Polymer nanoaggregate pharmaceutical compositions and uses thereof

Abstract

The present disclosure is directed to a pharmaceutical composition for treating or preventing a disease. The pharmaceutical composition can include a polymer and a polymer-drug nanoaggregate having at least one bioactive agent that is water insoluble or poorly water soluble. The polymer is water soluble and includes at least one first end group modified by H or a hydrophobic moiety and a second end group modified by a hydrophilic moiety, and can be a modified symmetric or asymmetric branched polymer. The present disclosure is also directed to a method for treating or preventing a disease, including one or more of immune disorders, infectious diseases, and cancer, using the pharmaceutical composition disclosed herein. The pharmaceutical composition can be a vaccine or a vaccine adjuvant.

Description

[Technical field]

[0001]

[01] The present disclosure relates to a pharmaceutical composition that can be used to treat a disease in a patient in need of such treatment. The composition can include nanoaggregates formed from a water-soluble polymer and a water-insoluble or poorly water-soluble bioactive agent. [Background technology]

[0002]

[02] Synthetic polymers have been shown to have important applications in pharmaceutical formulations as effective delivery vehicles or other types of excipients.

[03] Symmetrically branched polymers (SBPs) such as dendritic polymers including starburst dendrimers (or dense star polymers) and combburst dendrigrafts (or hypercomb branched polymers) are some examples. These polymers often have (a) a well-defined core molecule, (b) at least two concentric dendritic layers (generations) with symmetric (equal length) branches and branch junctions, and (c) external surface groups such as polyamidoamine (PAMAM)-based branched polymers and dendrimers described in U.S. Patents 4,435,548, 4,507,466, 4,568,737, 4,587,329, 5,338,532, 5,527,524, and 5,714,166. Other examples include polyethyleneimine (PEI) dendrimers such as those disclosed in U.S. Pat. No. 4,631,337; polypropyleneimine (PPI) dendrimers such as those disclosed in U.S. Pat. Nos. 5,530,092, 5,610,268 and 5,698,662; Frechet-type polyether and polyester dendrimers, core-shell dendrimers, and the like, as described, for example, in "Dendritic Molecules" edited by Newkome et al. (VCH Weinheim, 1996); "Dendrimers and Other Dendritic Polymers" edited by Frechet and Toroalia (John Wiley & Sons, Ltd., 2001); and U.S. Pat. No. 7,754,500.

[0003]

[04] Combburst dendrigrafts are constructed by a stepwise synthesis process with concentric layers of a core molecule and symmetric branches. In contrast to dendrimers, combburst dendrigrafts or combburst polymers are produced using monodisperse linear polymer building blocks (U.S. Pat. Nos. 5,773,527, 5,631,329 and 5,919,442). Furthermore, the branching pattern differs from that of dendrimers. For example, combburst dendrigrafts form branched junctions along the polymer backbone (chain branching), whereas starburst dendrimers are often branched at the ends (terminal branching). The living polymerization technique used determines the molecular weight distribution (M w / M n ) are often narrow. Thus, the combburst dendrigrafts generated by the graft-on-graft process are well defined and M w / M n The ratio is often close to 1.

[0004]

[05] SBPs such as dendrimers are primarily produced by repeated protection and deprotection steps, either by divergent or convergent synthetic approaches. Since dendrimers use small molecules as building blocks at the core and branches, the molecular weight distribution of dendrimers is often well-defined. At lower generations, single molecular weight dendrimers are often obtained. Dendrimers often use small molecule monomers as building blocks, while dendrigrafts use linear polymers as building blocks.

[0005]

[06] Other SBPs may include, in addition to dendrimers and dendrigrafts, symmetric star or comb polymers such as polyethylene oxide (PEO), polyethylene glycol (PEG), polyethyleneimine (PEI), polypropyleneimine (PPI), polyoxazoline (POX), polymethyloxazoline (PMOX), polyethyloxazoline (PEOX), polypropyloxazoline (PPOX), polystyrene, polymethylmethacrylate (PMMA), or polydimethylsiloxane.

[0006]

[07] Asymmetric branched polymers (ABPs) can have two different types: regular ABPs and random ABPs. Asymmetric branched dendrimers or regular ABPs (reg-ABPs) often have a core, controlled and well-defined asymmetric (unequal length) branches and asymmetric branch connections, as described in U.S. Pat. Nos. 4,289,872, 4,360,646 and 4,410,688. On the other hand, random ABPs (ran-ABPs) a) have no core, b) have functional groups both on the exterior and in the interior, c) have random / variable branch lengths and patterns (i.e., terminal branches and chain branches), and d) have non-uniformly distributed interior spaces.

[0007]

[08] The synthesis and mechanism of ran-ABPs, such as those made from PEI, were reported by Jones et al., J. Org. Chem. 9, 125 (1944), Jones et al., J. Org. Chem. 30, 1994 (1965), and Dick et al., J. Macromol. Sci. Chem. A4(6), 1301-1314 (1970). ran-ABPs, such as those made from POX, poly(2-oxazoline), poly(2-methyloxazoline) (PMOX) and poly(2-ethyloxazoline) (PEOX), have been reported by Litt (J. Macromol. Sci. Chem. A 9(5):703-727 (1975)) and Warakomski (J. Polym. Sci. Polym. Chem. 28(3551):35 (1990)). The synthesis of ran-ABPs can often involve one-pot divergent or one-pot convergent methods.

[0008]

[09] A polymer can also be a homopolymer or a copolymer. A copolymer is a polymer or polymer backbone polymerized from different monomers or different monomer repeat units. A homopolymer can refer to a polymer or polymer backbone that is made of the same repeat units, i.e., a homopolymer is produced from the same monomer. A monomer can be a single compound or a complex or collection of compounds, where the complex or complex refers to the repeat units in a homopolymer.

[0009]

[0010] Branched polymers, including SBPs and ABPs, have been used for drug delivery, but these efforts have focused primarily on chemically binding the drug to the polymer or on physically encapsulating the drug within the polymer by monomolecular encapsulation (such as those described in U.S. Pat. Nos. 5,773,527, 5,631,329, 5,919,442, and 6,716,450). For example, dendrimers and dendrigrafts are believed to physically entrap bioactive molecules using monomolecular encapsulation methods, as described in U.S. Pat. Nos. 5,338,532, 5,527,524, and 5,714,166 for dense star polymers, and U.S. Pat. No. 5,919,442 for hypercomb-branched polymers. Similarly, monomolecular encapsulation of various drugs using SBP to form "dendrimer boxes" was reported in Tomalia et al., Angew. Chem. Int. Ed. Engl., 1990, vol. 29, p. 138, and in "Dendrimers and Other Dendritic Polymers," edited by Fréchet and Tomalia (John Wiley & Sons, Ltd., 2001, pp. 387-424).

[0010]

[0011] Branched core-shell polymers with hydrophobic cores and hydrophilic shells can be used to capture poorly water-soluble drugs by molecular encapsulation. Randomly branched and hyperbranched core-shell structures with hydrophilic cores and hydrophobic shells have also been used to carry drugs by monomolecular encapsulation and preformed nanomicelles (U.S. Patent No. 6,716,450 and Liu et al., Biomaterials 2010, vol. 10, pp. 1334-1341). However, those monomolecular and preformed micelle structures are generated in the absence of drugs.

[0011]

[0012] Block copolymers such as miktoarm polymers (i.e., Y-shaped / AB2-type star polymers) and linear (A)-dendritic (B) block copolymers have been observed to form stereocomplexes with paclitaxel (Nederberg et al., Biomacromolecules 2009, vol. 10, pp. 1460-1468 and Luo et al., Bioconjugate Chem. 2010, vol. 21, pp. 1216). These block copolymers are similar to traditional lipids or AB-type linear block copolymers, which are well-known surfactants used to generate micelles. However, such branched block copolymers are difficult to make and therefore not suitable for mass production.

[0012]

[0013] Water-insoluble or poorly water-soluble bioactive agents are difficult to formulate. Usually, multiple surfactants, detergents and other materials or complex high-energy emulsification processes may be required. Large biomolecules such as albumin have been used in certain formulations of water-insoluble paclitaxel, such as Abraxane®, available under the respective trade names from Celgene and Bristol-Myers Squibb. However, the availability and large-scale production of such biomolecules poses significant challenges.

[0013]

[0014] Vaccines can help the body recognize and destroy specific targets, such as cancer cells or microbes that cause infection. Adjuvants are typically used to modify, enhance or increase the effectiveness or potency of vaccines to achieve better immunity against certain diseases. Aluminum-containing adjuvants have been used in vaccines since the 1930s. Small amounts of aluminum are added to help the body build stronger immunity against microbes. Monophosphoryl lipid A (MPL) (also known as "AS04") is used in US vaccines (Cervarix®) and can have immune-enhancing effects. MF59, an oil-in-water emulsion-based adjuvant, contains squalene, a natural oil found in many plant and animal cells, as well as humans. MF59 adjuvant has been used in Fluad (an influenza vaccine licensed for adults 65 years and older) since 1997 in Europe and since 2016 in the US. Another adjuvant, AS01B, is an adjuvant suspension used with the antigen component of the Shingrix vaccine. AS01B is made from monophosphoryl lipid A (MPL) and QS-21, a natural compound extracted from the Chilean soapbark tree (Quillaja saponaria Molina). AS01B is also a component of vaccines currently being tested in clinical trials, including malaria and HIV vaccines. CpG1018, a 22-mer CpG ODN containing sequences with modified phosphorothioate backbones, is a recently developed adjuvant used in the Heplisav-B vaccine (registered trademark of Dynavax Technologies Corporation). CpG1018 contains a synthetic oligodeoxynucleotide with a cytosine phosphoguanine (CpG) motif (CpG ODN), which is an agonist of TLR9, mimicking the activity of natural CpG motifs found in DNA foreign to the body, such as bacterial and viral DNA. Summary of the Invention [Problem to be solved by the invention]

[0014]

[0015] There is a continuing need for new pharmaceutical formulations that can deliver drugs more effectively or improve vaccine efficacy by stimulating better immunity. [Means for solving the problem]

[0015]

[0016] In some cases, the present invention provides a pharmaceutical composition comprising nanoaggregates comprising a polymer and at least one water insoluble or poorly water soluble bioactive agent, and optionally a suitable carrier for pharmaceutical use, wherein the pharmaceutical composition is soluble in an aqueous solution to provide at least 1 mg / mL of the bioactive agent in the aqueous solution, the polymer is water soluble, the polymer comprises a first polymer comprising at least one first end group modified with H or a hydrophobic moiety, and a second end group modified with a hydrophilic moiety, wherein the first end group comprises in the range of 1%-99% H, and in the range of 1%-99% hydrophobic moieties comprising saturated or unsaturated aliphatic hydrocarbons, aromatic hydrocarbons, or combinations thereof having 1 to about 22 carbons, and the second end group comprises an amine, amide, imine, imide, carboxyl, hydroxyl, ester, ether, acetate, phosphite ... the first polymer as described above, or one or more of hydroxyl dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl terminated 4th, 5th, 6th, 7th, 8th, 9th, 10th generation dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); Pluronics® (PPO-PEO); poly(gamma-L-glutamic acid) (PGA); poly(L-phenylalanine ethyl ester) (PAE); poly(L-lysine) (PLL); methyl-PEG (mPEG); poly(aspartic acid) (PGA); poly(aspartic acid) ... acid)(PasP);poly(L-histidine)(PLH);poly(ethyleneamine)(PEI);poly(N-vinylpyrrolidone)(PVP);poly(L-leucine)(PLLeu);deoxycholic acid (DOCA);hydroxypropyl methylcellulose (HPMC);poly(hydroxybutyrate)(PHB);poly(ethylene oxide)(PEO);poly(gamma-benzyl-L-glutamate)(PBLG);phosphatidylserine (PS);poly(isohexyl-cyanoacrylate)(PIHCA);The present invention relates to pharmaceutical compositions comprising a second polymer comprising poly(allylamine hydrochlorine) (PAH); poly(γ-propargyl) (PP); or a combination thereof.

[0016]

[0017] In some cases, the pharmaceutical composition can be a medicament for treating or preventing a disease selected from one or more immune disorders, infectious diseases, cancer, and combinations thereof.

[0017]

[0018] In some cases, the pharmaceutical composition may be an adjuvant for a vaccine.

[0019] In some cases, the pharmaceutical composition may be a prophylactic vaccine, a therapeutic vaccine, or a combination thereof, and the pharmaceutical composition further comprises at least one immunological agent that stimulates an immune response in a subject in need thereof.

[0018]

[0020] In some cases, the present invention is directed to a method of treating or preventing a disease in a subject in need thereof, comprising administering to the subject an effective dose of a pharmaceutical composition disclosed herein.

[0019]

[0021] In some cases, the present invention provides a nanoaggregate comprising a polymer and at least one water insoluble or poorly water soluble bioactive agent, wherein the nanoaggregate is soluble in an aqueous solution to yield at least 1 mg / mL of the bioactive agent in the aqueous solution, the polymer is water soluble, the bioactive agent comprises a natural or synthetic small molecule based drug, an inorganic based drug, a biopharmaceutical, a natural or synthetic macromolecule based drug, derivatives thereof, or combinations thereof, the polymer has at least one first end group modified with H or a hydrophobic moiety, and a hydrophilic moiety. a first polymer comprising a second end group modified with a moiety, the first end group comprising in the range of 1%-99% H and in the range of 1%-99% hydrophobic moieties comprising saturated or unsaturated aliphatic hydrocarbons having 1 to about 22 carbons, aromatic hydrocarbons, or combinations thereof, and the second end group comprising a group modified with an amine, an amide, an imine, an imide, a carboxyl, a hydroxyl, an ester, an ether, an acetate, a phosphate, a ketone, an aldehyde, a sulfonate, or combinations thereof; Multiple hydroxyl dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated 4th, 5th, 6th, 7th, 8th, 9th, 10th generation dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); Pluronics® (PPO-PEO); poly(gamma-L-glutamic acid) (PGA); poly(L-phenylalanine ethyl ester) ... poly(L-lysine) (PLL); methyl-PEG (mPEG); poly(aspartic acid) (PasP); poly(L-histidine) (PLH); poly(ethyleneamine) (PEI); poly(N-vinylpyrrolidone) (PVP); poly(L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly(hydroxybutyrate) (PHB); poly(ethylene oxide) (PEO); poly(gamma-benzyl-L-glutamate) (PBLG); phosphatidylserine (PS);The nanoaggregates include a second polymer, the second polymer comprising poly(isohexyl-cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); or a combination thereof. [Brief description of the drawings]

[0020] [Figure 1A]

[0022] Figure 1A is an example of an SBP that contains a dendrimer. Figure 1B is an example of an SBP that contains a dendrigraft. Figure 1C is an example of an SBP that contains a regular comb-branched polymer. Figure 1D is an example of an SBP that contains a star-branched polymer. All have either a spherical or linear core. [Figure 1B] Figure 1A is an example of an SBP that contains a dendrimer. Figure 1B is an example of an SBP that contains a dendrigraft. Figure 1C is an example of an SBP that contains a regular comb-branched polymer. Figure 1D is an example of an SBP that contains a star-branched polymer. All have either a spherical or linear core. [Figure 1C] Figure 1A is an example of an SBP that contains a dendrimer. Figure 1B is an example of an SBP that contains a dendrigraft. Figure 1C is an example of an SBP that contains a regular comb-branched polymer. Figure 1D is an example of an SBP that contains a star-branched polymer. All have either a spherical or linear core. [Figure 1D] Figure 1A is an example of an SBP that contains a dendrimer. Figure 1B is an example of an SBP that contains a dendrigraft. Figure 1C is an example of an SBP that contains a regular comb-branched polymer. Figure 1D is an example of an SBP that contains a star-branched polymer. All have either a spherical or linear core. [Figure 2A]

[0023] Figure 2 shows examples of chemical structures of symmetrically branched polypropyleneimine (PPI) dendrimers. Figure 2A: Dendrimer with 4-PPI. Figure 2B: Dendrimer with an additional 8-PPI. [Figure 2B]Figure 2 shows examples of chemical structures of symmetrically branched polypropyleneimine (PPI) dendrimers. Figure 2A: Dendrimer with 4-PPI. Figure 2B: Dendrimer with an additional 8-PPI. [Diagram 3]

[0024] Figure 3 shows examples of chemical modification reactions of symmetrically branched PPI dendrimers. The numbers 8, 16, 32, 64, 128, etc. indicate the number of reactive groups on the surface of the dendrimer. [Figure 4]

[0025] Figure 4A is an example of a schematic diagram of a random asymmetrically branched polymer (ABP) with symmetric branch junctions and patterns. Figure 4B is an example of a schematic diagram of a regular asymmetrically branched polymer (ABP) with symmetric branch junctions and patterns. [Diagram 5]

[0026] FIG. 5 is an example of the chemical structure of a random asymmetrically branched PEI homopolymer. [Figure 6A]

[0027] Figures 6A-6C are examples of synthesis schemes. Figure 6A: Chemical modification reaction of random asymmetrically branched PEI homopolymer. Figure 6B: Example of one-pot synthesis of hydrophobically modified random branched poly(2-ethyloxazoline) with a primary amino group at the focal point of the polymer. The initiator / surface group (I) is a brominated hydrocarbon. This reaction opens the oxazoline ring. Figure 6C: Non-limiting example of a polymer with different first and second end groups. [Figure 6B] Figures 6A-6C are examples of synthesis schemes. Figure 6A: Chemical modification reaction of random asymmetrically branched PEI homopolymer. Figure 6B: Example of one-pot synthesis of hydrophobically modified random branched poly(2-ethyloxazoline) with a primary amino group at the focal point of the polymer. The initiator / surface group (I) is a brominated hydrocarbon. This reaction opens the oxazoline ring. Figure 6C: Non-limiting example of a polymer with different first and second end groups. [Figure 6C]Figures 6A-6C are examples of synthesis schemes. Figure 6A: Chemical modification reaction of random asymmetrically branched PEI homopolymer. Figure 6B: Example of one-pot synthesis of hydrophobically modified random branched poly(2-ethyloxazoline) with a primary amino group at the focal point of the polymer. The initiator / surface group (I) is a brominated hydrocarbon. This reaction opens the oxazoline ring. Figure 6C: Non-limiting example of a polymer with different first and second end groups. [Figure 7]

[0028] FIG. 7A is an example of an exemplary schematic diagram of a drug loaded in or on a surface domain or region of a branched polymer SBP. In this and other figures, R represents a surface group and the filled circle illustrates a bioactive agent such as a drug of interest. FIG. 7B is an example of an exemplary schematic diagram of a drug loaded in or on a surface domain or region of a branched polymer ABP. In this and other figures, R represents a surface group and the filled circle illustrates a bioactive agent such as a drug of interest. [Figure 8]

