composition comprises a population ofFNP at a concentration of 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7% 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.2%, 3.4%, 3.6%, 3.8%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% w / v.

[0359] In some embodiments, the pharmaceutical composition comprises a population ofFNP in an amount from about 5 mg / mL to about 50 mg / mL, from about 10 mg / mL to about 30 mg / mL, or from about 15 mg / mL to about 25 mg / mL.

[0360] In some embodiments, the pharmaceutical composition comprises polyphosphatepolymer in an amount from about 1 mg / mL to about 20 mg / mL, from about 2 mg / mL to about 10 mg / mL, or from about 3 mg / mL to about 5 mg / mL.

[0361] In some embodiments, the pharmaceutical composition comprises a population ofsilica nanoparticles (SNP) in an amount from about 4 mg / mL to about 40 mg / mL, from about 10 mg / mL to about 30 mg / mL, or from about 15 mg / mL to about 20 mg / mL. 99 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0362] In some embodiments, the pharmaceutical composition comprises a population ofFNP in an amount from 5 mg / mL to 50 mg / mL, from 10 mg / mL to 30 mg / mL, or from 15 mg / mL to 25 mg / mL.

[0363] In some embodiments, the pharmaceutical composition comprises polyphosphatepolymer in an amount from 1 mg / mL to 20 mg / mL, from 2 mg / mL to 10 mg / mL, or from 3 mg / mL to 5 mg / mL.

[0364] In some embodiments, the pharmaceutical composition comprises a population ofSNP in an amount from 4 mg / mL to 40 mg / mL, from 10 mg / mL to 30 mg / mL, or from 15 mg / mL to 20 mg / mL.

[0365] In some embodiments, the pharmaceutical composition comprises a population ofFNP at a concentration of about 5 mg / mL, about 7.5 mg / mL, about 10 mg / mL, about 12.5 mg / mL, about 15 mg / mL, about 17.5 mg / mL, about 20 mg / mL, about 22.5 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, or about 50 mg / mL.

[0366] In some embodiments, the pharmaceutical composition comprises polyphosphatepolymer at a concentration of about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, or about 20 mg / mL.

[0367] In some embodiments, the pharmaceutical composition comprises a population ofSNP at a concentration of about 4 mg / mL, about 6 mg / mL, about 8 mg / mL, about 10 mg / mL, about 12 mg / mL, about 14 mg / mL, about 16 mg / mL, about 18 mg / mL, about 20 mg / mL, about 22 mg / mL, about 24 mg / mL, about 26 mg / mL, about 28 mg / mL, about 30 mg / mL, about 32 mg / mL, about 32 mg / mL, about 34 mg / mL, about 36 mg / mL, about 38 mg / mL, or about 40 mg / mL.

[0368] In some embodiments, the pharmaceutical composition comprises a population ofFNP at a concentration of 5 mg / mL, 7.5 mg / mL, 10 mg / mL, 12.5 mg / mL, 15 mg / mL, 17.5 mg / mL, 20 mg / mL, 22.5 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, or 50 mg / mL.

[0369] In some embodiments, the pharmaceutical composition comprises polyphosphatepolymer at a concentration of 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, or 20 mg / mL.

[0370] In some embodiments, the pharmaceutical composition comprises a population ofSNP at a concentration of 4 mg / mL, 6 mg / mL, 8 mg / mL, 10 mg / mL, 12 mg / mL, 14 mg / mL, 16 100 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) mg / mL, 18 mg / mL, 20 mg / mL, 22 mg / mL, 24 mg / mL, 26 mg / mL, 28 mg / mL, 30 mg / mL, 32 mg / mL, 34 mg / mL, 36 mg / mL, 38 mg / mL, or 40 mg / mL.

[0371] In some embodiments, the pharmaceutical composition comprises about 4 mg / mLpolyphosphate polymer and about 16 mg / mL SNP. In some embodiments, the pharmaceutical composition comprises 4 mg / mL polyphosphate polymer and 16 mg / mL SNP. In some embodiments, the polyphosphate polymer and SNP are present in the pharmaceutical composition as a population of FNP. In some embodiments, the percentage of the total polyphosphate polymer mass in the pharmaceutical composition that exists as free polyphosphate polymers (i.e., (mass of free polyphosphate polymers in the pharmaceutical composition / mass of total polyphosphate polymers in the pharmaceutical composition) × 100%) is no more than about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1%. In some embodiments, the percentage of the total polyphosphate polymers in the pharmaceutical composition that exist as free polyphosphate polymers is no more than 55%, 50%, 45%, 40%, 45%, 30%, 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.

[0372] In certain embodiments, the pharmaceutical composition comprises a population ofFNP and at least one cryoprotectant.

[0373] In some embodiments, the cryoprotectant is an amino acid, a sugar, or a sugaralcohol. In some embodiments, the cryoprotectant is a combination of at least one amino acid and at least one sugar or sugar alcohol. In some embodiments, the amino acid is selected from the group consisting of glycine, phenylalanine, leucine, and isoleucine. In some embodiments, the sugar or sugar alcohol is selected from the group consisting of dextrose, trehalose (e.g., trehalose dihydrate), sucrose, mannitol, galactose, sorbitol, lactose, glycerol, maltose, and isomalt.

[0374] The at least one amino acid can be present in the pharmaceutical composition inany suitable amount. In an embodiment, the concentration of the at least one amino acid in the pharmaceutical composition is between about 0.1% and about 10%, between about 0.1% and about 5%, between about 0.2% and about 2%, or between about 0.5% and about 1% w / v. In an embodiment, the concentration of the at least one amino acid in the pharmaceutical composition is between 0.1% and 10%, between 0.1% and 5%, between 0.2% and 2%, between 0.5% and 2%, or between 0.5% and 1% w / v. In an embodiment, the concentration of the at least one amino acid 101 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) in the pharmaceutical composition is about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2.0% w / v. In an embodiment, the concentration of the at least one amino acid in the pharmaceutical composition is 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, or 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or 2.0% w / v. In some embodiments, the at least one amino acid is glycine.

[0375] In an embodiment, the concentration of the at least one amino acid in thepharmaceutical composition is between about 1 mg / mL and about 20 mg / mL, between about 2 mg / mL and about 10 mg / mL, between about 5 mg / mL and about 10 mg / mL. In an embodiment, the concentration of the at least one amino acid in the pharmaceutical composition is between 1 mg / mL and 20 mg / mL, between 2 mg / mL and 10 mg / mL, between 5 mg / mL and 10 mg / mL. In an embodiment, the concentration of the at least one amino acid in the pharmaceutical composition is about 6.5 mg / mL, about 6.6 mg / mL, about 6.7 mg / mL, about 6.8 mg / mL, about 6.9 mg / mL, about 7 mg / mL, about 7.1 mg / mL, about 7.2 mg / mL, about 7.3 mg / mL, about 7.4 mg / mL, or about 7.5 mg / mL. In an embodiment, the concentration of the at least one amino acid in the pharmaceutical composition is 6.5 mg / mL, 6.6 mg / mL, 6.7 mg / mL, 6.8 mg / mL, 6.9 mg / mL, 7 mg / mL, 7.1 mg / mL, 7.2 mg / mL, 7.3 mg / mL, 7.4 mg / mL, or 7.5 mg / mL. In some embodiments, the at least one amino acid is glycine.

[0376] The at least one sugar or sugar alcohol can be present in the pharmaceuticalcomposition in any suitable amount. In an embodiment, the concentration of the at least one sugar or sugar alcohol in the pharmaceutical composition is between about 0.1% and about 10%, between about 0.5% and about 5%, between about 1% and about 5%, or between about 3% and about 5% w / v. In an embodiment, the concentration of the at least one sugar or sugar alcohol in the pharmaceutical composition is between 0.1% and 10%, between 0.5% and 5%, between 1% and 5%, or between 3% and 5% w / v. In an embodiment, the concentration of the at least one sugar or sugar alcohol is about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% w / v. In an embodiment, the concentration of the at least one sugar or sugar alcohol is 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% w / v. In some embodiments, the at least one sugar or sugar alcohol is dextrose, 102 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) trehalose (e.g., trehalose dihydrate), sucrose, or mannitol. In some embodiments, the at least one sugar or sugar alcohol is dextrose or trehalose (e.g., trehalose dihydrate).