[0029] FIG. 8 is a schematic diagram of an example of a nanoparticle containing both a drug molecule (filled circle) and a branched polymer with surface groups (R). [Figure 9]

[0030] Figure 9A is an exemplary schematic diagram of a water-insoluble or poorly water-soluble drug loaded onto a hydrophobic surface group of a branched polymer SBP. In this and other figures, the thin wavy lines illustrate the hydrophobic surface group. And / or Figure 9B is an exemplary schematic diagram of a water-insoluble or poorly water-soluble drug loaded onto a hydrophobic surface group of a branched polymer ABP. In this and other figures, the thin wavy lines illustrate the hydrophobic surface group. [Figure 10]

[0031] Figure 10A is a schematic example of various drug-containing nanoparticles SBPs that also have at least one targeting group or moiety, such as an antibody, depicted as "Y" in this and other figures. Figure 10B is a schematic example of various drug-containing nanoparticles ABPs that also have at least one targeting group or moiety, such as an antibody, depicted as "Y" in this and other figures. [Figure 11]

[0032] FIG. 11A is an example of light scattering (LS) measurement data of nanoaggregates. Polymer A1 and rapamycin are in a ratio of 5:1. FIG. 11B is an example of light scattering (LS) measurement data of nanoaggregates. Polymer A1 and rapamycin are in a ratio of 7.5:1. FIG. 11C is an example of light scattering (LS) measurement data of nanoaggregates. Polymer B1 and rapamycin are in a ratio of 5:1. [Figure 12A]

[0033] Formulas of examples of STING agonists. Formulas (1) to (6). Figure 12A: Formulas (7) to (12). Figure 12C: Formulas (13) to (18). Figure 12D: Formulas (19) to (24). Figure 12E: Formulas (25) to (29). [Figure 12B] Formulas of examples of STING agonists. Formulas (1) to (6). Figure 12A: Formulas (7) to (12). Figure 12C: Formulas (13) to (18). Figure 12D: Formulas (19) to (24). Figure 12E: Formulas (25) to (29). [Figure 12C] Formulas of examples of STING agonists. Formulas (1) to (6). Figure 12A: Formulas (7) to (12). Figure 12C: Formulas (13) to (18). Figure 12D: Formulas (19) to (24). Figure 12E: Formulas (25) to (29). [Figure 12D] Formulas of examples of STING agonists. Formulas (1) to (6). Figure 12A: Formulas (7) to (12). Figure 12C: Formulas (13) to (18). Figure 12D: Formulas (19) to (24). Figure 12E: Formulas (25) to (29). [Figure 12E] Formulas of examples of STING agonists. Formulas (1) to (6). Figure 12A: Formulas (7) to (12). Figure 12C: Formulas (13) to (18). Figure 12D: Formulas (19) to (24). Figure 12E: Formulas (25) to (29). [Figure 13A] Figure 13A is a representative molecule of an example bioactive agent: SN-38, 7-ethyl-10-hydroxycamptothecin. [Figure 13B] Figure 13B is a representative molecule of an example bioactive agent: irinotecan, also known by the trade names CPT-11, Camptosar®, Campto, and Onivyde®, respectively. [Figure 13C]Figure 13C is a representative molecule of an example bioactive agent: Camptothecin (CPT). [Figure 13D] Figure 13D is a representative molecule of an example bioactive agent: Topotecan, also known as Hycamtin. [Figure 13E] Figure 13E shows representative molecules of examples of bioactive agents, with trade names SN-38ADC and TRODELVY® (hRS7-SN38ADC), respectively. [Figure 14A]

[0034] Figures 14A-14E are representative measurement data for nanoaggregate particles. Figure 14A: One example of nanoaggregates (formulation 1). Figure 14B: Another example of nanoaggregates (formulation 2). Figure 14C: Another example of nanoaggregates (formulation 3). Figure 14D: Another example of nanoaggregates (formulation 4). Figure 14E: Another example of nanoaggregates (formulation 5). [Figure 14B] Figures 14A-14E are representative measurement data for nanoaggregate particles. Figure 14A: One example of nanoaggregates (formulation 1). Figure 14B: Another example of nanoaggregates (formulation 2). Figure 14C: Another example of nanoaggregates (formulation 3). Figure 14D: Another example of nanoaggregates (formulation 4). Figure 14E: Another example of nanoaggregates (formulation 5). [Figure 14C] Figures 14A-14E are representative measurement data for nanoaggregate particles. Figure 14A: One example of nanoaggregates (formulation 1). Figure 14B: Another example of nanoaggregates (formulation 2). Figure 14C: Another example of nanoaggregates (formulation 3). Figure 14D: Another example of nanoaggregates (formulation 4). Figure 14E: Another example of nanoaggregates (formulation 5). [Figure 14D] Figures 14A-14E are representative measurement data for nanoaggregate particles. Figure 14A: One example of nanoaggregates (formulation 1). Figure 14B: Another example of nanoaggregates (formulation 2). Figure 14C: Another example of nanoaggregates (formulation 3). Figure 14D: Another example of nanoaggregates (formulation 4). Figure 14E: Another example of nanoaggregates (formulation 5). [Figure 14E]Figures 14A-14E are representative measurement data for nanoaggregate particles. Figure 14A: One example of nanoaggregates (formulation 1). Figure 14B: Another example of nanoaggregates (formulation 2). Figure 14C: Another example of nanoaggregates (formulation 3). Figure 14D: Another example of nanoaggregates (formulation 4). Figure 14E: Another example of nanoaggregates (formulation 5). [Figure 15]

[0035] FIG. 15 shows representative SN-38 cytotoxicity data using the HCT-116 cell line. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021]

[0036] The features and advantages of the present invention will be more readily understood by those skilled in the art from a reading of the following detailed description. It should be understood that certain features of the present invention described above and below in the context of separate embodiments may also be provided in combination with a single embodiment. Conversely, various features of the present invention that are described for brevity in the context of a single embodiment may also be provided separately or in any combination or subcombination. Furthermore, references in the singular may also include the plural (e.g., "a" and "an" may refer to one, or one or more) unless the context specifically dictates otherwise.

[0022]

[0037] The use of various ranges of numerical values ​​specified in this application are described as approximations, as if the word "about" preceded both the minimum and maximum values ​​in the stated range, unless expressly indicated otherwise. In this manner, slight variations above and below the stated range can be used to achieve substantially the same results as values ​​within the range. Similarly, the disclosure of ranges is intended as a continuous range including all values ​​between the minimum and maximum values, and including the recited minimum and maximum values.

[0023]

[0038] Solubility of drugs in this disclosure is defined as <30 (soluble), 30-100 (slightly soluble), and >100 (insoluble) relative to the number of parts of solvent required to dissolve one part bioactive agent or drug. Water solubility is defined herein as <30 (soluble), 30-100 (slightly soluble), and >100 (insoluble) relative to the number of parts of water required to dissolve one part bioactive agent or drug.

[0024]

[0039] For the purposes of this disclosure, randomly branched PEI is considered a homopolymer because, although there are branches of different lengths and the branches occur randomly, the branched polymer is composed of a single monomer, ethyleneimine or aziridine repeat unit. A polymer having the structure "(AB)-(AB)-(AB)-..." can also be considered a homopolymer because of the (AB) repeat unit. A homopolymer can be linear or branched. Similarly, one or more of the monomers or complex monomer components can be modified, substituted, derivatized, etc., e.g., modified to have functional groups. Such molecules are homopolymers for the purposes of this disclosure because the polymer backbone is composed of a single type of simple or complex monomer.

[0025]

[0040] The term "polymer" refers to any polymer suitable for the present invention, as defined above and hereinafter. In an example, the polymer can include a polyoxazoline or modified polyoxazoline as disclosed herein. In a further example, the polymer can include a modified polyoxazoline, where the modified polyoxazoline is selected from the group consisting of -NH2, -NH, -NH3, -NH4, -NH5, -NH6, -NH7, -NH8, -NH9, -NH10, -NH11, -NH12, -NH13, -NH14, -NH15, -NH16, -NH17, -NH18, -NH19, -NH21, -NH22, -NH33, -NH34, -NH35, -NH36, -NH37, -NH38, -NH39, -NH41 ... + , other basic groups, or combinations thereof, provided that in the range of 0.01%-100% of the second end groups are free of primary amines. In some cases, in the range of 0.01%-100%, 0.1%-100%, or 1%-100% of the second end groups are free of primary amines. In some cases, in the range of 1%-100% of the second end groups can include hydroxyl groups. All percentages are based on the total number of second end groups.

[0026]

[0041] The term "bioactive agent" or "bioactive agents" refers to a molecule, a compound, a complex of one or more compounds or molecules, or a combination thereof, that can provide a biological activity in vivo, in vitro, or a combination thereof. A pharmaceutical composition can include one or more bioactive agents, such as a pharma- ceutical active agent (PAA) or active pharmaceutical ingredient (API), and other bioactive or inactive compounds, which can include emollients, bleaches, antiperspirants, medicines, moisturizers, perfumes, colorants, pigments, dyes, antioxidants, oils, fatty acids, lipids, inorganic salts, organic molecules, opacifiers, vitamins, pharmaceuticals, keratolytic agents, UV blocking agents, tanning accelerators, depigmenting agents, deodorants, fragrances, insect repellents, or combinations thereof. Some examples of bioactive agents are described in detail in this disclosure.

[0027]

[0042] The term "taxane" refers to paclitaxel, docetaxel, cabazitaxel, larotaxel, mirataxel, ortataxel, tesetaxel, or combinations thereof. In some cases, paclitaxel may be preferred.

[0028]

[0043] The term "rapamycin" may also be referred to as "sirolimus" and used interchangeably throughout this disclosure.

[0044] The term "mTOR" refers to the mammalian target of rapamycin, which comprises a protein kinase that regulates cell growth, survival, metabolism and immunity. mTOR can be organized into several complexes, such as mTOR complex 1 (mTORC1), mTOR complex 2 (mTORC2) and mTOR complex 3 (mTORC3). Activation of mTOR can promote tumor growth and metastasis. Inhibition of mTOR with one or more mTOR inhibitors can be used to treat cancer.

[0029]

[0045] The terms "mTOR inhibitor", "mTOR inhibitors", "inhibitor of mTOR" or "inhibitors of mTOR" refer to molecules that inhibit the activity of mTOR or the mTOR complex. Some examples of mTOR inhibitor drugs or molecules include everolimus available as AFINITOR® and tablets / AFINITOR DISPERZ® (trademarks of Novartis), Zortress® (Pfizer); temsirolimus available as Torisel® (Pfizer); sirolimus (rapamycin) available as Rapamune® (Pfizer) and FYARRO™ (Aadi trademarks of Bioscience, Inc.; zotarolimus; Torin-1; Torin-2; bistusertib; ridaforolimus (also known as AP23573 and MK-8669 or deforolimus); one or more dual PI3K-mTOR inhibitors (such as PKI-402, SPR965, PI-103, GNE477, WJD008, GSK2126458); one or more ATP-competitive mTORC1 / 2 inhibitors (such as AZD-8055, OSI-027, INK128, WYE-132, Torin-1); apitolisib (GDC-0980 or RG7422), AZD8055, BGT226, CC-223, CH5132799, chrysophanol, dactolisib, ETP-46464, GDC-0349, gedatolisib, GNE-493, GSK1059615, INK128, KU-0063794, LY3023414, MHY1485, mTOR-IN-1, omipalisib, OSI-027, palomido 529, PF-04691502, PF-04979064, PI-103, PP121, QL-IX-55, SF1126, tacrolimus, tolquinib, bistusertib, voxtalisib, VS-5584, WAY-600, WYE-125132, WYE-354, WYE-687, XL388, derivatives thereof, or combinations thereof. Commercially available mTOR inhibitors, such as those available from Adooq Biosciences, may be suitable.

[0030]

[0046] SN-38 (7-ethyl-10-hydroxycamptothecin) is a topoisomerase 1 (herein, "Top1" or "TopI") inhibitor and camptothecin derivative. Irinotecan (CPT-11) is a water-soluble camptothecin analog and a prodrug of SN-38. Since the discovery of camptothecin in the bark of Camptotheca acuminata, the development of camptothecin derivatives as anticancer drugs has led to the approval of several drugs, such as irinotecan for the treatment of colon or colorectal cancer, topotecan for the treatment of small cell lung cancer, ovarian cancer and cervical cancer, as well as antibody drug conjugates (ADCs) using SN-38 as the payload. SN-38 drug products are not currently approved for chemotherapy due to their low solubility and high toxicity. Studies have been reported on polymer-conjugated SN-38 (Sapra, P. et al., Clin. Cancer Res., vol. 14(6):1888, 2008) and polymeric micelle SN-38 (Carie, A. et al., J. Drug Delivery, vol. 2011, pp. 9, 2011, doi:10.1155 / 2011 / 869027), which were made by linking SN-38 with multi-arm polyethylene glycol via a glycine linker. However, their synthesis and production are complicated.

[0031]

[0047] In some cases, other topoisomerase inhibitors, such as topoisomerase II (herein "Top2" ​​or "TopII") inhibitors, such as doxorubicin, etoposide, quinolone, fluoroquinolone or combinations thereof, may also be suitable for the pharmaceutical compositions, processes and methods disclosed herein.In some cases, quinolones that target the two essential Top2 enzymes of bacteria, DNA gyrase and DNA topoisomerase IV, may be suitable.In some cases, the pharmaceutical compositions may be suitable for treating infectious diseases.

[0032]

[0048] The term "medicinal suitable carrier", "medicinal suitable carriers", "pharmaceutical suitable carrier" or "pharmaceutical suitable carriers" refers to one or more inactive ingredients present in an approved drug product. Inactive ingredients listed in the database "Inactive Ingredients in Approved Drug Products" maintained and updated by the US Food and Drug Administration (FDA) may be suitable. In some cases, a pharmaceutical suitable carrier may also be referred to as an excipient.

[0033]

[0049] The term "subject" or "subjects" as used throughout this disclosure refers to animals, humans, or human patients. The term "animal" refers to wild animals, captive animals, or animals kept in zoos, as well as domesticated animals, including horses, cows, pigs, donkeys, mules, camels, goats, sheep, monkeys, rabbits, dogs, cats, mice, rats, and other poultry, livestock, pets, and laboratory animals. Warm-blooded animals are preferred. The term "human" refers to a human patient having one or more diseases requiring treatment, a human having one or more medical conditions unrelated to treatment, or a healthy human. In some cases, the subject may be a human patient or a healthy human.

[0034]

[0050] The terms "antibody," "antibodies," or "fragment of an antibody" can include natural or synthetic antibodies that selectively bind to an antigen. The term includes polyclonal and monoclonal antibodies produced in animals, cells, including eukaryotic or prokaryotic cells, cell-free systems, or chemical synthesis. The term "antibody" includes intact immunoglobulin molecules, as well as fragments or polymers of those immunoglobulin molecules, and human or humanized forms of immunoglobulin molecules that selectively bind to a target antigen.

[0035]

[0051] The term "aqueous solution" or "aqueous solutions" as used throughout this disclosure refers to a solution containing water in the range of 80%-100% as a percentage of the total non-solid weight of the aqueous solution. The aqueous solution may further contain additional components such as salts, acids, bases, buffers, solvents, organic solvents, particles, emulsions, solids or non-solids, detergents, small molecules, large molecules, other ingredients, or combinations thereof. The term "non-solid weight" refers to the weight derived from the solids content after the aqueous solution has been dried, such as by removing all water or other liquids.

[0036]

[0052] The term "infectious disease" or "infectious diseases" refers to a disease caused by a harmful organism (pathogen) such as a bacterium, a virus, a fungus, a protozoan, an insect, a parasite, a prion, a portion thereof, or a combination thereof. Infectious diseases can be transmitted between humans through contact with animals, insects, or from contaminated food, water, or soil. Some examples of infectious diseases may include Chicken Pox (Varicella), Coronavirus, Dengue Fever, Diphtheria, Ebola, Influenza (Influenza), Hepatitis, Hib Disease, HIV / AIDS, HPV (Human Papilloma Virus), Japanese Encephalitis, Measles, Meningococcal Disease, Empox, Mumps, Norovirus, Pneumococcal Disease, Polio, Rabies, Respiratory Syncytial Virus (RSV), Rotavirus, Rubella (German Measles), Shingles (Herpes Zoster), Tetanus (Lockjaw), Whooping Cough (Pertussis), Zika and other known diseases or diseases yet to emerge or be identified.

[0037]

[0053] The term "vaccine" or "vaccines" refers to a substance or group of substances designed to induce a response from the immune system of a subject, such as a human or animal, against a microorganism, such as a bacteria, a virus, a fungus, a protozoan, an insect, a parasite, a prion, other harmful organisms (pathogens), or a tumor. A vaccine can help the body recognize and destroy a microorganism or a cancer cell. In some cases, a vaccine can include a protein from a microorganism or from a cancer cell, a nucleic acid encoding a protein, a toxin, a nucleic acid, an oligonucleic acid, DNA, RNA; mRNA; siRNA; sgRNA; or a combination thereof. In some cases, a vaccine can include a modified protein, a nucleic acid encoding a modified protein, a toxin, a nucleic acid, a modified nucleic acid, an oligonucleic acid, or a modified oligonucleic acid; DNA, RNA; mRNA; siRNA; sgRNA; or a combination thereof that is designed to induce a response from the immune system to a microorganism or a cancer cell. Modified or synthetic DNA, RNA, mRNA, siRNA, sgRNA, or a combination thereof may also be suitable.

[0038]

[0054] The term "adjuvant" or "adjuvants" refers to a drug, substance, reagent, or combination thereof used to modify, enhance, or increase the effectiveness or potency of a vaccine to provide better immunity against a particular disease. Adjuvants can include one or more organic molecules; antigenic molecules that can mimic certain pathogen-associated molecular patterns (this includes liposomes, liposaccharides, molecular cages of antigens, components of bacterial cell walls, and endocytosed nucleic acids such as RNA, double-stranded RNA (dsRNA), DNA, single-stranded DNA (ssDNA), methylated or unmethylated CpG dinucleotide-containing DNA); inorganic compounds such as potassium alum, aluminum hydroxide, aluminum phosphate, calcium hydroxide phosphate; oils such as paraffin oil, propolis, peanut oil, bacterial products such as killed bacteria, plant products such as those derived from soybeans or other plants; cytokines such as IL-1, IL-2, or IL-12; or combinations thereof.