[0377] In some embodiments, the at least one sugar or sugar alcohol is a combination ofdextrose and trehalose (e.g., trehalose dihydrate), each of which are present in an amount listed above. In some embodiments, the dextrose is present at a concentration between about 1% and about 6%, between about 2% and about 5%, between about 2% and about 4%, between about 2.5% and about 3.5%, or between about 2.8% and about 3.2% w / v. In some embodiments, the dextrose is present at a concentration between 1% and 6%, between 2% and 5%, between 2% and 4%, between 2.5% and 3.5%, or between 2.8% and 3.2% w / v. In some embodiments, the dextrose is present at a concentration about 3% or 3% w / v. In some embodiments, the trehalose (e.g., trehalose dihydrate) is present at a concentration of between about 0.5% and about 5%, between about 3% and about 5% or between about 4% and about 5% w / v. In some embodiments, the trehalose (e.g., trehalose dihydrate) is present at a concentration of between 0.5% and 5%, between 3% and 5% or between 4% and 5% w / v. In some embodiments, the trehalose (e.g., trehalose dihydrate) is present at a concentration of about 5% or 5% w / v.

[0378] In an embodiment, the concentration of the at least one sugar or sugar alcohol inthe pharmaceutical composition is between about 1 mg / mL and about 200 mg / mL, between about 5 mg / mL and about 150 mg / mL, between about 10 mg / mL and about 100 mg / mL, or between about 20 mg / mL and about 50 mg / mL. In an embodiment, the concentration of the at least one sugar or sugar alcohol in the pharmaceutical composition is between 1 mg / mL and 200 mg / mL, between 5 mg / mL and 150 mg / mL, between 10 mg / mL and 100 mg / mL, or between 20 mg / mL and 50 mg / mL. In an embodiment, the concentration of the at least one sugar or sugar alcohol in the pharmaceutical composition is about 1, about 2.5, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, or about 200 mg / mL. In an embodiment, the concentration of the at least one sugar or sugar alcohol in the pharmaceutical composition is 1, 2.5, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg / mL. In some embodiments, the at least one sugar or sugar alcohol is dextrose, trehalose (e.g., 103 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) trehalose dihydrate), sucrose, or mannitol. In some embodiments, the at least one sugar or sugar alcohol is dextrose or trehalose (e.g., trehalose dihydrate).

[0379] In some embodiments, the at least one sugar or sugar alcohol is a combination ofdextrose and trehalose (e.g., trehalose dihydrate), each of which are present in an amount listed above. In some embodiments, the dextrose is present at a concentration between about 10 mg / mL and about 50 mg / mL, between about 20 mg / mL and about 40 mg / mL, or between about 25 mg / mL and about 35 mg / mL. In some embodiments, the dextrose is present at a concentration between 10 mg / mL and 50 mg / mL, between 20 mg / mL and 40 mg / mL, or between 25 mg / mL and 35 mg / mL. In some embodiments, the dextrose is present at a concentration of about 30 mg / mL or 30 mg / mL. In some embodiments, the trehalose (e.g., trehalose dihydrate) is present at a concentration between about 30 mg / mL and about 70 mg / mL, between about 40 mg / mL and about 60 mg / mL, or between about 45 mg / mL and about 55 mg / mL. In some embodiments, the trehalose (e.g., trehalose dihydrate) is present at a concentration between 30 mg / mL and 70 mg / mL, between 40 mg / mL and 60 mg / mL, or between 45 mg / mL and 55 mg / mL. In some embodiments, the trehalose (e.g., trehalose dihydrate) is present at a concentration of about 50 mg / mL or 50 mg / mL.

[0380] In some embodiments, the pharmaceutical composition comprises additionalexcipients, buffers, or other components, e.g., suitable for intravenous administration to a subject. In some embodiments, the pharmaceutical composition may comprise non-functionalized nanoparticles. In some embodiments, the pharmaceutical composition comprises an additional therapeutic agent, such as, for example, an additional agent, e.g., hemostatic agent.

[0381] In certain embodiments, the pharmaceutical composition is provided as alyophilized material.

[0382] In some embodiments, the lyophilized material comprises a population of FNP at aconcentration from about 5% to about 50%, from about 10% to about 25%, or from about 15% to about 20% w / w.

[0383] In some embodiments, the lyophilized material comprises polyphosphate polymerat a concentration from about 1% to about 20%, from about 2% to about 10%, or from about 3% to about 5% w / w.

[0384] In some embodiments, the lyophilized material comprises a population of SNP at aconcentration from about 2% to about 40%, from about 10% to about 25%, or from about 12% to about 16% w / w. 104 BUSINESS.33102490.1Docket No.: 410007-001WO (218613)

[0385] In some embodiments, the lyophilized material comprises a population of FNP at aconcentration from 5% to 50%, from 10% to 25%, or from 15% to 20% w / w.

[0386] In some embodiments, the lyophilized material comprises polyphosphate polymerat a concentration from 1% to 20%, from 2% to 10%, or from 3% to 5% w / w.

[0387] In some embodiments, the lyophilized material comprises a population of SNP at aconcentration from 2% to 40%, from 10% to 25%, or from 12% to 16% w / w.

[0388] In some embodiments, the lyophilized material comprises a population of FNP at aconcentration of about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 32%, about 34%, about 36%, about 38%, about 40%, about 42%, about 44%, about 46%, about 48%, or about 50% w / w. In some embodiments, the lyophilized material comprises a population of FNP at a concentration of about 18.1, about 18.2, about 18.3, about 18.4, about 18.5, about 18.6, about 18.7, about 18.8, or about 18.9% w / w.

[0389] In some embodiments, the lyophilized material comprises polyphosphate polymerat a concentration of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% w / w. In some embodiments, the lyophilized material comprises polyphosphate polymer at a concentration of about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, or about 3.9% w / w.

[0390] In some embodiments, the lyophilized material comprises a population of SNP at aconcentration of about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 32%, about 34%, about 36%, about 38%, or about 40% w / w. In some embodiments, the lyophilized material comprises a population of SNP at a concentration of about 14.1%, about 14.2%, about 14.3% about 14.4%, about 14.5%, about 14.6%, about 14.7%, about 14.8%, or about 14.9% w / w.

[0391] In some embodiments, the lyophilized material comprises a population of FNP at aconcentration of 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 46%, 48%, or 50% w / w. In some embodiments, the lyophilized material comprises a 105 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) population of FNP at a concentration of 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, or 18.9% w / w.

[0392] In some embodiments, the lyophilized material comprises polyphosphate polymerat a concentration of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% w / w. In some embodiments, the lyophilized material comprises polyphosphate polymer at a concentration of 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, or 3.9% w / w.

[0393] In some embodiments, the lyophilized material comprises a population of SNP at aconcentration of 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 32%, 34%, 36%, 38%, or 40% w / w. In some embodiments, the lyophilized material comprises a population of SNP at a concentration of 14.1%, 14.2%, 14.3% 14.4%, 14.5%, 14.6%, 14.7%, 14.8%, or 14.9% w / w.

[0394] In some embodiments, the concentration of the at least one amino acid in thelyophilized material is between about 1% and about 20%, between about 2% and about 10%, or between about 5% and about 10% w / w. In some embodiments, the concentration of the at least one amino acid in the lyophilized material is between 1% and 20%, between 2% and 10%, or between 5% and 10% w / w. In some embodiments, the concentration of the at least one amino acid in the lyophilized material is about 6.5%, about 6.6%, about 6.7%, about 6.8%, about 6.9%, about 7%, about 7.1%, about 7.2%, about 7.3%, about 7.4%, or about 7.5% w / w. In some embodiments, the concentration of the at least one amino acid in the lyophilized material is 6.5%, 6.6%, 6.7%, 6.8%, 6.9%, 7%, 7.1%, 7.2%, 7.3%, 7.4%, or 7.5% w / w. In some embodiments, the at least one amino acid is glycine.

[0395] In some embodiments, the concentration of the at least one sugar or sugar alcoholin the lyophilized material is between about 5% and about 80%, between about 10% and about 60%, or between about 20% and about 50% w / w. In some embodiments, the concentration of the at least one sugar or sugar alcohol in the lyophilized material is between 5% and 80%, between 10% and 60%, or between 20% and 50% w / w. In some embodiments, the concentration of the at least one sugar or sugar alcohol in the lyophilized material is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80% w / w. In some embodiments, the concentration of the at least one sugar or sugar alcohol in the lyophilized material is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% w / w. In some 106 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) embodiments, the at least one sugar or sugar alcohol is dextrose, trehalose (e.g., trehalose dihydrate), sucrose, or mannitol. In some embodiments, the at least one sugar or sugar alcohol is dextrose or trehalose (e.g., trehalose dihydrate).

[0396] In some embodiments, the at least one sugar or sugar alcohol is a combination ofdextrose and trehalose (e.g., trehalose dihydrate), each of which are present in the lyophilized material in an amount listed above. In some embodiments, the dextrose is present in the lyophilized material at a concentration between about 25% and 30%, between about 27.5% and about 28.5%, or between about 27.8% and about 28.0% w / w. In some embodiments, the dextrose is present in the lyophilized material at a concentration between 25% and 30%, between 27.5% and 28.5%, or between 27.8% and 28.0% w / w. In some embodiments, the dextrose is present in the lyophilized material at a concentration of about 27.9% or 27.9% w / w. In some embodiments, the trehalose (e.g., trehalose dihydrate) is present in the lyophilized material at a concentration between about 40 and about 50%, between about 45% and about 47%, or between about 46.4% and about 46.6% w / w. In some embodiments, the trehalose (e.g., trehalose dihydrate) is present in the lyophilized material at a concentration between 40 and 50%, between 45% and 47%, or between 46.4% and 46.6% w / w. In some embodiments, the trehalose (e.g., trehalose dihydrate) is present in the lyophilized material at a concentration of about 46.5% or 46.5% w / w.

[0397] In some embodiments, the pharmaceutical composition may be diluted (e.g., 1.5x,2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, or 10x) prior to administration to a subject. In some embodiments, the osmolality of the pharmaceutical composition to be administered to the subject (e.g., aqueous suspension for intravenous administration) is between about 100 mOsm / kg and about 500 mOsm / kg, between 250 mOsm / kg and 500 mOsm / kg, between about 225 and about 350 mOsm / kg, between about 250 and about 350 mOsm / kg, or between about 275 and about 300 mOsm / kg. In some embodiments, the osmolality of the pharmaceutical composition to be administered to the subject is between 100 mOsm / kg and 500 mOsm / kg, between 250 mOsm / kg and 500 mOsm / kg, between 225 and 350 mOsm / kg, between 250 and 350 mOsm / kg, or between 275 and 300 mOsm / kg.

[0398] In some embodiments, the osmolality of the pharmaceutical composition to beadministered to the subject is about 100 mOsm / kg, about 110 mOsm / kg, about 120 mOsm / kg, about 130 mOsm / kg, about 140 mOsm / kg, about 150 mOsm / kg, about 160 mOsm / kg, about 170 mOsm / kg, about 180 mOsm / kg, about 190 mOsm / kg, about 200 mOsm / kg, about 210 mOsm / kg, about 220 mOsm / kg, about 225 mOsm / kg, about 230 mOsm / kg, about 235 mOsm / kg, about 240 107 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) mOsm / kg, about 245 mOsm / kg, about 250 mOsm / kg, about 255 mOsm / kg, about 260 mOsm / kg, about 275 mOsm / kg, about 280 mOsm / kg, about 285 mOsm / kg, about 290 mOsm / kg, about 295 mOsm / kg, about 300 mOsm / kg, about 305 mOsm / kg, about 310 mOsm / kg, about 315 mOsm / kg, about 320 mOsm / kg, about 325 mOsm / kg, about 330 mOsm / kg, about 335 mOsm / kg, about 340 mOsm / kg, about 345 mOsm / kg, about 350 mOsm / kg, about 360 mOsm / kg, about 370 mOsm / kg, about 380 mOsm / kg, about 390 mOsm / kg, about 400 mOsm / kg, about 410 mOsm / kg, about 420 mOsm / kg, about 430 mOsm / kg, about 440 mOsm / kg, about 450 mOsm / kg, about 460 mOsm / kg, about 470 mOsm / kg, about 480 mOsm / kg, about 490 mOsm / kg, or about 500 mOsm / kg.

[0399] In some embodiments, the osmolality of the pharmaceutical composition to beadministered to the subject is 100 mOsm / kg, 110 mOsm / kg, 120 mOsm / kg, 130 mOsm / kg, 140 mOsm / kg, 150 mOsm / kg, 160 mOsm / kg, 170 mOsm / kg, 180 mOsm / kg, 190 mOsm / kg, 200 mOsm / kg, 210 mOsm / kg, 220 mOsm / kg, 225 mOsm / kg, 230 mOsm / kg, 235 mOsm / kg, 240 mOsm / kg, 245 mOsm / kg, 250 mOsm / kg, 255 mOsm / kg, 260 mOsm / kg, 275 mOsm / kg, 280 mOsm / kg, 285 mOsm / kg, 290 mOsm / kg, 295 mOsm / kg, 300 mOsm / kg, 305 mOsm / kg, 310 mOsm / kg, 315 mOsm / kg, 320 mOsm / kg, 325 mOsm / kg, 330 mOsm / kg, 335 mOsm / kg, 340 mOsm / kg, 345 mOsm / kg, 350 mOsm / kg, 360 mOsm / kg, 370 mOsm / kg, 380 mOsm / kg, 390 mOsm / kg, 400 mOsm / kg, 410 mOsm / kg, 420 mOsm / kg, 430 mOsm / kg, 440 mOsm / kg, 450 mOsm / kg, 460 mOsm / kg, 470 mOsm / kg, 480 mOsm / kg, 490 mOsm / kg, or 500 mOsm / kg.

[0400] In any of the above embodiments, the pharmaceutical composition may be a unitdosage form.

[0401] In an embodiment, the unit dosage form comprises the FNP as a dry formulationfor dissolution such as a lyophilized material, e.g., a cake or a powder; freeze-dried material; or water-free concentrate. In an embodiment, the dry formulation is comprised in a hermetically sealed container such as a vial, an ampoule, or a sachet.

[0402] In an embodiment, the unit dosage form comprises the FNP as a liquid formulation(e.g., injection or infusion solution). In an embodiment, the liquid formulation is comprised in a hermetically sealed container such as a vial, a sachet, a pre-filled syringe, a pre-filled autoinjector, or a cartridge for a reusable syringe or applicator.

[0403] In an embodiment, the unit dosage per vial may contain 0.5 m...

Claims

Docket No.: 410007-001WO (218613) CLAIMS 1. A population of functionalized nanoparticles (FNP) each comprising a population of polyphosphate polymers attached to a nanoparticle, wherein the average chain length of the polyphosphate polymers in the population of FNP is no more than 65 phosphate units.

2. The population of FNP of claim 1, wherein the average chain length of the polyphosphate polymers in the population of FNP is no more than 60 phosphate units.

3. The population of FNP of claim 1 or 2, wherein the average chain length of the polyphosphate polymers in the population of FNP is between 30 and 60 phosphate units; between 40 and 60 phosphate units; between 45 and 60 phosphate units; between 50 and 60 phosphate units; or between 55 and 60 phosphate units.

4. The population of FNP of any one of claims 1-3, wherein the average chain length of the polyphosphate polymers in the population of FNP is between 42 and 59 phosphate units; between 54 and 59 phosphate units; or between 55 and 58 phosphate units.