[0039]

[0055] The terms "isomer" or "isomers" refer to molecules that share the same chemical formula but have their atoms connected differently or arranged differently in space, including structural isomers where the atoms are bonded together in a different order, geometric isomers where the atoms are bonded in the same order but have different configurations around the bonds (such as cis isomers or trans isomers), and enantiomers that have the same chemical structure but differ in the three-dimensional arrangement of atoms around an asymmetric carbon and are thus mirror images of one another.

[0040]

[0056] In some cases, the disclosure provides:

[0057] nanoaggregates comprising a polymer and at least one water-insoluble or poorly water-soluble bioactive agent;

[0058] A pharmaceutical composition, which may include a suitable carrier for pharmaceutical use,

[0059] the pharmaceutical composition is soluble in an aqueous solution to provide at least 1 mg / mL of the bioactive agent in the aqueous solution;

[0060] The polymer is water soluble;

[0061] The polymer

[0062] a first polymer comprising at least one first end group modified with H or a hydrophobic moiety, and a second end group modified with a hydrophilic moiety, wherein the first end group comprises in the range of 1%-99% H and in the range of 1%-99% hydrophobic moiety, which may comprise saturated or unsaturated aliphatic hydrocarbons having 1 to about 22 carbons, aromatic hydrocarbons, or combinations thereof, and the second end group comprises a group modified with an amine, amide, imine, imide, carboxyl, hydroxyl, ester, ether, acetate, phosphate, ketone, aldehyde, sulfonate, or combinations thereof; or

[0063] One or more hydroxyl dendrimers (HD) (also known as hydroxyl-terminated dendrimers); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated generation 4, 5, 6, 7, 8, 9, 10 dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); Pluronics® (PPO-PEO); poly(gamma-L-glutamic acid) (PGA); poly(L-phenylalanine ethyl ester) (PAE); poly(L-lysine ) (PLL); methyl-PEG (mPEG); poly(aspartic acid) (PasP); poly(L-histidine) (PLH); poly(ethyleneamine) (PEI); poly(N-vinylpyrrolidone) (PVP); poly(L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly(hydroxybutyrate) (PHB); poly(ethylene oxide) (PEO); poly(gamma-benzyl-L-glutamate) (PBLG); phosphatidylserine (PS); poly(isohexyl-cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(gamma-propargyl) (PP);

[0064] or a combination of these A second polymer comprising: The present invention is directed to a pharmaceutical composition which may include:

[0041]

[0065] In some cases, the polymer can include a first polymer as disclosed herein comprising at least one first end group modified with H or a hydrophobic moiety, and a second end group modified with a hydrophilic moiety, wherein the first end group comprises in the range of 1%-99% H and in the range of 1%-99% hydrophobic moiety, which can include saturated or unsaturated aliphatic hydrocarbons having 1 to about 22 carbons, aromatic hydrocarbons, or combinations thereof, and the second end group comprises a group modified with an amine, amide, imine, imide, carboxyl, hydroxyl, ester, ether, acetate, phosphate, ketone, aldehyde, sulfonate, or combinations thereof.

[0042]

[0066] In some cases, the polymer may consist of a first polymer as disclosed herein comprising at least one first end group modified with H or a hydrophobic moiety, and a second end group modified with a hydrophilic moiety, wherein the first end group comprises in the range of 1%-99% H and in the range of 1%-99% hydrophobic moiety, which may include saturated or unsaturated aliphatic hydrocarbons having 1 to about 22 carbons, aromatic hydrocarbons, or combinations thereof, and the second end group comprises a group modified with an amine, amide, imine, imide, carboxyl, hydroxyl, ester, ether, acetate, phosphate, ketone, aldehyde, sulfonate, or combinations thereof. In some cases, the pharmaceutical composition comprises one or more of hydroxyl dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated generation 4, 5, 6, 7, 8, 9, 10 dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); Pluronics® (PPO-PEO); poly(gamma-L-glutamic acid) (PGA); poly(L-phenylalanine ethyl ester) (PAE); poly(L-lysine) (PLL); methyl-PEG (mPEG). ; poly(aspartic acid) (PasP); poly(L-histidine) (PLH); poly(ethyleneamine) (PEI); poly(N-vinylpyrrolidone) (PVP); poly(L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly(hydroxybutyrate) (PHB); poly(ethylene oxide) (PEO); poly(γ-benzyl-L-glutamic acid) (PBLG); phosphatidylserine (PS); poly(isohexyl-cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); and combinations thereof.

[0043]

[0067] In some cases, the polymer may be one or more of hydroxyl dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated generation 4, 5, 6, 7, 8, 9, 10 dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); Pluronics® (PPO-PEO); poly(gamma-L-glutamic acid) (PGA); poly(L-phenylalanine ethyl ester) (PAE); poly(L-lysine) (PLL); methyl-PEG (mPEG); poly(propylene oxide) (PPO ... The second polymer may include poly(aspartic acid) (PasP); poly(L-histidine) (PLH); poly(ethyleneamine) (PEI); poly(N-vinylpyrrolidone) (PVP); poly(L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropylmethylcellulose (HPMC); poly(hydroxybutyrate) (PHB); poly(ethylene oxide) (PEO); poly(γ-benzyl-L-glutamic acid) (PBLG); phosphatidylserine (PS); poly(isohexyl-cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); or a combination thereof.

[0044]

[0068] In some cases, the polymer may be one or more of hydroxyl dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated generation 4, 5, 6, 7, 8, 9, 10 dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); Pluronics® (PPO-PEO); poly(gamma-L-glutamic acid) (PGA); poly(L-phenylalanine ethyl ester) (PAE); poly(L-lysine) (PLL); methyl-PEG (mPEG); poly (aspartic acid) (PasP); poly(L-histidine) (PLH); poly(ethyleneamine) (PEI); poly(N-vinylpyrrolidone) (PVP); poly(L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropylmethylcellulose (HPMC); poly(hydroxybutyrate) (PHB); poly(ethylene oxide) (PEO); poly(γ-benzyl-L-glutamic acid) (PBLG); phosphatidylserine (PS); poly(isohexyl-cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); and combinations thereof. In some cases, the polymer may only include the polymers listed above and may not include the above-mentioned polymers that include at least one first end group modified with H or a hydrophobic moiety and a second end group modified with a hydrophilic moiety.

[0045]

[0069] In some cases, the polymer comprises a first polymer and one or more of hydroxyl dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated 4th, 5th, 6th, 7th, 8th, 9th, 10th generation dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); Pluronics® (PPO-PEO); poly(gamma-L-glutamic acid) (PGA); poly(L-phenylalanine ethyl ester) (PAE); poly(L-lysine) (PLL); methyl-PEG (mPEG); poly(aspartic acid ) (PasP); poly(L-histidine) (PLH); poly(ethyleneamine) (PEI); poly(N-vinylpyrrolidone) (PVP); poly(L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropylmethylcellulose (HPMC); poly(hydroxybutyrate) (PHB); poly(ethylene oxide) (PEO); poly(γ-benzyl-L-glutamic acid) (PBLG); phosphatidylserine (PS); poly(isohexyl-cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); and combinations thereof.

[0046]

[0070] In some cases, the polymer can include a polyoxazoline (POX) that includes a linear portion, a branched portion, or a combination thereof, and the polyoxazoline (POX) can include poly(2-methyloxazoline), poly(2-ethyloxazoline), poly(2-propyloxazoline), poly(isopropyloxazoline), or a combination thereof. In some cases, the polyoxazoline can be poly(2-ethyloxazoline).

[0047]

[0071] In some cases, the polyoxazoline may include a molar ratio of monomer to initiator ranging from 50:1 to 80:1.

[0072] In some cases, 1% to 100% of the second terminal groups are free of primary amines. In some cases, the pharmaceutical compositions disclosed herein may include 1% to 100% of the second terminal groups as hydroxyl groups. All percentages are based on the total number of second terminal groups.

[0048]

[0073] In some cases, the first end groups, as a percentage of the total number of first end groups in the polymer, are 1%-99% H and 1%-99% hydrophobic moieties, 1%-90% H and 10%-99% hydrophobic moieties, 1%-85% H and 15%-99% hydrophobic moieties, 1%-80% H and 20%-99% hydrophobic moieties, 1%-75% H and 25%-99% hydrophobic moieties, 1%-70% H and 30%-99% hydrophobic moieties, 1%-65% H and 35%-99% hydrophobic moieties, 1%-60% H and 40%-99% hydrophobic moieties, 1%-55% H and 45%-99% hydrophobic moieties, 1%-50% H and and 65%-99% hydrophobic portion, 1%-45% H and 55%-99% hydrophobic portion, 1%-40% H and 60%-99% hydrophobic portion, 1%-35% H and 65%-99% hydrophobic portion, 1%-30% H and 70%-99% hydrophobic portion, 1%-25% H and 75%-99% hydrophobic portion, 1%-20% H and 80%-99% hydrophobic portion, 1%-15% H and 85%-99% hydrophobic portion, 1%-10% H and 90%-99% hydrophobic portion, 1%-5% H and 95%-99% hydrophobic portion, 1% H and 99% hydrophobic portion, including percentages within the ranges. In some cases, the first end groups, as a percentage of the total number of first end groups in the polymer, include 1%-50% H and 50%-99% hydrophobic moieties, 1%-40% H and 60%-99% hydrophobic moieties, 1%-30% H and 70%-99% hydrophobic moieties, 1%-20% H and 80%-99% hydrophobic moieties, 1%-10% H and 90%-99% hydrophobic moieties, 1%-5% H and 95%-99% hydrophobic moieties, or 1%-2% H and 98%-99% hydrophobic moieties, including all percentages within that range. In some cases, the percentage is based on the number of moles of first end groups in the polymer.

[0049]

[0074] Alternatively, a ratio of H to hydrocarbon groups ("hydrocarbon") can be used to describe the polymer, such as H:hydrocarbon = 0.01:1 to 100:1. In some cases, the first end group comprises a ratio of H:hydrophobic moieties in the range of 0.01:1 to 100:1, including all ratios within that range. In some cases, the first end group comprises a ratio of H:hydrophobic moieties in the range of 0.01:1 to 100:1, 0.1:1 to 100:1, 0.2:1 to 100:1, 0.5:1 to 100:1, 0.7:1 to 100:1, 1:1 to 100:1, 2.0:1 to 100:1, 5:1 to 100:1, 10:1 to 100:1, 20:1 to 100:1, 30:1 to 100:1, 40:1 to 100:1, 50:1 to 100:1, 60:1 to 100:1, 70:1 to 100:1, 80:1 to 100:1, 90:1 to 100:1, and 95:1 to 100:1, including all ratios therein. In some cases, the first end group comprises a ratio of H:hydrophobic moiety in the range of 0.01:1 to 10:1, 0.1:1 to 10:1, 0.1:1 to 10:1, 0.2:1 to 10:1, 0.5:1 to 10:1, 0.7:1 to 10:1, 1:1 to 10:1, 2.0:1 to 10:1, 5:1 to 10:1, 10:1, 20:1 to 10:1, 30:1 to 10:1, 40:1 to 10:1, 50:1 to 10:1, 60:1 to 10:1, 70:1 to 10:1, 80:1 to 10:1, 90:1 to 10:1, and 95:1 to 10:1, including all ratios therein. In some cases, the first end group comprises a ratio of H:hydrophobic moiety in the range of 0.01:1 to 5:1, 0.1:1 to 5:1, 0.1:1 to 5:1, 0.2:1 to 5:1, 0.5:1 to 5:1, 0.7:1 to 5:1, 1:1 to 5:1, 2.0:1 to 5:1, 5:1, 10:1, 20:1 to 5:1, 30:1 to 5:1, 40:1 to 5:1, 50:1 to 5:1, 60:1 to 5:1, 70:1 to 5:1, 80:1 to 5:1, 90:1 to 5:1, and 95:1 to 5:1, including all ratios therein.In some cases, the first end group comprises a ratio of H:hydrophobic moieties that can be selected from 0.01:1, 0.1:1, 0.2:1, 0.5:1, 0.7:1, 1:1, 2.0:1, 3.0:1, 4.0:1, 5;1, 6;1, 7:1, 8:1, 9:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 95:1, and 100:1, including all ratios within the range, which can be based on the molar ratio of H to hydrocarbon groups.

[0050]

[0075] Percentages and ratios can be readily converted by conventional methods, for example, a ratio of 0.01:1 can be converted to about 1%, 0.2:1 can be converted to about 17%, 0.5:1 can be converted to about 33%, 1:1 can be converted to about 50%, 1.5:1 can be converted to about 60%, 2:1 can be converted to about 67%, 5:1 can be converted to about 83%, 10:1 can be converted to about 90%, 20:1 can be converted to about 95%, and 100:1 can be converted to about 99%.

[0051]

[0076] The percentage or ratio of hydrogen-modified and hydrocarbon-modified first end groups can be measured using HPLC, as known to those skilled in the art.

[0077] In the pharmaceutical compositions disclosed herein, the first terminal group can include a hydrophobic moiety that can include H or a saturated or unsaturated aliphatic hydrocarbon having 1 to about 22 carbons, an aromatic hydrocarbon, or a combination thereof, and the second terminal group can include a group modified with an amine, an amide, an imine, an imide, a carboxyl, a hydroxyl, an ester, an ether, an acetate, a phosphate, a ketone, an aldehyde, a sulfonate, or a combination thereof.

[0052]

[0078] The first end group can include, in one example, hydrogen (H), in one example, 2-22 carbons, in another example, 4-22 carbons, in yet another example, 6-22 carbons, in yet another example, 7-22 carbons, in yet another example, 8-22 carbons, in yet another example, 10-22 carbons, in yet another example, 12-22 carbons, in yet another example, 14-22 carbons, in yet another example, 16-22 carbons, and in a further example, 18-22 carbons. In one particular example, the first end group can include, in one example, a hydrocarbon having (CH3(CH2) 17 In some cases, the first end group can include 18 carbons, such as a 1-alkyl-1,1-dimethyl-2-propanediol (A1)-group. In some cases, the first end group can include a hydrocarbon having 7 to 22 carbons. In some cases, the first end group can include H. In some cases, the first end group can include 1% to 99% H and a hydrophobic portion in the range of 1% to 99% that can include a saturated or unsaturated aliphatic hydrocarbon, aromatic hydrocarbon, or combinations thereof having 1 to about 22 carbons. The first end group can be modified by selecting different initiators. In some cases, p-toluenesulfonic acid, trifluoroacetic acid, methyl tosylate, HCl, HBr, HI, H-Br, hydrocarbon-Br (C1 to C2). 22 -Br, etc., or combinations thereof may be utilized as initiators. The polymers prepared herein may be mixed together in a given ratio.

[0053]

[0079] The initiator can include hydrophobic electrophilic molecules including hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons or combinations thereof, along with halide functional groups such as alkyl halides, aralkyl halides, acyl halides or combinations thereof. Examples of such compounds can include monofunctional initiators such as hydrocarbons including 1 to about 22 hydrocarbons with either saturated or unsaturated chemical bonds, such as methyl iodide / methyl bromide / methyl chloride, ethyl iodide / ethyl bromide / ethyl chloride, 1-iodobutane / 1-bromobutane / 1-chlorobutane, 1-iodohexane / 1-bromohexane / 1-chlorohexane, 1-iodododecane / 1-bromododecane / 1-chlorododecane, 1-iodooctadodecane / 1-bromooctadodecane / 1-chlorooctadodecane, benzyl iodide / benzyl bromide / benzyl chloride, etc. Other initiators can include allyl bromide / allyl chloride. Acyl halides such as acyl bromide / chloride, benzoyl bromide / chloride, and tosyl-containing compounds (such as p-toluenesulfonic acid, methyl tosylate, and other tosylate esters) may also be used. Any one or more initiators may be used in combination. In some cases, the initiator may also include a hydrophilic portion that includes a proton / H-containing molecule such as p-toluenesulfonic acid, trifluoroacetic acid, methyl tosylate, HCl, HBr, HI, or a combination thereof.

[0054]

[0080] During polymerization, an initiator may be used to start the polymerization. If used, various molar ratios of monomer to initiator may be used to obtain a particular polymer. The particular polymer may have different properties, such as molecular weight, branch size, and other properties, including those unexpectedly discovered by the applicants disclosed herein. In some cases, suitable molar ratios of monomer to initiator include 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 65:1, 70:1, 75:1, 80:1, 85:1, 90:1, 95:1, and 100:1 (20;1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29 ... :1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54;1, 55:1, 56:1, 57:1, 58:1, 59:1, 60:1, 61:1, 62:1, 63:1, 64:1, 65:1, 66:1, 67:1, 68:1, 69:1, 70:1, 71:1, 72:1, 73:1, 74:1, 75:1, 76:1, 77:1, 78:1, 79:1, 80:1, 81:1, 82:1, 83:1, 84:1, 85:1, 86:1, 87:1, 88:1, 89:1, 90:1, 91:1, 92:1, 93:1, 94:1, 95:1, 96:1, 97:1, 98:1, 99:1, 100:1, 101:1, 102:1, 103:1, 104:1, 105:1, 106:1, 107:1, 108:1, 109:1, 109:1, 101 9:1, 60:1, 61:1, 62:1, 63:1, 64:1, 65:1, 66:1.67:1, 68:1, 69:1, 70:1, 71:1, 72:1, 73:1, 74:1, 75:1, 76:1, 77:1, 78:1, 79:1, 80:1, 81:1, 82:1, 83:1, 84:1, 85:1, 86:1, 87:1, 88:1, 89:1 The molar ratio of monomer to initiator may range from 20:1 to 100:1, including any and all ratios within the range, such as 90:1, 91:1, 92:1, 93:1, 94:1, 95:1, 96:1, 97:1, 98:1, 99:1, 100:1, etc., meaning that a molar ratio of monomer to initiator in the range specified above may be used to produce a selected polymer. In some cases, the polyoxazolines disclosed herein may include a molar ratio of monomer to initiator in the range of 50:1 to 80:1, including any and all ratios within that range, meaning that a molar ratio of monomer to initiator in the range of 50:1 to 80:1 may be used to produce a selected polymer.

[0055]

[0081] The polymers can be prepared using monomers and initiators as described herein and in prior PCT Publication No. WO2014 / 123791, which is hereby incorporated by reference in its entirety.

[0056]

[0082] Hydrogen-modified randomly branched PEOX polymers having specific monomer to initiator molar ratios ranging from 20:1 to 100:1 can be prepared using initiators selected from hydrophilic moieties including proton / H-containing molecules such as p-toluenesulfonic acid, trifluoroacetic acid, methyl tosylate, HCl, HBr, HI or combinations thereof, as described above.