5. The population of FNP of any one of claims 1-4, wherein the shortest 10% of the polyphosphate polymers in the population of FNP are no longer than a length between 10 and 40 phosphate units; between 15 and 35 phosphate units; between 20 and 30 phosphate units; or between 25 and 35 phosphate units.

6. The population of FNP of any one of claims 1-5, wherein the longest 90% of the polyphosphate polymers in the population of FNP are no shorter than a length between 10 and 40 phosphate units; between 15 and 35 phosphate units; between 20 and 30 phosphate units; or between 25 and 35 phosphate units.

7. The population of FNP of any one of claims 1-5, wherein the shortest 90% of the polyphosphate polymers in the population of FNP are no longer than a length between 70 and 140 142 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) phosphate units; between 75 and 135 phosphate units; between 80 and 130 phosphate units; or between 80 and 100 phosphate units.

8. The population of FNP of any one of claims 1-7, wherein the population of FNP comprises an FNP with an average chain length of the polyphosphate polymers attached to the FNP of no more than 60 phosphate units; between 30 and 60 phosphate units; between 40 and 60 phosphate units; between 45 and 60 phosphate units; between 50 and 60 phosphate units; between 55 and 60 phosphate units; between 42 and 59 phosphate units; between 54 and 59 phosphate units; or between 55 and 58 phosphate units.

9. The population of FNP of any one of claims 1-8, wherein the total mass of polyphosphate polymers in the population of FNP is no more than 24% of the total mass of the population of FNP.

10. The population of FNP of any one of claims 1-9, wherein the total mass of polyphosphate polymers in the population of FNP is between 16% and 24% of the total mass of the population of FNP.

11. The population of FNP of any one of claims 1-10, wherein the total mass of polyphosphate polymers in the population of FNP is no more than 22% of the total mass of the population of FNP.

12. The population of FNP of any one of claims 1-10, wherein the total mass of polyphosphate polymers in the population of FNP is between 15% and 22% of the total mass of the population of FNP.

13. The population of FNP of any one of claims 1-12, wherein the total mass of polyphosphate polymers in the population of FNP is between 17% and 21% of the total mass of the population of FNP.

14. The population of FNP of any one of claims 1-13, wherein the total mass of polyphosphate polymers in the population of FNP is between 19% and 21% of the total mass of the population of FNP. 143 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 15. The population of FNP of any one of claims 1-14, wherein the total mass of polyphosphate polymers in the population of FNP is about 20% of the total mass of the population of FNP.

16. The population of FNP of any one of claims 1-15, wherein the Z-average size of the nanoparticles in the population of FNP is 100 nm or less; 90 nm or less; 80 nm or less; 70 nm or less; 60 nm or less; between 30 nm and 70 nm; between 35 nm and 60 nm; between 38 nm and 59 nm; between 45 nm and 58 nm; between 50 nm and 60 nm; about 50 nm; or about 55 nm.

17. The population of FNP of any one of claims 1-16, wherein the D10(i) of the nanoparticles in the population of FNP is less than 45 nm, and the D90(i) of the nanoparticles in the population of FNP is less than 180 nm.

18. The population of FNP of any one of claims 1-17, wherein the D10(i) of the nanoparticles in the population of FNP is greater than 20 nm, and the D90(i) of the nanoparticles in the population of FNP is less than 180 nm.

19. The population of FNP of any one of claims 1-15, wherein the Z-average size of the FNP in the population of FNP is 200 nm or less; 180 nm or less; 100 nm or less; 90 nm or less; 80 nm or less; 70 nm or less; 60 nm or less; between 40 nm and 200 nm; between 40 nm and 80 nm; between 50 nm and 180 nm; between 50 nm and 80 nm; between 55 nm and 75 nm; between 55 nm and 65 nm; between 65 nm and 75 nm; about 55 nm; about 60 nm; about 65 nm; about 70 nm; or about 75 nm.

20. The population of FNP of any one of claims 1-15 or 19, wherein the D10(i) of the FNP in the population of FNP is less than 45 nm, and the D90(i) of the FNP in the population of FNP is less than 200 nm.

21. The population of FNP of any one of claims 1-15 or 19-20, wherein the D10(i) of the FNP in the population of FNP is greater than 20 nm, and the D90(i) of the FNP in the population of FNP is less than 200 nm. 144 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 22. The population of FNP of any one of claims 1-15 or 19-21, wherein the D10(i) of the FNP in the population of FNP is greater than 20 nm, and the D90(i) of the FNP in the population of FNP is less than 120 nm.

23. The population of FNP of any one of claims 1-22, wherein the nanoparticles in the population of FNP comprise an oxide of silicon.

24. The population of FNP of any one of claims 1-23, wherein the nanoparticles in the population of FNP comprise silica or a silica mixture.

25. The population of FNP of claim 24, wherein the nanoparticles in the population of FNP are silica nanoparticles.

26. The population of FNP of any one of claims 1-25, wherein the polyphosphate polymers are attached to the nanoparticles through non-covalent bonds.

27. The population of FNP of claim 26, wherein the non-covalent bonds comprise hydrogen bonds, Van der Waals forces, or a combination thereof.

28. A population of functionalized nanoparticles (FNP) each comprising a population of polyphosphate polymers attached to a nanoparticle, wherein the total mass of polyphosphate polymers in the population of FNP is no more than 24% of the total mass of the population of FNP.

29. The population of FNP of claim 28, wherein the total mass of polyphosphate polymers in the population of FNP is between 16% and 24% of the total mass of the population of FNP.

30. The population of FNP of claim 28 or 29, wherein the total mass of polyphosphate polymers in the population of FNP is no more than 22% of the total mass of the population of FNP. 145 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 31. The population of FNP of any one of claims 28-30, wherein the total mass of polyphosphate polymers in the population of FNP is between 15% and 22% of the total mass of the population of FNP.

32. The population of FNP of any one of claims 28-31, wherein the total mass of polyphosphate polymers in the population of FNP is between 17% and 21% of the total mass of the population of FNP.

33. The population of FNP of any one of claims 28-32, wherein the total mass of polyphosphate polymers in the population of FNP is between 19% and 21% of the total mass of the population of FNP.

34. The population of FNP of any one of claims 28-33, wherein the total mass of polyphosphate polymers in the population of FNP is about 20% of the total mass of the population of FNP.

35. The population of FNP of any one of claims 28-34, wherein the Z-average size of the nanoparticles is 100 nm or less; 90 nm or less; 80 nm or less; 70 nm or less; 60 nm or less; between 30 nm and 70 nm; between 35 nm and 60 nm; between 38 nm and 59 nm; between 45 nm and 58 nm; between 50 nm and 60 nm; about 50 nm; or about 55 nm.

36. The population of FNP of any one of claims 28-35, wherein the D10(i) of the nanoparticles in the population of FNP is less than 45 nm, and the D90(i) of the nanoparticles in the population of FNP is less than 180 nm.

37. The population of FNP of any one of claims 28-34, wherein the Z-average size of the FNP in the population of FNP is 200 nm or less; 180 nm or less; 100 nm or less; 90 nm or less; 80 nm or less; 70 nm or less; 60 nm or less; between 40 nm and 200 nm; between 40 nm and 80 nm; between 50 nm and 180 nm; between 50 nm and 80 nm; between 55 nm and 75 nm; between 55 nm and 65 nm; between 65 nm and 75 nm; about 55 nm; about 60 nm; about 65 nm; about 70 nm; or about 75 nm. 146 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 38. The population of FNP of any one of claims 28-34 or 37, wherein the D10(i) of the FNP in the population of FNP is less than 45 nm, and the D90(i) of the FNP is less than 200 nm.

39. The population of FNP of any one of claims 28-34 or 37-38, wherein the D10(i) of the FNP in the population of FNP is greater than 20 nm, and the D90(i) of the FNP in the population of FNP is less than 200 nm.