[0057]

[0083] Hydrocarbons C1-(CH3(CH2)) with monomer to initiator molar ratios ranging from 20:1 to 100:1 21 )-modified random branched PEOX polymers are CH3-Br, (CH3(CH2))-Br, (CH3(CH2)2)-Br, (CH3(CH2)3)-Br, (CH3(CH2)4)-Br, (CH3(CH2)5)-Br, (CH3(CH2)6)-Br, (CH3(CH2)7)-Br, (CH3(CH2)8)-Br, (CH3(CH2)9)-Br, (CH3(CH2) 10 )-Br, (CH3(CH2) 12 )-Br, (CH3(CH2) 12 )-Br(CH3(CH2) 13 )-Br, (CH3(CH2) 14 )-Br, (CH3(CH2) 15 )-Br, (CH3(CH2) 16 )-Br, (CH3(CH2) 17 )-Br, (CH3(CH2) 18 )-Br, (CH3(CH2) 19 )-Br, (CH3(CH2) 20 )-Br and (CH3(CH2) 21 )-Br. Mixtures of initiators may also be suitable.

[0058]

[0084] In some cases, C1~(CH3(CH2) 21Polymers containing a mixture of hydrocarbons such as H-modified first end groups and H-modified first end groups can be prepared by combining the hydrogen-modified random branched PEOX polymers and the hydrocarbons C1-(CH3(CH2) 21 )-modified random branched PEOX polymers in a predetermined ratio. In some cases, the polymers may be produced by mixing C1-(CH3(CH2) 21 ) modified first end groups in the range of 1% to 99% and H-modified first end groups in the range of 1% to 99%.

[0059]

[0085] In some cases, the first end groups are H to C1-C in a ratio ranging from 0.01:1 to 100:1. 22 Hydrocarbons ((CH3(CH2) 17 In some cases, the first end group may include a hydrophobic portion having a ratio of H to C1-C2 in an arrangement of 0.1:1 to 5:1. 22 Hydrocarbons ((CH3(CH2) 17 )-, etc.

[0060]

[0086] Hydrocarbons (CH3(CH2) 17 A polymer containing a mixture of H / C modified first ends and H modified first ends is referred to as an "H / C" polymer. 18 Polymers with specific initiator molar ratios, such as 60:1, 70:1, and 80:1, can be referred to as "H / C PEOXABPs." 18 PEOXABP60, H / C 18 PEOXABP70, H / C 18 It can be called "PEOXABP80" etc.

[0061]

[0087] The polymers disclosed above and hereinafter may be suitable and may include linear polymers, branched polymers, symmetrically branched polymers, asymmetrically branched polymers, dendrimers, dendrigraft polymers, comb-branched polymers, star-branched polymers, or combinations thereof. The polymers are water-soluble. In examples, the polymers may be dissolved in water to produce, for example, a 12% by weight or greater aqueous solution.

[0062]

[0088] The second end group can include groups modified with ammonia, derivatives of ammonia, ethylenediamine (EDA), derivatives of ethylenediamine, piperazine, derivatives of piperazine, tris(2-aminoethyl)amine, 4-(aminomethyl)piperidine, 1,3-diaminopropane, 2,2'-(ethylenedioxy)bis(ethylamine), diethylenetriamine, 1,4,7,10-tetraazacyclododecane, hexamethylenediamine, triethylenetetramine, 1,8-diaminooctane, or combinations thereof. In yet another example, the second end group can include groups modified with ethylenediamine (EDA), derivatives of ethylenediamine, or combinations thereof. Any of the derivatives of ethylenediamine disclosed herein may be suitable. The polymer can have a reaction challenge molar ratio of polyoxazoline reactive chain ends to EDA in the range of 1:1 to 1:100. The polymer can have a polyoxazoline reactive chain end to EDA reactive challenge molar ratio in one example ranging from 1:1 to 1:100, in another example ranging from 1:2 to 1:100, in yet another example ranging from 1:2 to 1:50, in yet another example ranging from 1:2 to 1:40, in a further example ranging from 1:2 to 1:30, in yet another example ranging from 1:2 to 1:20, in yet another example ranging from 1:2 to 1:15, and in a further example ranging from 1:5 to 1:15. In a further example, the polymer can have a polyoxazoline reactive chain end to EDA reactive challenge molar ratio in a ratio of about 1:10. The EDA modified polyoxazolines disclosed herein can provide functional groups that can have a pH-dependent change in polymer charge as disclosed herein. In some cases, the pharmaceutical compositions disclosed herein can include a polymer that can have a polyoxazoline reactive chain end to EDA molar ratio of about 1:10. In some cases, the second terminal group may contain a group modified with EDA in a range of 1% to 99%, 1% to 90%, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, 1% to 10%, 1% to 5%, 1% to 4%, 1% to 3%, or 1% to 2%.In some cases, the second end groups may contain primary amines in the range of 1% to 99%, 1% to 90%, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, 1% to 10%, 1% to 5%, 1% to 4%, 1% to 3%, or 1% to 2%.

[0063]

[0089] In some cases, the second end groups can include groups modified with amines, amides, imines, imides, carboxyls, hydroxyls, esters, ethers, acetates, phosphates, ketones, aldehydes, sulfonates, or combinations thereof, provided that in the range of 0.01%-100%, 0.1%-100%, 1%-100%, 5%-100%, 10%-100%, 15%-100%, 20%-100%, 30%-100%, 40%-100%, 50%-100%, 60%-100%, 70%-100%, 80%-100%, 90%-100%, 95%-100%, 99%-100% of the second end groups can be free of primary amines. In some cases, about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the second end groups may not include a primary amine. In some cases, about 50%-100% of the second end groups may not include a primary amine. In some cases, about 75%-100% of the second end groups may not include a primary amine. In some cases, about 90%-100% of the second end groups may not include a primary amine.

[0064]

[0090] In some cases, 100% of the second end groups of the polymer can include a hydroxyl modified group. In some cases, as disclosed herein, CH3(CH2) 17-Br can be used as an initiator of 2-ethyloxazoline polymerization by cationic ring-opening process to generate random branched polymers, followed by, for example, dissolving the random branched polymers in water to generate second terminals modified by hydroxyl groups. In some cases, the initiator selected from the hydrophilic moiety includes a proton / H-containing molecule (such as p-toluenesulfonic acid, trifluoroacetic acid, methyl tosylate, HCl, HBr, HI, or a combination thereof) and can be used as an initiator of 2-ethyloxazoline polymerization by cationic ring-opening process to generate random branched polymers, followed by, for example, dissolving the random branched polymers in water to generate second terminals modified by hydroxyl groups. In some cases, about 100% of the second terminal groups can include hydroxyl groups. In some cases, about 100% of the second terminal groups can not include primary amines.

[0065]

[0091] In some cases, the pharmaceutical composition may have a pH value in the range of about 3.0 to about 10.0, and 1% to 100% of the second end groups are free of primary amines. In some cases, the pharmaceutical composition may have a pH value in the range of about 3.0 to about 6.9, 4.0 to about 6.9, or 5.6 to about 6.9, and about 100% of the second end groups are free of primary amines, i.e., 0% of the second end groups contain primary amines. In some cases, 1% to 100% of the second end groups may contain hydroxyl groups, as a percentage of the total number of second end groups.

[0066]

[0092] Polymer H / C having a hydroxyl group as the second end group 18 PEOXABP is H / C 18 Polymers with specific initiator molar ratios, such as 60:1, 70:1, and 80:1, can be referred to as "H / C 18 PEOXABP60-OH, H / C 18 PEOXABP70-OH, H / C 18 The polymer H / C having an amine group as the second terminal group can be referred to as "PEOXABP80-OH" or the like. 18PEOXABP is H / C 18 Polymers with specific initiator molar ratios, such as 60:1, 70:1, and 80:1, can be referred to as “H / C 18 PEOXABP60-NH2, H / C 18 PEOXABP70-NH2, H / C 18 PEOXABP80-NH2," etc. In some cases, mixtures of the polymers disclosed herein may be suitable.

[0067]

[0093] While not wishing to be bound by any particular theory or mechanism, applicants believe that certain levels of primary amines may interact with certain bioactive agents, such as rapamycin, resulting in degradation of the bioactive agent. Applicants have discovered that polymers that are free of primary amines or have varying percentages of primary amines in the second terminal group can be used to modulate properties such as the stability or degradation of certain bioactive agents, such as rapamycin, providing an additional approach in optimizing the formulation of pharmaceutical compositions.

[0068]

[0094] In any of the pharmaceutical compositions disclosed above and hereafter, the polymer can include a polyoxazoline (POX) that includes a linear portion, a branched portion, or a combination thereof. The polymer can include, in one example, multiple linear portions linked together, in another example, one or more linear portions linked to one or more branched portions, and in yet another example, one or more branched portions linked together, such as those illustrated in Figures 1A to 10B. Each linear portion can be independently of various lengths, various modifications, or combinations thereof. Each branched portion can be independently of various lengths, number of branches, various modifications, or combinations thereof.

[0069]

[0095] Polyoxazoline (POX) can include poly(2-substituted oxazolines), including poly(2-oxazoline), poly(2-methyloxazoline), poly(2-ethyloxazoline), poly(2-propyloxazoline), poly(isopropyloxazoline) (PiPOX), or combinations thereof. POX can include, in one example, poly(2-methyloxazoline) (PMOX), in another example, poly(2-ethyloxazoline) (PEOX), in yet another example, poly(2-propyloxazoline) (PPOX), in yet another example, poly(isopropyloxazoline) (PiPOX), or in yet a further example, a combination of two or more of poly(2-substituted oxazolines), where two or more poly(2-substituted oxazolines) can be repeat units (also referred to as composite monomers) in a polyoxazoline polymer. Polyoxazoline (POX) is hydrophilic. Polyoxazolines (POX) may not include monomers, either single or multiple monomers, with hydrophobic side chains, such as monomers with four or more carbons (C4 or greater).

[0070]

[0096] Several examples of symmetrically branched polymers (SBPs) are illustrated generally in Figures 1A-1D and 2A-2B with symmetric branches, where all of the homopolymers of interest have a core and exhibit symmetric branch junctions consisting of either terminal branches or chain branches throughout the homopolymer. The functional groups are primarily present on the exterior of the polymer.

[0071]

[0097] Modified SBPs can be obtained, for example, by chemically linking functional groups on symmetrically branched PAMAM or PPI dendrimers, polyether dendrimers, polyester dendrimers, comb- / star-branched polymers such as those containing PEO, PEG, PMOX or PEOX, polystyrene, and comb-branched dendrigrafts such as those containing PEOX, PMOX or PEI, available from, for example, Aldrich. Synthetic procedures for making such SBPs / dendrimers are known and are described above and hereinafter.

[0072]

[0098] In some cases, the higher branching density of SBPs makes the polymers molecularly compact and provides well-defined interior spaces that make such molecules suitable as carriers for water-insoluble or poorly water-soluble drugs, such as rapamycin, entrapped or encapsulated therein.

[0073]

[0099] Surface modification can enhance the properties and use of the resulting modified SBP. For example, suitable modification can make water-insoluble SBP water-soluble, while SBP with high charge density can be modified to carry very low or no charge on the polymer or on the polymer surface. On the other hand, water-soluble SBP can be modified with hydrophobic surface groups to enhance the ability to solubilize water-insoluble or poorly water-soluble drugs on or within its surface. Modification can be performed at any site of the polymer, such as at the end, at the branch, at the backbone residue, etc.

[0074]

[0100] In one embodiment of the present disclosure, the SBP (e.g., either symmetrically branched PEI dendrimers, PPI dendrimers, PAMAM dendrimers or symmetrically branched PEI dendrigrafts) can be modified with different types, e.g., primary amine groups, e.g., by Michael addition or addition of acrylic esters to the amine groups of the homopolymers. Thus, for example, methyl acrylate can be introduced to the primary and / or secondary amino groups of PEI, PPI and polylysine (PLL) homopolymers by Michael addition reaction. The ester groups can then be further derivatized, e.g., by amidation reaction. For example, such an amidation reaction, e.g., with ethylenediamine (EDA), can thus result in the addition of amino groups at the termini of the newly formed branches. Other modifications to homopolymers can be made using known chemistry, for example as presented in "Poly(amines) and Poly(ammonium salts)" in "Handbook of Polymer Synthesis," (Part A), Kricheldorf (ed.), New York, Marcel Dekker, 1994; and "Dendrimers and Other Dendritic Polymers" (Frechet & Tomalia (eds.), John Wiley & Sons, Ltd., 2001). Derivatives of EDA can also be used, including reactive EDA, substituted EDA, or any molecular entity including other members of the polyethyleneamine family, such as diethylenetriamine, triethylenetetramine, tetraethylenepentamine, pentaethylenehexamine, including polyethyleneamine, tetramethylethylenediamine, etc. For example, amidation reactions with ethylenediamine (EDA) can also modify the polymer charge density at the ends of newly formed branches. As disclosed herein, polymers having such amidation groups can have a pH-dependent change in charge, resulting in a pH-dependent change in polymer charge density.

[0075]

[0101] In some embodiments, the modification can include moieties that contribute to or enhance the hydrophobicity of the polymer or a portion thereof. For example, hydrophobic functional groups such as aliphatic chains, including hydrocarbon chains containing 1 to about 22 carbons, which can be saturated or unsaturated, linear, cyclic or branched, aromatic structures (e.g., containing one or more aromatic rings that can be fused), or combinations thereof, can be used as modifiers and can be added to the polymers taught herein by implementing the chemistry presented herein. Upon such addition, modified SBPs such as modified PEI, PPI, PAMAM dendrimers or PEI dendrigrafts can be formed. An example of a PAMAM modified PPI dendrimer is shown in FIG. 3. As an extension of SBPs such as PPI and PEI, the resulting modified SBPs are also symmetrically branched. Depending on the solvent environment (i.e., pH or polarity), the surface functional groups can have different charges and / or charge densities and / or hydrophobic groups. The molecular shape and the position of the surface functional groups (i.e., the folding of the surface functional groups) can then be further adjusted based on their properties.

[0076]

[0102] In another embodiment of the present disclosure, the modified SBP can be produced, for example, using any of a variety of synthetic schemes known to be suitable for reaction with suitable sites on the homopolymer. Additionally, any of a variety of reagents can be used in the selected synthetic scheme to provide any of a variety of modifications or additions to the homopolymer backbone. Thus, for example, in the case of the Michael addition reaction to the amine described above, any of a variety of substituent additions can be used, for example, in the alkylation step, using any of a variety of acrylate reagents, such as acrylates containing hydrocarbon substituents, such as saturated or unsaturated hydrocarbons containing 1 to about 22 carbons, which may be aliphatic, aromatic, cyclized, saturated, or combinations thereof, which may be substituted at one or more bonds. Thus, suitable reactants include methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, pentyl acrylate, hexyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate, decyl acrylate, undecyl acrylate, dodecyl acrylate, and the like, and mixtures thereof. Similarly, in the examples illustrated above, any of a variety of amines can be used in the amidation step. For example, EDA, monoethanolamine, tris(hydroxymethyl)aminomethane, alkylamines, allylamines, or any amino-modified polymer including those containing PEG, PEO, perfluoropolymers, polystyrene, polyethylene, polydimethylsiloxane, polyacrylates, polymethylmethacrylates, and the like, and mixtures thereof may be used.

[0077]

[0103] Such a synthetic strategy allows not only symmetric growth of the molecule, which can introduce more branches with different chemical compositions, but also allows the addition of multiple functional groups to the exterior of the polymer structure. The precursor homopolymers can be successively modified using the same or different synthetic processes until the desired SBP with the appropriate molecular weight and functional groups is obtained. Furthermore, the hydrophobic and hydrophilic properties and charge density of such polymers can be tailored to the needs of a particular application using appropriate monomers and suitable modification reactions to construct the homopolymers.

[0078]

[0104] In another embodiment of the present disclosure, when a branched synthesis procedure is used, the chain ends of symmetric star- or comb-branched homopolymers such as poly(2-oxazoline) or poly(2-substituted oxazoline) (including, for example, poly(2-methyloxazoline), poly(2-ethyloxazoline), poly(2-propyloxazoline) and poly(2-butyloxazoline) and the like), PEI, PEO / glycol, polyvinylpyrrolidone (PVP), polyphosphate, polyvinyl alcohol (PVA) or polystyrene can be modified with another small molecule or polymer to generate a variety of functional groups at the homopolymer chain ends, including primary, secondary or tertiary amine, carboxylate, hydroxyl, aliphatic (e.g., hydrocarbon chain), aromatic, fluoroalkyl, aryl, PEG, PEO, acetate, amide and / or ester groups. Alternatively, when a convergent synthetic approach is utilized, different initiators can be used to introduce the same type of functional group at the chain end (Dendritic Molecules, Newkome et al. (eds.), VCH, Weinheim, 1996; Dendrimers and Other Dendritic Polymers, Fréchet and Tomalia (eds.), John Wiley & Sons, Ltd., 2001; and J. Macromol. Sci. Chem. A, Vol. 9(5), pp. 703-727 (1975)).

[0079]

[0105] Some examples of asymmetrically branched polymers (ABPs) are illustrated in schematic form in Figures 4A-4B with asymmetric branches, where some of the homopolymers of interest do not have a core, but rather show asymmetric branched linkages consisting of both chain branches and terminal branches throughout the homopolymer. Linking groups are often present both on the exterior and interior. However, when larger functional groups (e.g., large hydrophobic or hydrophilic groups) are used, they may often be preferentially, and perhaps inevitably, attached to the exterior of the ABP, for example, perhaps due to steric effects. Thus, such surface-modified branched polymers (MBPs) can be utilized for solubilizing or forming nanoaggregates with water-insoluble or poorly water-soluble drugs.

[0080]

[0106] Modified ABPs can be obtained by chemically linking functional groups on regular ABPs such as polylysine (e.g., branched PLL), random ABPs such as PEI (commercially available from Aldrich, Polysciences or BASF under the trade name Lupasol®), or polyoxazolines, which can be prepared according to the procedure of Litt (J. Macromol. Sci. Chem. A vol. 9 (no. 5), pp. 703-727 (1975)). Other ABPs can include, but are not limited to, polyacrylamides, polyphosphates, PVP, PVA, and the like. Random asymmetrically branched PEI can be produced primarily by cationic ring-opening polymerization of ring-strained cyclic imine monomers such as aziridine (ethyleneimine) and azetidine (propyleneimine) using Lewis or Bronsted acids as initiators (Dernier et al., "Ethylenediamine and Other Aziridines," Academic Press, New York, (1969); and Pell, J. Chem. Soc. Vol. 71 (1959)). Many of the methods are essentially one-pot processes, so large quantities of random ABPs can be easily produced.