40. The population of FNP of any one of claims 28-34 or 37-39, wherein the D10(i) of the FNP in the population of FNP is greater than 20 nm, and the D90(i) of the FNP in the population of FNP is less than 120 nm.

41. The population of FNP of any one of claims 28-40, wherein the nanoparticles in the population of FNP comprise an oxide of silicon.

42. The population of FNP of any one of claims 28-34, wherein the nanoparticles in the population of FNP comprise silica or a silica mixture.

43. The population of FNP of claim 42, wherein the nanoparticles in the population of FNP are silica nanoparticles.

44. The population of FNP of any one of claims 28-43, wherein the polyphosphate polymers are attached to the nanoparticles through non-covalent bonds.

45. The population of FNP of claim 44, wherein the non-covalent bonds comprise hydrogen bonds, Van der Waals forces, or a combination thereof.

46. A population of functionalized nanoparticles (FNP) each comprising a population of polyphosphate polymers attached to a nanoparticle, wherein the Z-average size of the nanoparticles is 200 nm or less; 180 nm or less; 100 nm or less; 90 nm or less; 80 nm or less; 70 nm or less; 60 nm or less; between 30 nm and 70 nm; between 35 nm and 60 nm; between 38 nm and 59 nm; between 45 nm and 58 nm; between 50 nm and 60 nm; about 50 nm; or about 55 nm. 147 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 47. The population of FNP of claim 46, wherein the D10(i) of the nanoparticles in the population of FNP is less than 45 nm, and the D90(i) of the nanoparticles in the population of FNP is less than 180 nm.

48. The population of FNP of claim 46 or 47, wherein the Z-average size of the FNP in the population of FNP is 200 nm or less; 180 nm or less; 100 nm or less; 90 nm or less; 80 nm or less; 70 nm or less; 60 nm or less; between 40 nm and 200 nm; between 40 nm and 80 nm; between 50 nm and 180 nm; between 50 nm and 80 nm; between 55 nm and 75 nm; between 55 nm and 65 nm; between 65 nm and 75 nm; about 55 nm; about 60 nm; about 65 nm; about 70 nm; or about 75 nm.

49. The population of FNP of any one of claims 46-48, wherein the D10(i) of the FNP in the population of FNP is less than 45 nm, and the D90(i) of the FNP in the population of FNP is less than 200 nm.

50. The population of FNP of any one of claims 46-49, wherein the D10(i) of the FNP in the population of FNP is greater than 20 nm, and the D90(i) of the FNP in the population of FNP is less than 200 nm.

51. The population of FNP of any one of claims 46-50, wherein the D10(i) of the FNP in the population of FNP is greater than 20 nm, and the D90(i) of the FNP in the population of FNP is less than 120 nm.

52. The population of FNP of any one of claims 46-51, wherein the nanoparticles in the population of FNP comprise an oxide of silicon.

53. The population of FNP of any one of claims 46-52, wherein the nanoparticles in the population of FNP comprise silica or a silica mixture. 148 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 54. The population of FNP of claim 53, wherein the nanoparticles in the population of FNP are silica nanoparticles.

55. The population of FNP of any one of claims 46-54, wherein the polyphosphate polymers are attached to the nanoparticles through non-covalent bonds.

56. The population of FNP of claim 55, wherein the non-covalent bonds comprise hydrogen bonds, Van der Waals forces, or a combination thereof.

57. A pharmaceutical composition comprising the population of FNP of any one of claims 1- 56 and a pharmaceutically acceptable excipient.

58. The pharmaceutical composition of claim 57, wherein the pharmaceutical composition is an aqueous suspension.

59. The pharmaceutical composition of claim 58, wherein the population of FNP is present in the pharmaceutical composition at a concentration between 0.1% and 10% w / v, between 0.5% and 5% w / v, between 1% and 3% w / v, between 1.5% and 2.5% w / v, between 1.6% and 2.2% w / v, or between 1.8% and 2.2% w / v.

60. The pharmaceutical composition of claim 58 or 59, wherein the pharmaceutical composition is stable for at least 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 15 days, 20 days, 25 days, or 30 days at 5°C or 25°C.

61. The pharmaceutical composition of any one of claims 58-60, wherein the pH of the pharmaceutical composition is between 4.0 and 8.0, between 5.0 and 7.5, between 5.0 and 7.0, between 5.0 and 6.5, between 5.0 and 6.0, between 5.5 and 8.0, between 5.5 and 7.5, between 5.5 and 7.0, between 5.5 and 6.5, between 5.5 and 6.0, between 5.75 and 5.95, between 5.81 and 5.91, or about 5.

85. 149 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 62. The pharmaceutical composition of any one of claims 58-61, wherein the zeta potential of the pharmaceutical composition is between -60 mV and -25 mV, between -60 mV and -40 mV, between -50 mV and -40 mV, between -49 mV to -41 mV, between -49 mV to -44 mV, or between -48 mV to -45 mV.

63. The pharmaceutical composition of any one of claims 58-62, wherein the polydispersity index (PDI) of the pharmaceutical composition is no more than 0.3, no more than 0.25, no more than 0.2, less than 0.2, or between 0.1 and 0.

2.

64. The pharmaceutical composition of any one of claims 58-63, wherein the osmolality of the pharmaceutical composition is between 100 mOsm / kg and 500 mOsm / kg, between 250 mOsm / kg and 500 mOsm / kg, between 225 and 350 mOsm / kg, between 250 and 350 mOsm / kg, or between 275 and 300 mOsm / kg.

65. The pharmaceutical composition of any one of claims 57-64, further comprising a population of free polyphosphate polymers, wherein the mass of the population of free polyphosphate polymers is no more than 55%, 40%, 25%, 20%, 10%, 7.5%, 5%, 2%, or 1.5% of the total mass of polyphosphate polymers in the pharmaceutical composition.

66. The pharmaceutical composition of claim 65, wherein the concentration of the population of free polyphosphate polymers in the pharmaceutical composition is less than 0.08% w / v.

67. The pharmaceutical composition of claim 66, wherein the total concentration of polyphosphate polymers in the pharmaceutical composition is between 0.36% and 0.44% w / v.

68. The pharmaceutical composition of any one of claims 65-67, wherein: (i) the average chain length of the polyphosphate polymers in the population of FNP is no more than 65 phosphate units; (ii) the Z-average size of the population of FNP is between 50 nm and 80 nm; (iii) the polydispersity index (PDI) of the pharmaceutical composition is no more than 0.3, no more than 0.25, no more than 0.2, less than 0.2, or between 0.1 and 0.2; 150 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) (iv) the zeta potential of the pharmaceutical composition is between -60 mV and -25 mV; (v) the total mass of polyphosphate polymers in the population of FNP is between 16% and 24% of the total mass of the population of FNP; (vi) the pH of the pharmaceutical composition is between 5.0 and 7.5; (vii) the mass of the population of free polyphosphate polymers is no more than 25%, 20%, 10%, 7.5%, 5%, 2%, or 1.5% of the total mass of polyphosphate polymers in the pharmaceutical composition; and (viii) the osmolality of the pharmaceutical composition is between 250 and 350 mOsm / kg.

69. The pharmaceutical composition of claim 68, wherein: (i) the average chain length of the polyphosphate polymers in the population of FNP is no more than 60 phosphate units; (ii) the Z-average size of the population of FNP is between 65 nm and 75 nm; (iii) the polydispersity index (PDI) of the pharmaceutical composition is less than 0.2; (iv) the zeta potential of the pharmaceutical composition is between -60 mV and -40 mV; (v) the total mass of polyphosphate polymers in the population of FNP is between 16% and 24% of the total mass of the population of FNP; (vi) the pH of the pharmaceutical composition is between 5.0 and 7.5; (vii) the mass of the population of free polyphosphate polymers is no more than 25%, 20%, 10%, 7.5%, 5%, 2%, or 1.5% of the total mass of polyphosphate polymers in the pharmaceutical composition; and (viii) the osmolality of the pharmaceutical composition is between 250 and 350 mOsm / kg.

70. The pharmaceutical composition of claim 68 or 69, wherein the concentration of the population of FNP in the pharmaceutical composition is between 1.8% and 2.2% w / v; the concentration of the population of free polyphosphate polymers in the pharmaceutical composition is less than 0.08% w / v; and the total concentration of polyphosphate polymers in the pharmaceutical composition is between 0.36% and 0.44% w / v.

71. The pharmaceutical composition of claim 57, wherein the pharmaceutical composition is lyophilized. 151 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 72. The pharmaceutical composition of claim 71, wherein the pharmaceutical composition is produced by lyophilizing the pharmaceutical composition of any one of claims 58-70.

73. The pharmaceutical composition of claims 71 or 72, wherein the pharmaceutical composition is stable for at least 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days, 45 days, 50 days, 55 days, or 60 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, 4 years, or 5 years at 5°C or 25°C.

74. The pharmaceutical composition of any one of claims 58-70, wherein the pharmaceutical composition has been reconstituted as an aqueous suspension by adding water to the pharmaceutical composition of any one of claims 71-73.

75. A pharmaceutical composition comprising: a) a population of functionalized nanoparticles (FNP) each comprising a population of polyphosphate polymers attached to a nanoparticle; b) a population of free polyphosphate polymers, wherein the mass of the population of free polyphosphate polymers is no more than 20% of the total mass of polyphosphate polymers in the pharmaceutical composition; and c) a pharmaceutically acceptable excipient.

76. The pharmaceutical composition of claim 75, wherein the nanoparticles in the population of FNP are silica nanoparticles.

77. The pharmaceutical composition of claim 75 or 76, wherein the ratio of the total mass of polyphosphate polymers in the pharmaceutical composition to the mass of silica nanoparticles in the pharmaceutical composition is about 1:

4. 152 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 78. The pharmaceutical composition of any one of claims 75-77, wherein the average chain length of the polyphosphate polymers in the pharmaceutical composition is between 40 and 60 phosphate units.

79. The pharmaceutical composition of claim 78, wherein the shortest 10% of the polyphosphate polymers in the pharmaceutical composition are no longer than a length between 10 and 40 phosphate units; between 15 and 35 phosphate units; between 20 and 30 phosphate units; or between 25 and 35 phosphate units.

80. The pharmaceutical composition of any one of claims 75-79, wherein the longest 90% of the polyphosphate polymers in the pharmaceutical composition are no shorter than a length between 10 and 40 phosphate units; between 15 and 35 phosphate units; between 20 and 30 phosphate units; or between 25 and 35 phosphate units.

81. The pharmaceutical composition of any one of claims 75-80, wherein the shortest 90% of the polyphosphate polymers in the pharmaceutical composition are no longer than a length between 70 and 140 phosphate units; between 75 and 135 phosphate units; between 80 and 130 phosphate units; or between 80 and 100 phosphate units.

82. The pharmaceutical composition of any one of claims 75-81, wherein the Z-average size of the FNP in the population of FNP is between 40 nm and 80 nm.

83. The pharmaceutical composition of claim 82, wherein the D10(i) of the FNP in the population of FNP is greater than 20 nm, and the D90(i) of the FNP in the population of FNP is less than 120 nm.

84. The pharmaceutical composition of any one of claims 75-83, wherein the pH of the pharmaceutical composition is between 5.0 and 7.

0.

85. The pharmaceutical composition of any one of claims 75-84, wherein the PDI of the pharmaceutical composition is less than or equal to 0.

2. 153 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 86. The pharmaceutical composition of any one of claims 75-85, wherein the osmolality of the pharmaceutical composition is between 250 mOsm / kg and 500 mOsm / kg.

87. The pharmaceutical composition of any one of claims 75-86, wherein the pharmaceutical composition is an aqueous suspension.

88. The pharmaceutical composition of claim 87, wherein the total concentration of polyphosphate polymers in the pharmaceutical composition is between 0.36% and 0.44% w / v.

89. The pharmaceutical composition of claim 88, wherein the concentration of the population of free polyphosphate polymers in the pharmaceutical composition is less than 0.08% w / v, and wherein the concentration of the nanoparticles in the pharmaceutical composition is about 1.6% w / v, optionally wherein the nanoparticles in the pharmaceutical composition are silica nanoparticles.

90. The pharmaceutical composition of any one of claims 75-86, wherein the pharmaceutical composition is lyophilized.

91. The pharmaceutical composition of claim 90, wherein the pharmaceutical composition is produced by lyophilizing the pharmaceutical composition of any one of claims 87-89.

92. The pharmaceutical composition of claim 90 or 91, wherein the pharmaceutical composition is capable of being reconstituted into a clear suspension substantially free from visible particulates no more than 30 seconds after addition of water to the pharmaceutical composition.

93. The pharmaceutical composition of any one of claims 87-89, wherein the pharmaceutical composition has been reconstituted as an aqueous suspension by adding water to the pharmaceutical composition of any one of claims 90-92. 154 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 94. A pharmaceutical composition comprising: a) a population of functionalized nanoparticles (FNP) each comprising a population of polyphosphate polymers attached to a nanoparticle; and b) a pharmaceutically acceptable excipient comprising at least one cryoprotectant.

95. The pharmaceutical composition of claim 94, wherein the at least one cryoprotectant comprises an amino acid selected from the group consisting of glycine, phenylalanine, leucine, and isoleucine.

96. The pharmaceutical composition of claim 95, wherein the amino acid is glycine.

97. The pharmaceutical composition of any one of claims 94-96, wherein the at least one cryoprotectant comprises at least one sugar or sugar alcohol.

98. The pharmaceutical composition of claim 97, wherein the at least one sugar or sugar alcohol comprises dextrose, trehalose, sucrose, mannitol, galactose, sorbitol, lactose, glycerol, maltose, or isomalt.

99. The pharmaceutical composition of claim 98, wherein the at least one sugar or sugar alcohol comprises dextrose and trehalose.

100. The pharmaceutical composition of any one of claims 94-99, wherein the pharmaceutical composition is an aqueous suspension.

101. The pharmaceutical composition of claim 100, wherein the population of FNP is present in the pharmaceutical composition at a concentration between 0.1% and 10% w / v, between 0.5% and 5% w / v, between 1% and 3% w / v, between 1.5% and 2.5% w / v, between 1.6% and 2.2% w / v, or between 1.8% and 2.2% w / v. 155 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 102. The pharmaceutical composition of claim 100 or 101, wherein the at least one cryoprotectant comprises glycine at a concentration between 0.1% and 10% w / v, between 0.2% and 5% w / v, between 0.5% and 2% w / v, or about 0.75% w / v.

103. The pharmaceutical composition of any one of claims 100-102, wherein the at least one cryoprotectant comprises at least one sugar or sugar alcohol, and wherein each sugar or sugar alcohol is present in the pharmaceutical composition at a concentration between 0.1% and 10% w / v, between 0.5% and 5% w / v, or between 2% and 5% w / v.

104. The pharmaceutical composition of claim 103, wherein the at least one sugar or sugar alcohol comprises dextrose, and wherein the dextrose is present in the pharmaceutical composition at a concentration of between 1% and 6% w / v, between 2% and 5% w / v, between 2% and 4% w / v, between 2.5% and 3.5% w / v, between 2.8% and 3.2% w / v, or about 3% w / v.

105. The pharmaceutical composition of claim 103 or 104, wherein the at least one sugar or sugar alcohol comprises trehalose, and wherein the trehalose is present in the pharmaceutical composition at a concentration of between 0.5% and 5% w / v, between 3% and 5% w / v, between 4% and 5% w / v, or about 5% w / v.

106. The pharmaceutical composition of any one of claims 100-105, wherein the population of FNP is present in the pharmaceutical composition at a concentration between 0.1% and 10% w / v, between 0.5% and 5% w / v, between 1% and 3% w / v, between 1.5% and 2.5% w / v, between 1.6% and 2.2% w / v, or between 1.8% and 2.2% w / v.