[0081]

[0107] The synthetic methods for making ABPs often result in a variety of branching linkages within the macromolecule. In other words, a mixture of terminal and chain branching linkages are distributed throughout the molecular structure. Random ABPs may have a lower branching density and their molecular structure may be more open compared to dendrimers and dendrigrafts. Although the branching pattern is random, the average ratio of primary, secondary and tertiary amine groups may be relatively constant at a ratio of about 1:2:1, as described by Dick et al., J. Macromol. Sci. Chem., Vol. A4 (No. 6), pp. 1301-1314 (1970) and Lukovkin, Eur. Polym. J. Vol. 9, p. 559 (1973). In one example, the polymers disclosed herein may include a ratio of primary, secondary and tertiary amine groups of about 1:2:1.

[0082]

[0108] Due to the presence of branched connections, random ABPs such as asymmetrically branched PEIs allow the formation of macromolecules with possible spherical, elliptical or similar conformations. Inside the spherical structure, there are pockets of various sizes formed from the incomplete branched connections in the interior of the macromolecule. The pockets of random ABPs are unevenly spread throughout the molecule, unlike dendrimers and dendrigrafts, whose internal pockets are always located around the central core of the molecule. As a result, random ABPs have both external and unevenly distributed internal functional groups that can further react with various molecules and thus form new macromolecular structures, i.e. the desired modified random ABPs.

[0083]

[0109] The functional group of regular ABP also has a core, but can also be distributed on both the outside and inside, which is very similar to random ABP.One of such homopolymers is PLL, which can be made as described in U.S. Patent No. 4,289,872, U.S. Patent No. 4,360,646 and U.S. Patent No. 4,410,688, each of which is incorporated by reference in its entirety.Such homopolymers can also be modified in the same manner as random ABP, as taught herein and known in the art.

[0084]

[0110] In an embodiment of the present disclosure, the ABP (e.g., either asymmetric random branched PEI or asymmetric regular branched PLL) is modified with different types of primary and / or secondary amine groups, for example, by Michael addition, i.e., addition of acrylic esters to the amines of the polymer (e.g., PEI and PLL homopolymers). The ester groups can then be further derivatized, for example, by amidation reactions. For example, such an amidation reaction, for example, with EDA, can thus result in the addition of amino groups at the termini of the newly formed branches. Other modifications to the polymer can be made using known chemistry, for example, as presented in "Poly(amines) and Poly(ammonium salts)" above. Upon such addition, modified ABPs, such as modified PEI or PLL homopolymers, are formed. As an extension of ABPs, such as PEI and PLL, the resulting modified ABPs are also asymmetrically branched. Depending on the solvent environment (i.e., pH or polarity), the surface functional groups can have different charges and charge densities. The molecular shape and the position of the functional groups (i.e., folding of the surface functional groups) can then be further adjusted based on their properties.

[0085]

[0111] In another embodiment, the modified ABP can be produced using any of a variety of synthetic schemes known to be suitable for reaction with suitable sites on, for example, homopolymers. Furthermore, any of a variety of reagents can be used in the selected synthetic scheme to produce any of a variety of modifications or additions to the polymer backbone. Thus, for example, in the case of the Michael addition reaction to amines described above, as presented hereinbefore, any of a variety of substituents can be added to the alkylation step, for example, using acrylates, which can include saturated or unsaturated hydrocarbons, such as those containing 1 carbon to about 22 carbons, which can be aliphatic, branched, saturated, aromatic, cyclized, or a combination thereof. In one example, the hydrocarbon can have 2-22 carbons, in another example, 4-22 carbons, in yet another example, 6-22 carbons, in yet another example, 7-22 carbons, in yet another example, 8-22 carbons, in yet another example, 10-22 carbons, in yet another example, 12-22 carbons, in yet another example, 14-22 carbons, in yet another example, 16-22 carbons, in a further example, 18-22 carbons, and in yet a further example, 20-22 carbons. In one particular example, the first terminal group is (CH3(CH2) 17)-group. Suitable reactants include methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, pentyl acrylate, hexyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate, decyl acrylate, undecyl acrylate, dodecyl acrylate, and the like, and mixtures thereof. Similarly, in the above illustrated examples, any of a variety of amines may be used in the amidation step in the methods provided herein and known in the art. For example, EDA, monoethanolamine, tris(hydroxymethyl)aminomethane, alkylamines, allylamines, or any amino-modified polymers including PEG, perfluoropolymers, polystyrene, polyethylene, polydimethylsiloxane, polyacrylates, polymethylmethacrylates, and the like, and mixtures thereof may be used. Additionally, aliphatic (e.g., C1 to about C 22 Conjugation of hydrophilic polymers such as hydrophobic groups including hydrocarbon (up to 1000 nm), aromatic groups, polyethylene polymers, polystyrene polymers, perfluoropolymers, polydimethylsiloxanes, polyacrylates, polymethylmethacrylates, as well as hydrophilic groups including OH groups, PEOX, PEG, PEO, etc., to the modified ABPs can be achieved by using, for example, epoxy reactions, amidation reactions, Michael addition reactions including the use of -SH or -NH2 groups reacted with maleimides, aldehyde / ketone-amine / hydrazide coupling reactions, iodine / iodoacetyl-SH coupling reactions, hydroxylamine-aldehyde / ketone coupling reactions, etc. Such synthetic strategies allow for the addition of multiple functional groups both to the interior and exterior of the structure as well as asymmetric growth of the molecule where a greater number of pockets are introduced. The homopolymers can be further modified using the same or different synthetic methods until the desired ABP with the appropriate molecular weight and functional groups is obtained. Furthermore, the hydrophobic and hydrophilic properties of such homopolymers, as well as the charge density, can be tailored to the needs of a particular application using appropriate monomers and suitable modification reactions to construct the homopolymers. An example of a modified ABP is shown in Figure 5. A modified hyperbranched PEI is shown in Figure 6A.

[0086]

[0112] In another embodiment of the present disclosure, the focal point of a random ABP such as POX (converging from various reactive chain ends during convergent synthesis) can be terminated or reacted with another small molecule to generate various functional groups at the homopolymer chain ends, including primary, secondary or tertiary amines, carboxylates, hydroxyls, alkyls, fluoroalkyls, aryls, PEGs, acetates, amides and / or ester groups. Alternatively, various initiators can also be utilized, so that the same types of functional groups can also be introduced to the surface groups where polymerization begins during convergent synthesis (J. Macromol. Sci. Chem. A vol. 9 (no. 5), pp. 703-727 (1975)).

[0087]

[0113] Alkyl surface-modified randomly branched poly(2-ethyloxazoline) with primary amine groups at the focal points of the branched polymer can be prepared using the procedure of Litt and Warakomski, supra. For example, CH3(CH2) 17 -Br can be utilized as an initiator for 2-ethyloxazoline polymerization via a cationic ring-opening process to generate randomly branched polymers, followed by quenching with N-tert-butyloxycarbonylpiperazine (N-Boc-piperazine) or EDA. Termination with a large excess of EDA allows the hydrophobically modified branched poly(2-ethyloxazoline) polymer to be functionalized with a primary amine group at the focal point (Figure 6B). Alternatively, the hydrophobically modified N-Boc-piperazine terminated branched poly(2-ethyloxazoline) polymer can be deprotected to generate a free amino group at the focal point. In some cases, the polymer can include modified branched poly(2-ethyloxazoline) functionalized with primary, secondary or tertiary amine, carboxylate, hydroxyl, alkyl, fluoroalkyl, aryl, PEG, acetate, amide or ester groups at the focal point of the polymer where two or more reactive chain ends are joined during convergent synthesis.

[0088]

[0114] In some cases, the alkyl surface-modified randomly branched poly(2-ethyloxazoline) can have hydroxyl groups at the focal point of the branched polymer, which can be hydrolyzed, for example, to hydroxyl groups when dissolved in water (e.g., containing, for example, 1N Na2CO3).

[0089]

[0115] In some cases, the focal points of the polymers referred to herein can include a second end group modified with a hydrophilic moiety.

[0116] The introduction of primary amine groups into hydrophobically modified branched poly(2-oxazoline) homopolymers improves drug solubility and produces bioactive agent-derived nanoaggregates (such as those shown in Figures 7A-7B, 8, 9A-9B), but also allows for various targeting groups, such as antibodies, antigen-binding portions thereof, antigens, or members of binding pairs, to be attached to the hydrophobically modified branched poly(2-oxazoline) polymers (Figures 10A-10B). This can be particularly useful prior to mixing the polymer with a bioactive agent, such as rapamycin. Such nanoaggregates or nanoparticles containing such targeting groups and modifications thereto can provide targeting capabilities to the nanoaggregates containing a bioactive agent, such as rapamycin, allowing the bioactive agent to be released preferentially or exclusively to the desired treatment site. As noted above, when using polymers to mix with rapamycin to produce pharmaceutical compositions of the present disclosure, it is preferred to have the polymer free of primary amines in the range of 1% to 100% of the second end groups.

[0090]

[0117] As disclosed herein, modified branched polymers (MBPs), such as hydrophobically modified homopolymers (including SBP, ABP, or combinations thereof), can be used to generate encapsulating polymers or nanocapsules for solubilizing water-insoluble rapamycin. In an organic solvent environment, the hydrophilic or amphiphilic interior can be poly(2-oxazoline), poly(2-substituted oxazoline) (poly(2-substituted oxazoline) can include poly(2-methyloxazoline), poly(2-ethyloxazoline), poly(2-propyloxazoline), poly(isopropyloxazoline) (PiPOX), or combinations thereof), PEG, PEO, polyphosphonates, and the like. The hydrophobic exterior can be aliphatic hydrocarbons (C1 to about C 22 , etc.), aromatic hydrocarbons, polyethylene polymers, polystyrene polymers, perfluoropolymers, polydimethylsiloxanes, polyacrylates, polymethylmethacrylates, etc. In an aqueous environment, the opposite is true. In drug-induced nanoaggregates in an aqueous environment, drug molecules such as rapamycin or other water-insoluble bioactive agents can bind to the hydrophobic groups / domains of MBP (Figures 9A-9B). The branching density (e.g., from low generations such as star and comb homopolymers to high generations such as dendrimers and dendrigrafts) and the amount of hydrophobic surface group coverage of the branched homopolymer (e.g., coverage from 0% to 100%) can significantly affect the solubility of the homopolymer and, therefore, its ability to dissolve or adsorb / absorb rapamycin. For example, increased branching density and increased amount of hydrophobic group coverage make the homopolymer more compatible with, for example, rapamycin.

[0091]

[0118] In a further example, ABPs and SBPs having surface hydrophobic components of about 0.1 to about 30% or more by weight are effective in dissolving or dispersing poorly water-soluble or water-insoluble compounds such as rapamycin. Additionally, the branched homopolymers utilized, such as POX, PMOX, PEOX, PPOX, PEO / PEG, polyacrylamide, polyphosphate, PVP and PVA, are soluble in both water and various organic solvents, facilitating the formation of, for example, rapamycin-containing nanoparticles or nanoaggregates. Good water solubility and good hydrophobic drug miscibility in aqueous solutions with or without other organic solvents make such homopolymers useful for enhancing the solubility of poorly water-soluble bioactive agents. For example, the subject homopolymers simplify the manufacturing process and reduce production costs by reducing formulation steps, processing times, and the need to use complex and expensive equipment currently used in the pharmaceutical industry. If additional branching density is required, the SBP or ABP can first be modified with additional groups as described herein and then, for example, conjugated with further hydrophobic functional groups to, for example, increase the solubility of rapamycin.

[0092]

[0119] In one example, the polymer is configured to have an effective branching density, amount of hydrophobic groups on the polymer surface, or a combination thereof, to encapsulate a bioactive agent, such as water-insoluble rapamycin, to form water-soluble nanoaggregates. The effective branching density, amount of hydrophobic groups on the polymer surface, or a combination thereof, can be modified as described above and hereinafter.

[0093]

[0120] In one example, the polymer is an aliphatic (e.g., C to about C) polymer attached to a POX polymer, including a PEOX polymer, and further modified with EDA. 22Hydrophobic groups may include (up to 10 ...

[0094]

[0121] In some cases, the polymer can include an asymmetrically branched polymer (ABP) or a dendritic asymmetrically branched polymer such as an asymmetrically branched PEOX formed from an initiator and monomer in the ratios disclosed herein. In some cases, the polymer can include a randomly branched poly(2-ethyloxazoline) having one or more first end groups, such as a hydrophobic moiety as disclosed herein, and one second end group located at the focal point of the branched polymer, such as a modified randomly branched PEOX formed by polymerizing a reactive linear PEOX polymer by chain transfer polymerization convergent synthesis as illustrated in FIG. 6B.

[0095]

[0122] In some cases, the polymers can have different first end groups and different second end groups. Some examples are shown in FIG. 6C: polymer (1) through polymer (4) with -OH as the second end group, and polymer (5) through polymer (8) with -NH2 as the second end group, polymer (1) and polymer (5) with H as the first end group, polymer (2) and polymer (6) with -CH3 as the first end group, polymer (7) with C as the first end group, and polymer (8) with -NH2 as the second end group. 12 Polymer (3) and polymer (7) having a first end group 18The polyoxazoline (POX) polymers can be linear, branched, or have a combination of one or more linear portions and one or more branched portions. The polyoxazoline (POX) can include poly(2-methyloxazoline), poly(2-ethyloxazoline), poly(2-propyloxazoline), poly(isopropyloxazoline) (PiPOX), or combinations thereof. Although certain first and second end groups are described above, other first and second groups disclosed herein may be suitable. In some cases, the second end group can include groups modified with amine, amide, imine, imide, carboxyl, hydroxyl, ester, ether, acetate, phosphate, ketone, aldehyde, sulfonate, or combinations thereof. The first and second end groups can be modified in accordance with methods and processes known to those skilled in the art. If necessary, one or more reagents, linkers or intermediates known to those skilled in the art may be used.

[0096]

[0123] In any of the pharmaceutical compositions disclosed above or hereinafter, the polyoxazoline can comprise a molar ratio of monomer to initiator in the range of 50:1 to 80:1.

[0097]

[0124] The pharmaceutical composition can include additional polymers selected from ABP, ABP, MBP (such as symmetrically branched PAMAM or PPI dendrimers), polyether dendrimers, polyester dendrimers, comb-branched / star-branched polymers (such as those containing PEO, PEG, PMOX or PEOX), polystyrene, and comb-branched dendrigrafts (such as those containing PEOX, PMOX, PEI, polylysine (e.g., branched PLL), polyacrylamide, polyphosphate, PVP, PVA, or combinations thereof). Random asymmetrically branched PEI can be produced primarily by cationic ring-opening polymerization of ring-strained cyclic imine monomers such as aziridine (ethyleneimine) and azetidine (propyleneimine) or combinations thereof. Additional polymers can simply be mixed with the nanoaggregates disclosed herein. In one example, one or more additional polymers can be mixed with the nanoaggregates after they are formed.

[0098]

[0125] The term "bioactive agent" suitable for the pharmaceutical compositions, processes, methods and uses disclosed herein throughout this disclosure refers to a substance that may be a natural or synthetic small molecule-based drug, an inorganic-based drug, a biopharmaceutical, a natural or synthetic macromolecule-based drug, a modification and / or derivative thereof, or a combination thereof, as disclosed herein. The bioactive agent may include a natural or synthetic small molecule-based drug, an inorganic-based drug, a biopharmaceutical, a natural or synthetic macromolecule-based drug, a modification and / or derivative thereof, or a combination thereof, where at least one drug is poorly water-soluble or insoluble in water. The drug of interest may be a small molecule, a salt thereof where the molecule has been modified to be water-insoluble or insoluble in water, or a biomolecule modified to be water-insoluble or insoluble in water, particularly where the drug has improved properties such as improved bioavailability, lower toxicity, better pharmacokinetics, or a combination thereof, in the water-insoluble or insoluble form. Suitable examples include drugs that are poorly water-soluble or insoluble in water, or drugs that can be modified to be water-insoluble or insoluble in water to improve properties. Bioactive agents include growth agents; AIDS adjuvants; alcohol abuse preparations, such as agents for treating dependence or withdrawal; agents for treating Alzheimer's disease; agents for treating amyotrophic lateral sclerosis; analgesics; anesthetics; anticonvulsants; antidiabetic agents; detoxifying agents; antifibrotic therapeutic agents; antihistamines; anti-infective agents (antibiotics, antivirals, antifungals, amebicides, anthelmintics, antimalarials, antileprosy agents, etc.); anti-neoplastic agents (antineoplastic agents, anti-inflammatory ... agents);anti-Parkinson's agents;anti-rheumatic agents;appetite stimulants;biological response modifiers;biologics;blood modifying agents (anticoagulants, colony stimulating factors, hemostatic agents, plasma expanders, thrombin inhibitors, etc.);bone metabolism regulators;cardioprotectants;cardiovascular therapeutics (adrenergic blockers, adrenergic stimulants, angiotensin converting enzyme (ACE) inhibitors, antiarrhythmics, hyperlipidemic agents, calcium channel blockers, diuretics, vasopressors, etc.);central nervous system (CNS) stimulants;cholinesterase inhibitors;contraceptives;fertility treatments;ovulation stimulants;cystic fibrosis management;antidotes;diagnostics;nutraceuticals;dopamine receptor agonists;endometriosis management;enzymes;erectile dysfunction treatments;foot care products;gastrointestinal (GI) treatments (antacids, antidiarrheals, antiemetics, antiflatulants, bowel cleansers, digestive enzymes, histamine receptor agonists, laxatives, proton pump inhibitors, prostaglandins, etc.);Gaucher disease treatments;gout treatments;homeopathic remedies;skin treatments;vitamins;nutrients;hormones;hypercalcemia management treatments;hypocalcemia management treatments;immunomodulators;immunosuppressants;levocarnitine deficiency treatments;mast cell stabilizers;migraine treatments, motion sickness treatments (such as Benadryl and Phenergan);decongestants;antihistamines;cough suppressants;multiple sclerosis treatments;muscle relaxants;intranasal treatments (such as anti-inflammatories);smoking cessation aids;appetite suppressants;nucleoside analogues;obesity management;ophthalmic preparations (antibiotics, antiglaucoma agents, artificial tears, lubricants, etc.);sexual aids;osteoporosis treatments;ear preparations (anti-infectives and ear wax removers, etc.);minerals;uterine contractility promoters;parasympathetic blocking agents;parasympathomimetics;agents for patenting the ductus arteriosus;phosphate binders;porphyria drugs;prostaglandins;psychotherapeutic agents;radiopaque agents;respiratory agents (anti-inflammatory agents, antitussives, bronchodilators, decongestants, expectorants, leukotriene antagonists, surfactants, etc.);alternatives The bioactive agents may include over-the-counter medicines and products such as deodorants, Tourette's syndrome medications, tremor treatments, urinary tract agents (acidifiers, alkalizers, etc.), antispasmodics, hypnotics, skin and mucous membrane treatments (such as acne treatments), anorectal treatments (such as hemorrhoid treatments and enemas), antiperspirants, antipruritics, antipsoriatics, antiseborrheic agents, burn treatments, cleansing agents, bleaching agents, emollients, hair growth inhibitors, hair growth stimulants, keratolytics, hair trouble treatments, mouth and pharyngeal trouble treatments, photosensitizers, wart treatments, wound care treatments, or combinations thereof. The bioactive agents may also include over-the-counter medicines and products such as deodorants, Tourette's syndrome medications, tremor treatments, urinary tract agents (acidifiers, alkalizers, etc.), antispasmodics, benign prostatic hyperplasia treatments, calcium oxalate stone preventatives, enuresis management agents, vaginal preparations (anti-infectives, hormones, etc.), vasodilators, dizziness treatments, Wilson's disease treatments, etc.;

[0099]

[0126] Further examples of bioactive agents can include forms of drugs that can be modified as salts, ionized forms, or hydrophilic forms that can be modified, for example, to remove functional groups, modifications, etc., to result in unmodified or other forms of the bioactive agent that are poorly water soluble or insoluble in water. When more than one bioactive agent is included in the pharmaceutical composition, at least one bioactive agent can be or has been modified to be water insoluble or poorly water soluble. Examples of such bioactive agents include analgesics / antipyretics (e.g., aspirin, acetaminophen, ibuprofen, naproxen sodium, buprenorphine hydrochloride, propoxyphene hydrochloride, propoxyphene napsylate, meperidine hydrochloride, hydromorphone hydrochloride, morphine sulfate, oxycodone hydrochloride, codeine phosphate, dihydrocodeine bitartrate, pentazocine hydrochloride, hydrocodone bitartrate, levorphanol tartrate, diflunisal, trolamine salicylate, nalbuphine hydrochloride, mefenamic acid, butorphanol tartrate, choline salicylate, butalbital, phenyltoloxamine citrate, diphenhydramine citrate, methotrimeprazine, cinnamure hydrochloride, salts, meprobamate, etc.); anesthetics (e.g., cyclopropane, enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, propofol, etc.); antiasthmatics (e.g., azelastine, ketotifen, traxanox, amlexanox, cromolyn, ibudilast, montelukast, nedocromil, oxatomide, pranlukast, seratrodast, suplatast tosilate, tiaramide, zafirlukast, zileuton, beclomethasone, budesonide, dexamethasone, flunisolide, triamcinolone acetonide, etc.); antibiotics (e.g., neomycin, streptomycin, chloramphenicol, cephalosporins, ampicillin, penicillin, tetracycline, etc.);Quinolones, fluoroquinolones, antidepressants (e.g., nefopam, oxypertine, doxepin hydrochloride, amoxapine, trazodone hydrochloride, amitriptyline hydrochloride, maprotiline hydrochloride, phenelzine sulfate, desipramine hydrochloride, nortriptyline hydrochloride, tranylcypromine sulfate, fluoxetine hydrochloride, doxepin hydrochloride, imipramine hydrochloride, imipramine pamoate, nortriptyline, amitriptyline hydrochloride, isocarboxazid, trimipramine maleate, protriptyline hydrochloride, etc.); antidiabetic drugs (e.g., For example, biguanides, hormones, sulfonylurea derivatives, etc.; antifungal agents (for example, griseofulvin, ketoconazole, amphotericin B, nystatin, candicidin, etc.); antihypertensive agents (for example, propanolol, propafenone, oxyprenolol, nifedipine, reserpine, trimethaphan camsilate, phenoxybenzamine hydrochloride, pargyline hydrochloride, deserpidine, diazoxide, guanethidine monosulfate, minoxidil, resinamine, sodium nitroprusside, Indian jabok (rauwolfia serpentina), arsenicylone, phentolamine mesylate, reserpine, etc.); anti-inflammatory agents (e.g., non-steroidal compounds such as indomethacin, naproxen, ibuprofen, ramifenazone, piroxicam, etc., and steroidal compounds such as cortisone, dexamethasone, fluazacort, hydrocortisone, prednisolone, prednisone, etc.); antineoplastic agents (e.g., adriamycin, cyclophosphamide, actinomycin, bleomycin, daunorubicin, doxorubicin, epinephrine, etc.); Rubicin, gemcitabine, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (β-chloro-nitrosourea (BCNU) compounds), methyl-1-(-chloroethyl-cyclohexyl)-1-nitrosourea (CCNU), cisplatin, etoposide, interferon, camptothecin and its derivatives, phenesterine, taxol and its derivatives, taxotere and its derivatives, vinblastine, vincristine, tamoxifen, etoposide, piposulfan, etc.);Anti-anxiety drugs (e.g., lorazepam, buspirone hydrochloride, prazepam, chlordiazepoxide hydrochloride, oxazepam, clorazepate dipotassium, diazepam, hydroxyzine pamoate, hydroxyzine hydrochloride, alprazolam, droperidol, halazepam, chlormezanone, dantrolene, etc.); immunosuppressants (e.g., cyclosporine, azathioprine, mizoribine, FK506 (tacrolimus), rapamycin (sirolimus), etc.); anti-migraine drugs (e.g., ergotamine tartrate, propanolol hydrochloride, isometheptene mucate, dichloralphena sedatives / hypnotics (e.g., barbiturates (e.g., pentobarbital, pentobarbital sodium, secobarbital sodium, etc.) or benzodiazapines (e.g., fluazepam hydrochloride, triazolam, temazepam, midazolam hydrochloride, etc.)); antianginals (e.g., beta-adrenergic blockers, calcium channel blockers (e.g., nifedipine, diltiazem hydrochloride, etc.) and nitrates (e.g., nitroglycerin, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, etc.) etc.); antipsychotics (e.g., haloperidol, loxapine succinate, loxapine hydrochloride, thioridazine, thioridazine hydrochloride, thiothixene, fluphenazine hydrochloride, fluphenazine decanoate, fluphenazine enanthate, trifluoperazine hydrochloride, chlorpromazine hydrochloride, perphenazine, lithium citrate, prochlorperazine, etc.); antimanic drugs (e.g., lithium carbonate); antiarrhythmic drugs (e.g., bretylium tosylate, esmolol hydrochloride, verapamil hydrochloride, amiodarone, encamide hydrochloride, digoxin, digitoxin, mexilex, quinidine hydrochloride, disopyramide phosphate, procainamide hydrochloride, quinidine sulfate, quinidine gluconate, quinidine polygalacturonate, flecamide acetate, tocamide hydrochloride, lidocaine hydrochloride, etc.); anti-arthritic drugs (e.g., phenylbutazone, sulindac, penicillamine, salsalate, piroxicam, azathioprine, indomethacin, meclofenamate sodium, gold sodium thiomalate, ketoprofen, auranofin, aurothioglucose, tolmetin sodium, etc.); anti-gout drugs (e.g., colchicine, allopurinol, etc.);Anticoagulants (e.g., heparin, heparin sodium, warfarin sodium, etc.); thrombolytic agents (e.g., urokinase, streptokinase, altoplase, etc.); antifibrinolytic agents (e.g., aminocaproic acid); hemodynamic agents (e.g., pentoxifylline); platelet inhibitors (e.g., aspirin, empirin, asscriptin, etc.); anticonvulsants (e.g., valproic acid, sodium divalproate, phenytoin, phenyloin sodium, clonazepam, primidone, phenobarbital, phenobarbital sodium, carbamazepine, amobarbital sodium, methsuximide, metharbital, mephobarbital, mephenytoin, phensuximide, paramethadione, ethotoin, phenacemide, secobarbital sodium sodium), clorazepate dipotassium, trimethadione, etc.); antiparkinsonian drugs (e.g., ethosuximide, etc.); antihistamines / antipruritics (e.g., hydroxyzine hydrochloride, diphenhydramine hydrochloride, chlorpheniramine maleate, brompheniramine maleate, cyproheptadine hydrochloride, terfenadine, clemastine fumarate, triprolidine hydrochloride, carbinoxamine maleate, diphenylpyraline hydrochloride, phenindamine tartrate, azatadine maleate, tripelennamine hydrochloride, dexchlorpheniramine maleate, methdilazine hydrochloride, trimprazine tartrate, etc.); Agents useful for calcium regulation (e.g., calcitonin, parathyroid hormone, etc.); antibacterial agents (e.g., amikacin sulfate, aztreonam, chloramphenicol, chloramphenicol palmitate, chloramphenicol sodium succinate, ciprofloxacin hydrochloride, clindamycin hydrochloride, clindamycin palmitate, clindamycin phosphate, metronidazole, metronidazole hydrochloride, gentamicin sulfate, lincomycin hydrochloride, tobramycin sulfate, vancomycin hydrochloride, polymyxin B sulfate, colistin sodium methanesulfonate, colistin sulfate, etc.);Antiviral agents (e.g., interferon gamma, zidovudine, amantadine hydrochloride, ribavirin, acyclovir, etc.); antibacterial agents (e.g., cephalosporins (e.g., cefazolin sodium, cephradine, cefaclor, cephapirin sodium, ceftizoxime sodium, cefoperazone sodium, cefotetan disodium, ceftoxime azotil (cefutoxime azotil), cefotaxime sodium, cefadroxil monohydrate, ceftazidime, cephalexin, cephalothin sodium, cephalexin hydrochloride monohydrate, cefamandole naphthalate, cefoxitin sodium, cefonicid sodium, ceforanide, ceftriaxone sodium, ceftazidime, cefadroxil, cephradine, cefuroxime sodium, etc.), penicillins (e.g., ampicillin, amoxicillin, penicillin G benzathine, cyclacillin, ampicillin sodium, penicillin GK, penicillin VK, piperacillin sodium, oxacillin sodium, bacampicillin hydrochloride, cloxacillin sodium, ticarcillin disodium, azlocillin sodium, carbenicillin indanyl sodium, penicillin G procaine, methicillin sodium um, nafcillin sodium, etc.), erythromycin (e.g., erythromycin ethylsuccinate, erythromycin, erythromycin estolate, erythromycin lactobionate, erythromycin stearate, erythromycin ethylsuccinate, etc.), tetracyclines (e.g., tetracycline hydrochloride, doxycycline hyclate, minocycline hydrochloride, etc.); anti-infectives (e.g., granulocyte-macrophage colony-stimulating factor, GM-CSF); bronchodilators (e.g., sympathomimetics (e.g., epinephrine hydrochloride, metaproterenol sulfate, terbutaline sulfate, isoetharine, isoetharine mesylate, isoetharine hydrochloride, albuterol sulfate, albuterol, bitolterol, mesylate isoproterenol hydrochloride (mesylate isoproterenol hydrochloride), terbutaline sulfate, epinephrine bitartrate, metaproterenol sulfate, epinephrine, epinephrine bitartrate); anticholinergics (e.g., ipratropium bromide);xanthines (e.g., aminophylline, dyphylline, metaproterenol sulfate, aminophylline); mast cell stabilizers (e.g., cromolyn sodium); inhaled corticosteroids (e.g., flunisolide, beclomethasone dipropionate monohydrate, etc.), salbutamol, beclomethasone dipropionate (BDP), ipratropium bromide, budesonide, ketotifen, salmeterol, xinafoate, terbutaline sulfate, triamcinolone, theophylline, nedocromil sodium, metaproterenol sulfate, albuterol, flunisolide, etc.); hormones (e.g., androgens (e.g., danazol, testosterone cypionate, fluoxymesterone, ethyltestosterone, testosterone enanthate, methyltestosterone, fluoxymesterone, testosterone cypionate; onates, etc.; estrogens (e.g., estradiol, estropipate, conjugated estrogens, etc.), progestins (e.g., methoxyprogesterone acetate, norethindrone acetate, etc.), corticosteroids (e.g., triamcinolone, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate, prednisone, methylprednisolone acetate suspension, triamcinolone acetonide, methylprednisolone, prednisolone sodium phosphate, methylprednisolone sodium succinate, hydrocortisone sodium succinate, methylprednisolone sodium succinate, triamcinolone hexacetonide hexacatonide), hydrocortisone, hydrocortisone cypionate, prednisolone, fluorocortisone acetate, paramethasone acetate, prednisolone tebulate, prednisolone acetate, prednisolone sodium phosphate, hydrocortisone sodium succinate, etc.; thyroid hormones (e.g., levothyroxine sodium); etc.; hypoglycemic agents (e.g., human insulin, purified bovine insulin, purified porcine insulin, glyburide, chlorpropamide, glipizide, tolbutamide, tolazamide, etc.); lipid-lowering agents (e.g., clofibrate, dextrothyroxine sodium, probucol, lovastatin, niacin, etc.); proteins (e.g., DNase, arginase, superoxide dismutase, dismutases, lipases, etc.); nucleic acids (e.g., sense or antisense nucleic acids encoding any therapeutically useful protein (including any of the proteins described herein); agents useful in erythropoiesis (e.g., erythropoietin); antiulcer or antireflux agents (e.g., famotidine, cimetidine, ranitidine hydrochloride, etc.); antiemetic or antiemetic drugs (e.g., meclizine hydrochloride, nabilone, prochlorperazine, dimenhydrinate, promethazine hydrochloride, thiethylperazine, scopolamine, etc.); oil-soluble vitamins (e.g., vitamins A, D, E, K, etc.);mitotane, visadine, halonitrosoureas, anthrocyclines, ellipticines, etc.; stimulator of interferon genes (STING) inhibitors (C-176, C-170 and C-171, etc.); STING activators (3',3'-cGAMP (3',3'-cyclic GMP-AMP, cyclic GMP-AMP, cGAMP), etc.); STING agonists (SR-717 lithium, alpha-mangostin or diABZI STING agonists (diABZI STING agonist-1, compound 3), STING agonist-1 (G10), CF501 (formula (1)), CF502 (formula (5)), CF504 (formula (7)), CF505 (formula (8)), CF508 (formula (4)), CF509 (formula (6)), CF510 (formula (2)), CF511 (formula (9)) (Liu et al., Cell Research, pp. 1-19, 2022. https: / / doi.org / 10.1038 / s41422-022-00612-2) or MSA-2; STING antagonists (such as SN-011 (GUN35901) or H-151); indoleamine-2,3-dioxygenase (IDO or IDO-1) inhibitors or IDO1 inhibitors (such as epacadostat (INCB24360), BMS-986205, PF-0684003, navoximide, indoximod, NLG802 (indoximod prodrug) or LY3381916); and combinations thereof.

[0100]

[0127] In some cases, the bioactive agent can include any one of the bioactive agents listed above and below. In some cases, the bioactive agent can include two or more of the bioactive agents listed above and below.

[0101]

[0128] In some cases, in any of the pharmaceutical compositions disclosed herein, the bioactive agent can include a natural or synthetic small molecule based drug, an inorganic based drug, a biopharmaceutical, a natural or synthetic macromolecule based drug, a derivative thereof, or a combination thereof.

[0102]

[0129] In some cases, the bioactive agent can include one or more immunoglobulins, such as IgG, IgM, and the like, molecules prepared in accordance with the processes and methods disclosed and described in U.S. Pat. No. 10,688,048, which is incorporated herein by reference in its entirety.

[0103]

[0130] In some cases, the bioactive agent is a taxane, paclitaxel, docetaxel, cabazitaxel, larotaxel, mirataxel, ortataxel, tesetaxel, a topoisomerase 1 (Top1) inhibitor, a camptothecin derivative, irinotecan (CPT-11), SN-38, topotecan, a topoisomerase 2 (Top2) inhibitor, doxorubicin, etoposide, ciprofloxaxin, a mammalian target of rapamycin (mTOR) inhibitor, at least one STING polypeptide or portion thereof, a nucleic acid encoding a STING polypeptide or portion thereof, an STI The inhibitors may include NG inhibitors, STING activators, STING agonists, STING antagonists, STING modulating molecules, IDO inhibitors, IDO1 inhibitors or combinations thereof, and mTOR inhibitors include everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, bistusertib, ridaforolimus, one or more dual phosphopinositide 3-kinase (PI3K)-mTOR inhibitors, one or more ATP-competitive mTORC1 / 2 inhibitors, derivatives thereof or combinations thereof.

[0104]

[0131] In some cases, the bioactive agent can include 7-ethyl-10-hydroxycamptothecin (SN-38). In some cases, the bioactive agent can include 7-ethyl-10-hydroxycamptothecin (SN-38), irinotecan (also known as Camptosar, Campto, Onivyde, CPT-11), camptothecin (CPT), topotecan, or a combination thereof.

[0105]

[0132] In some cases, the bioactive agent can comprise at least one STING polypeptide or portion thereof, a nucleic acid encoding a STING polypeptide or portion thereof, a STING inhibitor, a STING activator, a STING agonist, a STING antagonist, a STING modulating molecule, an IDO inhibitor, an IDO1 inhibitor, or a combination thereof. The bioactive agent can comprise RNA, mRNA, siRNA, single guide RNA (sgRNA), DNA, oligos, or combinations thereof, each encoding one of the above-mentioned STING polypeptides or portions thereof, STING inhibitors, STING activators, STING agonists, STING antagonists, STING modulating molecules, or IDO inhibitors or IDO1 inhibitors.

[0106]

[0133] In some cases, the bioactive agent can include a STING (stimulator of interferon genes) protein, a STING agonist, a STING activator, a STING inhibitor, a STING antagonist, or a combination thereof. In some cases, the bioactive agent can include one or more IDO or IDO1 inhibitors. Any of the STING proteins, STING agonists, STING activators, STING inhibitors, STING antagonists, IDO inhibitors, or IDO1 inhibitors disclosed herein or discovered in the future may be suitable. In some cases, the bioactive agent may include a STING-modulating molecule, such as the benzimidazole compounds disclosed by Liu et al. (Cell Research, pp. 1-19, 2022) in patent publications WO2017175156(A1) and WO2020156363, the pyridinylimidazole compounds disclosed in patent publications WO2019134705, WO2020010451 and US20200031825, or a combination.