107. The pharmaceutical composition of any one of claims 100-106, wherein the pharmaceutical composition is stable for at least 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 15 days, 20 days, 25 days, or 30 days at 5°C or 25°C.

108. The pharmaceutical composition of any one of claims 100-107, wherein the pH of the pharmaceutical composition is between 4.0 and 8.0, between 5.0 and 7.5, between 5.0 and 7.0, between 5.0 and 6.5, between 5.0 and 6.0, between 5.5 and 8.0, between 5.5 and 7.5, between 5.5 156 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) and 7.0, between 5.5 and 6.5, between 5.5 and 6.0, between 5.75 and 5.95, between 5.81 and 5.91, or about 5.

85.

109. The pharmaceutical composition of any one of claims 100-108, wherein the zeta potential of the pharmaceutical composition is between -60 mV and -25 mV, between -60 mV and -40 mV, between -50 mV and -40 mV, between -49 mV to -41 mV, between -49 mV to -44 mV, or between -48 mV to -45 mV.

110. The pharmaceutical composition of any one of claims 100-109, wherein the polydispersity index (PDI) of the pharmaceutical composition is no more than 0.3, no more than 0.25, no more than 0.2, less than 0.2, or between 0.1 and 0.

2.

111. The pharmaceutical composition of any one of claims 100-110, wherein the osmolality of the pharmaceutical composition is between 100 mOsm / kg and 500 mOsm / kg, between 250 mOsm / kg and 500 mOsm / kg, between 225 and 350 mOsm / kg, between 250 and 350 mOsm / kg, or between 275 and 300 mOsm / kg.

112. The pharmaceutical composition of any one of claims 100-111, further comprising a population of free polyphosphate polymers, wherein the mass of the population of free polyphosphate polymers is no more than 55%, 40%, 25%, 20%, 10%, 7.5%, 5%, 2%, or 1.5% of the total mass of polyphosphate polymers in the pharmaceutical composition.

113. The pharmaceutical composition of claim 112, wherein the concentration of the population of free polyphosphate polymers in the pharmaceutical composition is less than 0.08% w / v.

114. The pharmaceutical composition of claim 113, wherein the total concentration of polyphosphate polymers in the pharmaceutical composition is between 0.36% and 0.44% w / v.

115. The pharmaceutical composition of any one of claims 112-114, wherein: (i) the average chain length of the polyphosphate polymers in the population of FNP is no more than 65 phosphate units; 157 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) (ii) the Z-average size of the population of FNP is between 50 nm and 80 nm; (iii) the polydispersity index (PDI) of the pharmaceutical composition is no more than 0.3, no more than 0.25, no more than 0.2, less than 0.2, or between 0.1 and 0.2; (iv) the zeta potential of the pharmaceutical composition is between -60 mV and -25 mV; (v) the total mass of polyphosphate polymers in the population of FNP is between 16% and 24% of the total mass of the population of FNP; (vi) the pH of the pharmaceutical composition is between 5.0 and 7.5; (vii) the mass of the population of free polyphosphate polymers is no more than 25%, 20%, 10%, 7.5%, 5%, 2%, or 1.5% of the total mass of polyphosphate polymers in the pharmaceutical composition; and (viii) the osmolality of the pharmaceutical composition is between 250 and 350 mOsm / kg.

116. The pharmaceutical composition of claim 115, wherein: (i) the average chain length of the polyphosphate polymers in the population of FNP is no more than 60 phosphate units; (ii) the Z-average size of the population of FNP is between 65 nm and 75 nm; (iii) the polydispersity index (PDI) of the pharmaceutical composition is less than 0.2; (iv) the zeta potential of the pharmaceutical composition is between -60 mV and -40 mV; (v) the total mass of polyphosphate polymers in the population of FNP is between 16% and 24% of the total mass of the population of FNP; (vi) the pH of the pharmaceutical composition is between 5.0 and 7.5; (vii) the mass of the population of free polyphosphate polymers is no more than 25%, 20%, 10%, 7.5%, 5%, 2%, or 1.5% of the total mass of polyphosphate polymers in the pharmaceutical composition; and (viii) the osmolality of the pharmaceutical composition is between 250 and 350 mOsm / kg.

117. The pharmaceutical composition of claim 115 or 116, wherein the concentration of the population of FNP in the pharmaceutical composition is between 1.8% and 2.2% w / v; the concentration of the population of free polyphosphate polymers in the pharmaceutical composition is less than 0.08% w / v; and the total concentration of polyphosphate polymers in the pharmaceutical composition is between 0.36% and 0.44% w / v. 158 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 118. The pharmaceutical composition of claim 94, wherein the pharmaceutical composition is lyophilized.

119. The pharmaceutical composition of claim 118, wherein the pharmaceutical composition is produced by lyophilizing the pharmaceutical composition of any one of claims 100-117.

120. The pharmaceutical composition of claim 118 or 119, wherein the population of FNP is present in the pharmaceutical composition at a concentration between 5% and 50% w / w, between 10% and 25% w / w, or between 15% and 20% w / w.

121. The pharmaceutical composition of any one of claims 118-120, wherein the population of polyphosphate polymers is present in the pharmaceutical composition at a concentration between 1% and 20% w / w, between 2% and 10% w / w, or between 3% and 5% w / w.

122. The pharmaceutical composition of any one of claims 118-121, wherein the nanoparticle is present in the pharmaceutical composition at a concentration between 2% and 40% w / w, between 10% and 25% w / w, or between 12% and 16% w / w.

123. The pharmaceutical composition of any one of claims 118-122, wherein the at least one cryoprotectant comprises glycine, and wherein the glycine is present in the pharmaceutical composition at a concentration between 1% and 20% w / w, between 2% and 10% w / w, or between 5% and 10% w / w.

124. The pharmaceutical composition of any one of claims 118-123, wherein the at least one cryoprotectant comprises at least one sugar or sugar alcohol, and wherein the at least one sugar or sugar alcohol is present in the pharmaceutical composition at a concentration between 5% and 80% w / w, between 10% and 60% w / w, or between 20% and 50% w / w.

125. The pharmaceutical composition of claim 124, wherein the at least one sugar or sugar alcohol comprises a combination of dextrose and trehalose, wherein each of dextrose and trehalose 159 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) are present in the pharmaceutical composition at a concentration between 5% and 80% w / w, between 10% and 60% w / w, or between 20% and 50% w / w.

126. The pharmaceutical composition of claim 125, wherein the dextrose is present in the pharmaceutical composition at a concentration between 25% and 30% w / w, between 27.5% and 28.5% w / w, or between 27.8% and 28.0% w / w.

127. The pharmaceutical composition of claim 125, wherein the trehalose is present in the pharmaceutical composition at a concentration between 40 and 50% w / w, between 45% and 47% w / w, or between 46.4% and 46.6% w / w.

128. The pharmaceutical composition of any one of claims 118-127, wherein the pharmaceutical composition is stable for at least 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days, 45 days, 50 days, 55 days, or 60 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, 4 years, or 5 years at 5°C or 25°C.

129. The pharmaceutical composition of any one of claims 69-86, wherein the pharmaceutical composition is reconstituted as an aqueous suspension by adding water to the pharmaceutical composition of any one of claims 118-128.

130. The pharmaceutical composition of any one of claims 94-129, wherein the nanoparticles in the population of FNP are silica nanoparticles.

131. The pharmaceutical composition of claim 130, wherein the ratio of the total mass of polyphosphate polymers in the pharmaceutical composition to the mass of silica nanoparticles in the pharmaceutical composition is about 1:

4. 160 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 132. The pharmaceutical composition of claim 130 or 131, wherein the average chain length of the polyphosphate polymers in the pharmaceutical composition is between 40 and 60 phosphate units.

133. The pharmaceutical composition of claim 132, wherein the shortest 10% of the polyphosphate polymers in the pharmaceutical composition are no longer than a length between 10 and 40 phosphate units; between 15 and 35 phosphate units; between 20 and 30 phosphate units; or between 25 and 35 phosphate units.