[0107]

[0134] In some cases, the bioactive agent can include one or more STING agonists. In some cases, the STING agonist can be one or more compounds having formulas (1)-(29) (FIGS. 12A-12E):

[0108] [ka]

[0109] [ka]

[0110] [ka]

[0111] [ka]

[0112] [ka]

[0113] It may include their corresponding salts, solvates, prodrugs, isomers, or combinations thereof.

[0135] In some cases, the bioactive agent is a compound represented by the formula (1):

[0114] [ka]

[0115] Formula (4)

[0116] [ka]

[0117] The present invention can include compounds having the formula:

[0136] In some cases, the bioactive agent may include a topoisomerase 1 (Top1) inhibitor, a camptothecin derivative, irinotecan (CPT-11), SN-38, topotecan, a topoisomerase 2 (Top2) inhibitor, doxorubicin, etoposide, ciprofloxacin, or a combination thereof. SN-38 (FIG. 13A), which has the chemical structure 7-ethyl-10-hydroxycamptothecin, is a topoisomerase 1 (Top1) inhibitor. Throughout this disclosure, the terms "7-ethyl-10-hydroxycamptothecin" and "SN-38" may be used interchangeably. Irinotecan (Figure 13B), also known by its respective trademarks Camptosar®, Campto, and Onivyde®, CPT-11 ((S)-(+)-7-ethyl-10-hydroxycamptothecin 10-[1,4'-bipiperidine]-1'-carboxylate monohydrochloride), is a water-soluble camptothecin analog and a prodrug of SN-38. Irinotecan can be converted to SN-38 in vivo by metabolism (Chabot GG. Clinical pharmacokinetics of irinotecan, Clin. Pharmacokinet. 1997, 33(4), 245-259). Camptothecin (CPT) (Figure 13C) is a pentacyclic monoterpene alkaloid that occurs naturally in the bark and stem of Camptotheca acuminiata. Topotecan, also known as Hycamtin (Figure 13D), is a water-soluble camptothecin derivative that is also approved in both IV injectable and oral forms. Examples of SN-38 antibody drug conjugates (ADCs) (SN-38ADCs) can include TRODELVY® (hRS7-SN38 ADC) (Figure 13E) under their respective trade names.

[0118]

[0137] In some cases, the nanoaggregates may be water-soluble and may include a polymer and at least one bioactive agent that is water-insoluble or poorly water-soluble. The pharmaceutical composition comprising the nanoaggregates is soluble in an aqueous solution and can yield at least 1 mg / mL of the bioactive agent in the aqueous solution. In some cases, the pharmaceutical composition comprising the nanoaggregates is soluble in an aqueous solution and can yield at least 2 mg / mL of the bioactive agent disclosed herein or combinations thereof in the aqueous solution. In some cases, the pharmaceutical composition comprising the nanoaggregates is soluble in an aqueous solution and can yield at least 1 mg / mL, 1.5 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 3.5 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL or more of the bioactive agent disclosed herein or combinations thereof in the aqueous solution.

[0119]

[0138] Any of the polymers disclosed herein may be suitable. In some examples, the polymer may include a polyoxazoline (POX) that includes a linear portion, a branched portion, or a combination thereof, and the polyoxazoline (POX) may include poly(2-oxazoline), poly(2-methyloxazoline), poly(2-ethyloxazoline), poly(2-propyloxazoline), poly(isopropyloxazoline) (PiPOX), or a combination thereof. In some examples, the polyoxazoline may be poly(2-ethyloxazoline).

[0120]

[0139] As used throughout this disclosure, nanoaggregates may be less than 150 nm in size prior to lyophilization. In some cases, nanoaggregates may be less than 120 nm in size prior to lyophilization. "Less than" means that the size may be less than a size defined in nm and may be about 0 nm, i.e., the solution of nanoaggregates may be a clear solution without measurable particles or aggregates. For example, "less than 150 nm" means a range of 0 nm to 150 nm, and "less than 120 nm" means a range of 0 nm to 120 nm. In some cases, the size of the nanoaggregates or nanoparticles may be in the range of about 0.01 nm to about 100 nm prior to lyophilization. In some cases, the size of the nanoaggregates or nanoparticles may be in the range of about 0.01 nm to about 120 nm prior to lyophilization. In some cases, the size of the nanoaggregates or nanoparticles may be in the range of about 0.01 nm to about 150 nm prior to lyophilization. In some cases, the size of the nanoaggregates or nanoparticles may be in the range of about 50 to about 100 nm prior to lyophilization. In some cases, the size of the nanoaggregates or nanoparticles may range from about 50 to about 120 nm before lyophilization. The particle size may be measured by light scattering methods.

[0121]

[0140] In some cases, in the pharmaceutical compositions of the present disclosure, the nanoaggregates may further comprise a targeting moiety comprising an antibody, an antigen-binding portion thereof, an antigen, a cell receptor, a cell receptor ligand, a ligand for a cell protein, a ligand for a membrane protein, a small molecule ligand, a lectin ligand, or a combination thereof.

[0122]

[0141] In some cases, the nanoaggregates may not include human serum albumin, organic solvents, detergents, or oils. In some cases, the nanoaggregates may not include human serum albumin, organic solvents, detergents, oils, or free acids. In some cases, the nanoaggregates may not include human serum albumin. In some cases, the nanoaggregates may not include organic solvents. In some cases, the nanoaggregates may not include detergents. In some cases, the nanoaggregates may not include oils. In some cases, the nanoaggregates may not include free acids. In some cases, the nanoaggregates may not include a substance selected from the group consisting of human serum albumin, organic solvents, detergents, oils, free acids, and combinations thereof.

[0123]

[0142] In some cases, the pharmaceutical composition may not include human serum albumin, organic solvent, detergent or oil. In some cases, the pharmaceutical composition may not include human serum albumin, organic solvent, detergent, oil or free acid. In some cases, the pharmaceutical composition may not include human serum albumin. In some cases, the pharmaceutical composition may not include an organic solvent. In some cases, the pharmaceutical composition may not include a detergent. In some cases, the pharmaceutical composition may not include an oil. In some cases, the pharmaceutical composition may not include a free acid. In some cases, the pharmaceutical composition may not include a substance selected from the group consisting of human serum albumin, organic solvent, detergent, oil, free acid and combinations thereof.

[0124]

[0143] In some cases, the bioactive agent can include one or more STING agonists. In some cases, the bioactive agent can include a compound having at least Formula (1)-Formula (29), a pharma- ceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof (FIGS. 12A-12E).

[0125]

[0144] In some cases, the bioactive agent is a compound represented by the formula (1):

[0126] [ka]

[0127] or equation (4)

[0128] [ka]

[0129] The present invention can include compounds having the formula:

[0145] The pharmaceutical composition of the present disclosure can be a drug for treating or preventing a disease selected from one or more immune disorders, infectious diseases, cancers, and combinations thereof. The immune disorder can include immune deficiency disorders, hyperactive immune disorders, autoimmune diseases, and other disorders or conditions with immune system abnormalities. In some cases, the immune disorder can be various autoinflammatory diseases, autoimmune diseases, and degenerative diseases, such as those related to the STING (stimulator of interferon genes) signaling pathway or IDO pathway. In some cases, the immune disorder can be related to STING-mediated inflammation in infection, cell stress, and tissue damage. In some cases, the pharmaceutical composition of the present disclosure can be a drug for cancer immunotherapy based on immune checkpoint blockade. In some cases, the pharmaceutical composition of the present disclosure can include a STING protein, a STING agonist, a STING activator, a STING inhibitor, a STING antagonist, an IDO inhibitor, an IDO1 inhibitor, or a combination thereof. In some cases, the pharmaceutical composition of the present disclosure can include one or more STING inhibitors. In some cases, the pharmaceutical composition of the present disclosure can include one or more STING activators.

[0130]

[0146] The term "cancer" or "cancers" as used herein and throughout this disclosure refers to cancer or tumor, and can include malignant and benign tumors, such as solid tumors, and blood cancers, such as leukemia. Malignant tumors can spread or invade adjacent tissues. Furthermore, as these tumors grow, some cancer cells can detach and travel to distant locations in the body via the blood or lymphatic system to form new tumors (metastatic tumors) away from the original tumor (primary cancer). Cancer can include primary cancer or metastatic tumors. The pharmaceutical compositions disclosed herein can be cancer treatment drugs for treating one or more cancers. In some cases, the term "cancer" or "cancers" as used herein refers to any cancer, tumor, or tumour that is a part of the body, including, but not limited to, acoustic neuroma, acute lymphoblastic leukemia (adult), acute lymphoblastic leukemia (childhood), acute myeloid leukemia, adenocarcinoma, anal cancer, anemia and neutropenia (low red and white blood cell count), basal cell carcinoma, basal cell skin cancer, B-cell lymphoma (diffuse large B-cell lymphoma), B-cell lymphoma (follicular lymphoma), B-cell lymphoma (mantle cell lymphoma), cholangiocarcinoma, biliary tract cancer, pulmonary fibrosis ...track) cancer, bladder cancer, bladder cancer, bone cancer, brain cancer (glioma), brain stem glioma, breast cancer, breast cancer (DCIS breast cancer), breast cancer (invasive breast cancer), breast cancer (metastatic breast cancer), triple negative breast cancer, estrogen receptor (ER)(+) locally advanced or metastatic breast cancer, bronchogenic carcinoma, central nervous system (CNS) cancer (primary central nervous system lymphoma), cervical cancer, choriocarcinoma, chronic lymphocytic leukemia, chronic lymphocytic lymphoma, chronic myeloid leukemia, colon cancer, colon cancer, colorectal cancer (CRC), diffuse large B-cell lymphoma, ependymoma , Esophageal cancer, Gallbladder and bile duct cancer, Gastric cancer, Intracranial germinoma, Glioblastoma, Astrocytoma, Mixed glioma, Graft-versus-host disease, Head and neck cancer, Head and neck cancer (nasopharyngeal cancer), Head and neck cancer (oral cancer), Head and neck cancer (oropharyngeal cancer), Hemangioblastoma, Hepatocellular carcinoma, Hepatoma, Hodgkin's lymphoma, Kidney cancer, Leukemia, Liver cancer, Lung cancer, Lung cancer (non-small cell lung cancer (NSCLC) - early stage and locally advanced), Lung cancer (non-small cell lung cancer - metastatic), Lung cancer NSCLC (non-small cell lung cancer), Lung cancer (small cell lung cancer), Lymphoid malignancies, Malignant pleural mesothelioma, Medullary carcinoma, Thyroid cancer Medullary adenocarcinoma, medulloblastoma, melanoma, meningioma, multiple myeloma, mycosis fungoides / Sezary syndrome, myelodysplastic syndrome, myeloproliferative neoplasm, neuroblastoma, neuroendocrine tumor (advanced), neuroendocrine tumor, oligodendroglioma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, papillary thyroid carcinoma, peripheral T-cell lymphoma, perivascular epithelioid cell (PEC) tumor, perivascular epithelioid cell tumor (advanced unresectable or metastatic malignancy), pheochromocytoma, pinealoma, primary cutaneous lymphoma, prostate cancer, The cancer may include one or more cancers selected from prostate cancer (advanced stage), prostate cancer (early stage), rectal cancer, recurrent endometrial cancer, recurrent ER(+) high-grade ovarian cancer, recurrent or refractory non-Hodgkin's lymphoma, renal cancer (metastatic clear cell), renal cell carcinoma, retinoblastoma and brain metastases, schwannoma, craniopharyngioma, sebaceous gland carcinoma, seminoma, soft tissue sarcoma, squamous cell carcinoma, squamous cell skin cancer, gastric cancer, sweat gland carcinoma, systemic mastocytosis, testicular tumor, thyroid cancer, uterine cancer, uterine sarcoma, Waldenstrom's macroglobulinemia, and combinations thereof.

[0131]

[0147] In some cases, the one or more cancers may be selected from any of the above cancers. In some cases, the one or more cancers may be selected from thyroid cancer, recurrent ER(+) high grade ovarian cancer, ER(+) locally advanced or metastatic breast cancer, progressive neuroendocrine tumors, diffuse large B-cell lymphoma, progressive solid tumors, metastatic clear cell renal cancer, recurrent or refractory non-Hodgkin's lymphoma, chronic lymphocytic lymphoma, recurrent endometrial cancer, perivascular epithelioid cell tumor (PEComa), progressive unresectable or metastatic malignant perivascular epithelioid cell tumor, ovarian cancer, lung cancer, NSCLC (non-small cell lung cancer), small cell lung cancer, cholangiocarcinoma, bladder cancer, cervical cancer, soft tissue sarcoma, uterine sarcoma, colon cancer, gastric cancer, melanoma, head and neck cancer, pancreatic cancer, metastatic cancer derived from one or more thereof, and combinations thereof. In some cases, the cancer or cancers may be progressive unresectable or metastatic malignant perivascular epithelioid cell tumors (PEComas).

[0132]

[0148] The pharmaceutical compositions of the present disclosure can be medicaments for treating or preventing one or more diseases disclosed herein.

[0149] In some cases, the pharmaceutical composition can include two or more bioactive agents, and at least one of the two or more bioactive agents is water-insoluble or poorly water-soluble.In some cases, at least one of the two or more bioactive agents is paclitaxel.In some cases, at least one of the two or more bioactive agents is rapamycin.In some cases, the pharmaceutical composition can include paclitaxel and one or more additional bioactive agents disclosed herein that are different from paclitaxel. In some cases, the pharmaceutical composition can include rapamycin and one or more additional bioactive agents selected from gemcitabine, paclitaxel, docetaxel, cabazitaxel, larotaxel, mirataxel, ortataxel, tesetaxel, temozolomide, platinum-based antineoplastic agents, daunorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (bis-chloroethylnitrosourea, also known as BCNU or BiCNU), methyl-CCNU, cisplatin, vinorelbine, capecitabine, or combinations thereof. In some cases, the pharmaceutical composition can include two or more bioactive agents in the nanoaggregates. In some cases, the pharmaceutical composition can include at least one water-insoluble or poorly water-soluble bioactive agent in the nanoaggregate, such as rapamycin, and one or more additional bioactive agents that are either included in the nanoaggregate or not included in the nanoaggregate. The pharmaceutical composition can include a nanoaggregate that includes a polymer and two or more bioactive agents, each of which is water-insoluble or poorly water-soluble. The pharmaceutical composition can include a nanoaggregate that includes a polymer and at least one water-insoluble or poorly water-soluble bioactive agent, and one or more additional bioactive agents, each of which is water-soluble. In one example, the pharmaceutical composition can include a nanoaggregate that includes rapamycin, a taxane, and gemcitabine, in another example, a nanoaggregate that includes rapamycin and a taxane, and in yet another example, a nanoaggregate that includes rapamycin and temozolomide.

[0133]

[0150] The term "combination thereof" as used with respect to the combinations of bioactive agents disclosed above means a combination of two or more bioactive agents, and such combinations do not have undesirable effects, such as undesirable interactions between two or more bioactive agents. It is understood that some combinations of bioactive agents may not be suitable or desirable, such as those with undesirable interactions. For example, the combination of theophylline and ciprofloxacin or warfarin and diflunisal may not be suitable. Thus, these combinations, or any combinations determined by appropriate guidelines or regulations as not suitable, are excluded.

[0134]

[0151] The pharmaceutical composition of the present invention disclosed herein may contain rapamycin in the range of 1 mg / ml to 10 mg / ml in an aqueous solution that does not contain human serum albumin, organic solvent, detergent, or oil. The pharmaceutical composition of the present invention disclosed herein may contain rapamycin in the range of 1 mg / ml to 10 mg / ml in an aqueous solution that does not contain human serum albumin, organic solvent, detergent, oil, or free acid. Rapamycin itself is insoluble in water. The pharmaceutical composition of the present invention may contain rapamycin in the range of 1 mg / ml to 10 mg / ml in one example, 2 mg / ml to 10 mg / ml in one example, 2 mg / ml to 7 mg / ml in another example, 2 mg / ml to 6 mg / ml in yet another example, 3 mg / ml to 10 mg / ml in yet another example, 3 mg / ml to 6 mg / ml in yet another example, or 3 mg / ml to 5 mg / ml in yet another example, in an aqueous solution that does not contain human serum albumin, organic solvent, detergent, oil, or free acid.

[0135]

[0152] As described above, the nanoaggregates may be less than 150 nm in size prior to lyophilization. In some cases, the nanoaggregates may be less than 120 nm in size prior to lyophilization. In some cases, the nanoaggregates may be in a range of about 0.01 nm or about 0 nm to about 150 nm in size prior to lyophilization. The nanoaggregates may be in a range of about 50 nm to about 150 nm in size prior to lyophilization. In some cases, the nanoaggregates or nanoparticles may be in a range of about 50 to about 100 nm in size prior to lyophilization. In some cases, the nanoaggregates or nanoparticles may be in a range of about 50 to about 120 nm in size prior to lyophilization. In a further example, the nanoaggregates may be in a range of about 70 to 90 nm in size prior to lyophilization. The particle size may be measured by light scattering.

[0136]

[0153] In any of the pharmaceutical compositions disclosed above and hereinafter, the nanoaggregates can have a weight ratio of polymer to bioactive agent ranging from about 2:1 to about 200:1. In one example, the nanoaggregates can be from about 2:1 to about 200:1, in another example, from about 2:1 to about 150:1, in yet another example, from about 2:1 to about 120:1, in yet another example, from about 2:1 to about 100:1, in yet another example, from about 2:1 to about 80:1, in yet another example, from about 2:1 to about 60:1, in yet another example, from about 2:1 to about 40:1, in yet another example, from about 2:1 to about 30:1, in yet another example, from about 2:1 to about 20:1, in another example, from about 2:1 to about 15:1, and in yet another example, from about 2:1 to about 15:1. In yet another example, the weight ratio of polymer to bioactive agent can range from about 2:1 to about 10:1, in yet another example, from about 2:1 to about 8:1, in yet another example, from about 5:1 to about 10:1, in yet another example, from about 5:1 to about 8:1, in yet another example, 5:1, in yet another example, from about 6:1 to about 8:1, in yet another example, 6:1, in yet another example, 7:1, in yet another example, 7.5:1, and in yet another example, 8:1. When the pharmaceutical composition includes two or more bioactive agents, the ratio of polymer to bioactive agent can be based on the total weight of the polymer and bioactive agent.

[0137]

[0154] In some cases, the pharmaceutical composition of interest may be an adjuvant for a vaccine.