134. The pharmaceutical composition of any one of claims 130-133, wherein the longest 90% of the polyphosphate polymers in the pharmaceutical composition are no shorter than a length between 10 and 40 phosphate units; between 15 and 35 phosphate units; between 20 and 30 phosphate units; or between 25 and 35 phosphate units.

135. The pharmaceutical composition of any one of claims 130-134, wherein the shortest 90% of the polyphosphate polymers in the pharmaceutical composition are no longer than a length between 70 and 140 phosphate units; between 75 and 135 phosphate units; between 80 and 130 phosphate units; or between 80 and 100 phosphate units.

136. The pharmaceutical composition of any one of claims 130-135, wherein the Z-average size of the FNP in the population of FNP is between 40 nm and 80 nm.

137. The pharmaceutical composition of claim 136, wherein the D10(i) of the FNP in the population of FNP is greater than 20 nm, and the D90(i) of the FNP in the population of FNP is less than 120 nm.

138. The pharmaceutical composition of any one of claims 130-137, wherein the pH of the pharmaceutical composition is between 5.0 and 7.

0.

139. The pharmaceutical composition of any one of claims 130-138, wherein the PDI of the pharmaceutical composition is less than or equal to 0.

2. 161 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 140. The pharmaceutical composition of any one of claims 130-139, wherein the osmolality of the pharmaceutical composition is between 250 mOsm / kg and 500 mOsm / kg.

141. The pharmaceutical composition of any one of claims 130-140, wherein the pharmaceutical composition is an aqueous suspension.

142. The pharmaceutical composition of claim 141, wherein the total concentration of polyphosphate polymers in the pharmaceutical composition is between 0.36% and 0.44% w / v.

143. The pharmaceutical composition of claim 142, wherein the concentration of the population of free polyphosphate polymers in the pharmaceutical composition is less than 0.08% w / v, and wherein the concentration of the nanoparticles in the pharmaceutical composition is about 1.6% w / v, optionally wherein the nanoparticles in the pharmaceutical composition are silica nanoparticles.

144. The pharmaceutical composition of any one of claims 130-143, wherein the pharmaceutical composition is lyophilized.

145. The pharmaceutical composition of claim 144, wherein the pharmaceutical composition is produced by lyophilizing the pharmaceutical composition of any one of claims 141-143.

146. The pharmaceutical composition of claim 144 or 145, wherein the pharmaceutical composition is capable of being reconstituted into a clear suspension substantially free from visible particulates no more than 30 seconds after addition of water to the pharmaceutical composition.

147. The pharmaceutical composition of any one of claims 141-143, wherein the pharmaceutical composition has been reconstituted as an aqueous suspension by adding water to the pharmaceutical composition of any one of claims 144-146. 162 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 148. The pharmaceutical composition of any one of claims 94-147, wherein the population of FNP is the population of FNP of any one of claims 1-56.

149. A method of promoting blood clotting in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the population of functionalized nanoparticles (FNP) or the pharmaceutical composition of any one of claims 1-148, thereby promoting blood clotting in the subject.

150. A method of preventing or controlling bleeding in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the population of functionalized nanoparticles (FNP) or the pharmaceutical composition of any one of claims 1-148, thereby preventing or controlling bleeding in the subject.

151. A method of reducing blood loss in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the population of functionalized nanoparticles (FNP) or the pharmaceutical composition of any one of claims 1-148, thereby reducing blood loss in the subject.

152. A method of promoting hemostasis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the population of functionalized nanoparticles (FNP) or the pharmaceutical composition of any one of claims 1-148, thereby promoting hemostasis in the subject.

153. A method of treating hemorrhage in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the population of functionalized nanoparticles (FNP) or pharmaceutical composition of any one of claims 1-148, thereby treating hemorrhage in the subject.

154. The method of claim 153, wherein the hemorrhage is selected from major hemorrhage, acute major hemorrhage, hemorrhage after traumatic injury, GI hemorrhage, hemorrhagic stroke, cerebral hemorrhage, intracranial hemorrhage, and postpartum hemorrhage. 163 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 155. A method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the population of functionalized nanoparticles (FNP) or pharmaceutical composition of any one of claims 1-148, thereby treating the subject.

156. The method of any one of claims 150-155, wherein the population of FNP or pharmaceutical composition is administered at a flat dose of 10 mg to 1000 mg, 25 mg to 500 mg, 50 mg to 250 mg, or about 100 mg.

157. The method of any one of claims 150-155, wherein the population of FNP or pharmaceutical composition is administered at a dose of 0.1 mg / kg to 100 mg / kg, 0.5 mg / kg to 80 mg / kg, or 1 mg / kg to 50 mg / kg.

158. The method of any one of claims 150-157, wherein the population of FNP or pharmaceutical composition is administered intravenously as a bolus injection, as a continuous infusion, or as a combination thereof.

159. The method of any one of claims 150-157, wherein the population of FNP or pharmaceutical composition is administered intraosseously, intramuscularly, intra-articularly, intrathecally, or intra-arterially.

160. The method of any one of claims 150-159, wherein the population of FNP or pharmaceutical composition is administered as a single administration or in repeated administrations.

161. A method of producing a composition comprising a population of functionalized nanoparticles (FNP), the method comprising suspending a population of silica nanoparticles in an acidic aqueous solution prior to addition of a population of polyphosphate polymers. 164 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) 162. The method of claim 161, wherein the silica nanoparticle suspension is adjusted to a pH of less than 7.0, between 4.0 and 7.0, between 5.0 and 6.0, about 6.0, about 5.5, or about 5.0 prior to addition of the population of polyphosphate polymers.

163. The method of claim 161 or 162, wherein the silica nanoparticle and the population of polyphosphate polymers are mixed at a temperature between 20℃ and 35℃.

164. The method of claim 163, wherein the silica nanoparticle and the population of polyphosphate polymers are mixed for at least 1 minute, for at least 5 minutes, for at least 15 minutes, for at least 30 minutes, for at least 1 hour, for at least 2 hours, for at least 6 hours, at least 12 hours, or at least 18 hours.

165. The method of any one of claims 161-164, wherein the population of polyphosphate polymers is filtered with an appropriate filter to narrow the molecular weight distribution of the polyphosphate polymers prior to addition to the silica nanoparticle suspension.

166. The population of FNP or the pharmaceutical composition of any one of claims 1-148 for use in promoting blood clotting in a subject in need thereof, preventing bleeding in a subject in need thereof, controlling bleeding in a subject in need thereof, reducing blood loss in a subject in need thereof, promoting hemostasis in a subject in need thereof, treating hemorrhage in a subject in need thereof, and / or treating a subject in need thereof.

167. The population of FNP or the pharmaceutical composition of any one of claims 1-148 for use in the manufacture of a medicament for promoting blood clotting in a subject in need thereof, preventing bleeding in a subject in need thereof, controlling bleeding in a subject in need thereof, reducing blood loss in a subject in need thereof, promoting hemostasis in a subject in need thereof, treating hemorrhage in a subject in need thereof, and / or treating a subject in need thereof.

168. Use of the population of FNP or the pharmaceutical composition according to any one of claims 1-148 for promoting blood clotting in a subject in need thereof, preventing bleeding in a 165 BUSINESS.33102490.1Docket No.: 410007-001WO (218613) subject in need thereof, controlling bleeding in a subject in need thereof, reducing blood loss in a subject in need thereof, promoting hemostasis in a subject in need thereof, treating hemorrhage in a subject in need thereof, and / or treating a subject in need thereof.

169. Use of the population of FNP or the pharmaceutical composition according to any one of claims 1-148 for the manufacture of a medicament for promoting blood clotting in a subject in need thereof, preventing bleeding in a subject in need thereof, controlling bleeding in a subject in need thereof, reducing blood loss in a subject in need thereof, promoting hemostasis in a subject in need thereof, treating hemorrhage in a subject in need thereof, and / or treating a subject in need thereof. 166 BUSINESS.33102490.1

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