[0155] In some cases, the pharmaceutical composition can be a preventive vaccine, a therapeutic vaccine, or a combination thereof, and the pharmaceutical composition can further comprise at least one immunological agent that stimulates an immune response in a subject that requires such stimulation.The immunological agent can comprise an inactive microorganism selected from bacteria, viruses, fungi, protozoa, insects, parasites, prions, parts thereof, or combinations thereof; a toxin; a nucleic acid that codes for a toxin; a protein; a nucleic acid that codes for a protein; an oligonucleic acid; DNA; RNA; mRNA; siRNA; sgRNA; a fragment thereof; or a combination thereof.

[0138]

[0156] In some cases, the pharmaceutical composition may be formulated to treat or prevent at least one infectious disease.In some cases, the pharmaceutical composition may be formulated to treat or prevent at least one infectious disease selected from chickenpox (varicella), coronavirus, dengue fever, diphtheria, Ebola, influenza (influenza), hepatitis, Hib disease, HIV / AIDS, human papillomavirus (HPV), Japanese encephalitis, measles, meningococcal disease, EMPOCH, mumps, norovirus, pneumococcal disease, polio, rabies, respiratory syncytial virus (RSV), rotavirus, rubella (German measles), shingles (shingles), tetanus (tetanus), whooping cough (pertussis), Zika fever, and combinations thereof.

[0139]

[0157] In some cases, the pharmaceutical composition may have a pH value in the range of 3.0 to 6.9. In some cases, the pharmaceutical composition may have a pH value in the range of 4.0 to about 6.9 or 5.6 to about 6.9. The pH value may be measured in an aqueous solution of the pharmaceutical composition.

[0140]

[0158] In some cases, the pharmaceutical compositions can include one or more bioactive agents disclosed herein, derivatives thereof, or combinations thereof, where in the range of 1%-100% of the second terminal groups are free of primary amines and in the range of 1%-100% of the second terminal groups are hydroxyl groups.

[0141]

[0159] In some cases, the pharmaceutical compositions can include an mTOR inhibitor including everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, bistusertib, ridaforolimus, derivatives thereof, or combinations thereof, where in the range of 1%-100% of the second terminal groups are free of primary amines and in the range of 1%-100% of the second terminal groups are hydroxyl groups.

[0142]

[0160] In some cases, the pharmaceutical compositions can include an mTOR inhibitor including everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, bistusertib, ridaforolimus, derivatives thereof, or combinations thereof, where in the range of 50%-100% of the second terminal groups are free of primary amines and in the range of 50%-100% of the second terminal groups are hydroxyl groups.

[0143]

[0161] In some cases, the pharmaceutical compositions can include an mTOR inhibitor including everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, bistusertib, ridaforolimus, derivatives thereof, or combinations thereof, where in the range of 80%-100% of the second terminal groups are free of primary amines and in the range of 80%-100% of the second terminal groups include hydroxyl groups.

[0144]

[0162] In some cases, the pharmaceutical compositions can include an mTOR inhibitor including everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, bistusertib, ridaforolimus, derivatives thereof, or combinations thereof, where in the range of 90%-100% of the second terminal groups are free of primary amines and in the range of 90%-100% of the second terminal groups are hydroxyl groups.

[0145]

[0163] In some cases, the pharmaceutical composition may further comprise one or more subsequent bioactive agents selected from a protein, a peptide, an antibody, a fragment of an antibody, a chemical compound, a small molecule drug, one or more chemotherapeutic agents, and combinations thereof.

[0146]

[0164] The pharmaceutical compositions disclosed above and hereafter can further include an additional bioactive agent that is formulated without a polymer, specifically the polymers disclosed herein. The phrase "additional bioactive agent formulated without a polymer" refers to a formulation of a bioactive agent that includes a bioactive agent and does not include the polymers disclosed herein, where the additional bioactive agent can be a salt, a base, a bioactive agent (formulated with an organic solvent, a detergent, an oil, or a free acid), a protein, a lipid, or a combination thereof. In a particular example, the additional taxane does not include a polyoxazoline (POX) polymer disclosed herein. In some cases, the pharmaceutical compositions can include an additional taxane that is formulated with human serum albumin in one example, a taxane that is formulated with ethanol or Cremophor® (polyethoxylated castor oil) in another example, a taxane modified with acid, ammonium, alkyl, or aryl in yet another example, a taxane that is formulated in lipids in yet another example, a taxane that is formulated in cationic lipids in yet another example, and a combination thereof in further examples. Commercially available taxane formulations such as Abraxane® available from Celgene under their respective trademarks and Taxol® available from Bristol-Myers Squibb under their respective trademarks may be suitable. In one embodiment, the pharmaceutical composition may further comprise Abraxane, in another embodiment, Taxol, or in yet another embodiment, a combination of Abraxane and Taxol.

[0147]

[0165] The term "soluble in aqueous solution" refers to a solution containing no detectable particles or particles that can be filtered through a 0.22 μm filter, with a filterability (R f) in the range of 50 to 100 percent. The term "0.22 μm filter" as used throughout this disclosure refers to a filter assembly having a filtration pore size of 0.22 μm. The term "0.8 μm filter" refers to a filter assembly having a filtration pore size of 0.8 μm.

[0148]

[0166] In any of the pharmaceutical compositions disclosed above or hereinafter, the nanoaggregates can have a filtration rating through a 0.22 μm filter in the range of 50 to 100 percent. f and is defined in detail in a later section of this disclosure.

[0149]

[0167] In embodiments, the nanoaggregates have a filtration rate of at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or higher; or 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95-100%, 55-95 ...60-100%, 65-100%, 70-100%, 75- It may have a filtration rate in the ranges of 5-95%, 75-95%, 85-95%, 50-95%, 60-95%, 70-95%, 80-95%, 90-95%, 50-90%, 60-90%, 70-90%, 80-90%, 55-90%, 65-90%, 75-90%, 85-90%; or in any range of filtration rates, it must be greater than or equal to 50%.

[0150]

[0168] The nanoaggregates can be filtered through a 0.22 μm filter to produce sterile nanoaggregates prior to lyophilization, where the nanoaggregates are filtered through a 0.22 μm filter to a filterability (R) in the range of 50-100 percent. f) in another example, the pharmaceutical composition can be filtered through a 0.22 μm filter to produce a filtered pharmaceutical composition. Briefly, the polymer-drug nanoaggregate sample can be dissolved in water, saline, phosphate buffered saline (PBS), or a solvent described herein to a predetermined final concentration. The sample is then filtered through a selected filter with a predetermined filtration surface area, such as a 25 mm diameter sterile syringe filter assembly with a filtration pore size of 0.22 μm, at a predetermined starting volume, V0. The volume of the passage through the filter, V p The filtration rate of the sample R f can be calculated based on the following formula: R f =V p / V0

[0169] Filtration R f can be expressed as a percentage or fraction of a given filtration surface area. In some cases, as disclosed herein, a standard sterilizing filter with a diameter of 25 mm can be used. Filtration R f can be expressed as a percentage or fraction of a 25 mm diameter sterile filter having a given filtration surface area. Filtration measured using different size filters can be converted or normalized relative to a standard 25 mm diameter filter. Percentages are used in this disclosure. In embodiments of this process, the nanoaggregates are at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more; or 50-100%, 60-100%, 70-100%, 80-100%, 90-100%, 55-100%, 65-100%, 75-100%, 85-100%, 95-100%, 55-95%, 6 It may have a degree of filtration in the ranges of 5-95%, 75-95%, 85-95%, 50-95%, 60-95%, 70-95%, 80-95%, 90-95%, 50-90%, 60-90%, 70-90%, 80-90%, 55-90%, 65-90%, 75-90%, 85-90%; or in any range of degree of filtration, it must be not less than 50%.

[0151]

[0170] The pharmaceutical compositions disclosed herein can be formulated for parenteral, oral, nasal, transdermal (topical), transmucosal, rectal administration, or a combination thereof, and can include one or more suitable carriers for the pharmaceutical. In some cases, the pharmaceutical compositions disclosed herein can be formulated for intravenous (IV), intradermal (ID), subcutaneous (SC), oral, transdermal (topical), transmucosal, rectal administration, or a combination thereof. In some cases, the pharmaceutical compositions disclosed herein can be formulated for intravenous (IV), intradermal (ID), subcutaneous (SC), transdermal (topical) or transmucosal administration. In some cases, the pharmaceutical compositions disclosed herein can be formulated for oral administration, such as tablets, capsules, oral sprays, solutions or suspensions. In some cases, the pharmaceutical compositions disclosed herein can be formulated for nasal administration, such as nasal sprays. Suitable carriers for the pharmaceuticals disclosed herein can be suitable.

[0152]

[0171] In some cases, the pharmaceutical composition comprises the steps of:

[0172] (1) forming nanoaggregates comprising a polymer and at least one water-insoluble or poorly water-soluble bioactive agent by mixing the polymer and the bioactive agent in a nanoaggregate solution comprising at least one organic solvent;

[0173] (2) removing the organic solvent from the nanoaggregates to form dried nanoaggregates;

[0174] (3) dissolving the dried nanoaggregates in water, saline or PBS to form an aqueous nanoaggregate solution; and

[0175] (4) freeze-drying the aqueous nanoaggregate solution to form freeze-dried nanoaggregates. The method of claim 1, further comprising:

[0176] the polymer is water soluble and comprises at least one first end group modified with H or a hydrophobic moiety and a second end group modified with a hydrophilic moiety;

[0177] the first end group comprises in the range of 1%-99% H and a hydrophobic moiety in the range of 1%-99%, which may include saturated or unsaturated aliphatic hydrocarbons having 1 to about 22 carbons, aromatic hydrocarbons, or combinations thereof, and the second end group comprises a group modified with an amine, an amide, an imine, an imide, a carboxyl, a hydroxyl, an ester, an ether, an acetate, a phosphate, a ketone, an aldehyde, a sulfonate, or a combination thereof; It can be prepared by the method.

[0153]

[0178] Prior to lyophilization, the aqueous nanoaggregate solution can be filtered through a 0.22 μm filter to produce sterile nanoaggregates.

[0179] In some cases, the nanoaggregates may be produced by dissolving the polymer and the bioactive agent together in a nanoaggregate solution that includes an organic solvent to form the nanoaggregates. Any organic solvent or mixture thereof may be suitable. In some cases, the organic solvent may be acetic acid, acetone, acetonitrile, benzene, 1-butanol, 2-butanol, 2-butanone, t-butyl alcohol, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, diethylene glycol, diethyl ether, diglyme (diethylene glycol, dimethyl ether), 1,2-dimethoxyethane, dimethoxyethane (DME, also known as glyme), dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, ethyl acetate ... The solvent may include coal, glycerin, heptane, hexamethylphosphoramide, (HMPA), hexamethylphosphoric triamide (HMPT), hexane, methanol, methyl t-butyl ether (MTBE), methylene chloride, N-methyl-2-pyrrolidinone (NMP), nitromethane, pentane, petroleum ether (ligroin or ligroine), 1-propanol, 2-propanol, pyridine, tetrahydrofuran (THF), toluene, triethylamine, o-xylene, m-xylene, p-xylene, or combinations thereof.

[0154]

[0180] In some cases, the nanoaggregates may be produced by dissolving a polymer in a first organic solvent to form a polymer solution, dissolving a bioactive agent in a second organic solvent to form a bioactive agent solution, and mixing the polymer solution and the bioactive agent solution to form the nanoaggregates, where the first organic solvent and the second organic solvent can be the same or different and can be independently selected from the organic solvents disclosed above.

[0155]

[0181] In some cases, the nanoaggregates can be produced by dissolving a polymer in an aqueous solution, a first organic solvent, or a combination thereof to form a polymer solution, dissolving a bioactive agent in a second solvent including a second organic solvent to form a bioactive agent solution, and mixing the polymer solution and the bioactive agent solution to form the nanoaggregates, where the first organic solvent and the second organic solvent can be the same or different, and the second organic solvent is a water-miscible organic solvent. The first solvent can be selected from water, an aqueous solution such as saline, a buffer such as phosphate buffered saline (PBS), a first organic solvent, or a combination thereof. The first organic solvent and the second organic solvent can be independently selected from water-miscible organic solvents such as methanol, ethanol, acetone, propanol, isopropanol, and combinations thereof. In some cases, the first organic solvent and the second organic solvent can independently comprise a mixture of two or more solvents. In some cases, the first organic solvent and the second organic solvent can independently comprise a chloroform / ethanol mixture.

[0156]

[0182] The pharmaceutical composition may have a pH value in the range of about 3.0 to about 10.0. In some cases, the pharmaceutical composition may have a pH value in the range of about 7.0 to about 9.0. In some cases, the pharmaceutical composition may have a pH value in the range of about 7.0 to about 8.0. In some cases, the pharmaceutical composition may have a pH value in the range of about 7.0 to about 7.5. In some cases, the pharmaceutical composition may have a pH value in the range of about 3.0 to about 6.9. In some cases, the pharmaceutical composition may have a pH value in the range of about 3.0 to about 7.0. In some cases, the pharmaceutical composition may have a pH value in the range of about 4.0 to about 7.5. In some cases, the pharmaceutical composition may have a pH value in the range of about 3.0 to about 6.9, 4.0 to about 6.9, or 5.6 to about 6.9. The pharmaceutical composition may be adjusted with an acid or base to reach the desired pH range. An acid such as HCl or other acid may be suitable. A base such as NaOH or other base may be suitable.

[0157]

[0183] The nanoaggregates of the pharmaceutical composition produced by the method of the present invention may not include human serum albumin, organic solvents, detergents, or oils, as described above. The nanoaggregates of the pharmaceutical composition produced by the method of the present invention may not include human serum albumin, organic solvents, detergents, oils, or free acids, as described above. In a further example, the pharmaceutical composition produced by the method of the present invention may not include human serum albumin, organic solvents, detergents, oils, or free acids, as described above.

[0158]

[0184] The methods disclosed above and hereinafter may further comprise the step of mixing additional bioactive agents that are formulated without polymers into the pharmaceutical composition. In some cases, chemical or small molecule drugs, chemical therapeutic drugs, inorganic based drugs, biomolecular or macromolecule based drugs, modifications or derivatives thereof and combinations thereof, formulated without the polymers mentioned above, individually or in combination, may be suitable.

[0159]

[0185] In some cases, the present disclosure provides a method of treating or preventing a disease in a subject in need thereof, comprising administering to the subject an effective dose of:

[0186] nanoaggregates comprising a polymer and at least one water-insoluble or poorly water-soluble bioactive agent;

[0187] administering a pharmaceutical composition, which may include a suitable carrier for pharmaceutical use;

[0188] the pharmaceutical composition is soluble in an aqueous solution to provide at least 1 mg / mL of the bioactive agent in the aqueous solution;

[0189] The polymer is water soluble;

[0190] The polymer

[0191] a first polymer comprising at least one first end group modified with H or a hydrophobic moiety, and a second end group modified with a hydrophilic moiety, wherein the first end group comprises in the range of 1%-99% H and in the range of 1%-99% hydrophobic moieties comprising saturated or unsaturated aliphatic hydrocarbons having 1 to about 22 carbons, aromatic hydrocarbons, or combinations thereof, and the second end group comprises a group modified with an amine, amide, imine, imide, carboxyl, hydroxyl, ester, ether, acetate, phosphate, ketone, aldehyde, sulfonate, or combinations thereof; or

[0192] One or more hydroxyl dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated generation 4, 5, 6, 7, 8, 9, 10 dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); Pluronics® (PPO-PEO); poly(gamma-L-glutamic acid) (PGA); poly(L-phenylalanine ethyl ester) (PAE); poly(L-lysine) (PLL); methyl-PEG ( mPEG; poly(aspartic acid) (PasP); poly(L-histidine) (PLH); poly(ethyleneamine) (PEI); poly(N-vinylpyrrolidone) (PVP); poly(L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly(hydroxybutyrate) (PHB); poly(ethylene oxide) (PEO); poly(γ-benzyl-L-glutamic acid) (PBLG); phosphatidylserine (PS); poly(isohexyl-cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); or

[0193] A second polymer, including combinations thereof The present invention is further directed to a method, which may include:

[0160]

[0194] In some cases, the polymer can include a first polymer disclosed herein.

[0195] In some cases, the polymer can be comprised of the first polymer disclosed herein.In some cases, the pharmaceutical composition can comprise one or more of hydroxyl dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated 4th, 5th, 6th, 7th, 8th, 9th, 10th generation dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); Pluronics® (PPO-PEO); poly(gamma-L-glutamic acid) (PGA); poly(L-phenylalanine ethyl ester) (PAE); poly(L-lysine) (PLL); methyl-PEG (mPEG); The polymer may not comprise a polymer selected from poly(aspartic acid) (PasP); poly(L-histidine) (PLH); poly(ethyleneamine) (PEI); poly(N-vinylpyrrolidone) (PVP); poly(L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly(hydroxybutyrate) (PHB); poly(ethylene oxide) (PEO); poly(γ-benzyl-L-glutamic acid) (PBLG); phosphatidylserine (PS); poly(isohexyl-cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); and combinations thereof.

[0161]

[0196] In some cases, the polymer may be one or more of hydroxyl dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated generation 4, 5, 6, 7, 8, 9, 10 dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); Pluronics® (PPO-PEO); poly(gamma-L-glutamic acid) (PGA); poly(L-phenylalanine ethyl ester) (PAE); poly(L-lysine) (PLL); methyl-PEG (mPEG); poly(propylene oxide) (PPO ... The second polymer may include poly(aspartic acid) (PasP); poly(L-histidine) (PLH); poly(ethyleneamine) (PEI); poly(N-vinylpyrrolidone) (PVP); poly(L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropylmethylcellulose (HPMC); poly(hydroxybutyrate) (PHB); poly(ethylene oxide) (PEO); poly(γ-benzyl-L-glutamic acid) (PBLG); phosphatidylserine (PS); poly(isohexyl-cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); or a combination thereof.

[0162]

[0197] In some cases, the polymer comprises a first polymer and one or more of hydroxyl dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated 4th, 5th, 6th, 7th, 8th, 9th, 10th generation dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); Pluronics® (PPO-PEO); poly(gamma-L-glutamic acid) (PGA); poly(L-phenylalanine ethyl ester) (PAE); poly(L-lysine) (PLL); methyl-PEG (mPEG); poly(aspartic acid ) (PasP); poly(L-histidine) (PLH); poly(ethyleneamine) (PEI); poly(N-vinylpyrrolidone) (PVP); poly(L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropylmethylcellulose (HPMC); poly(hydroxybutyrate) (PHB); poly(ethylene oxide) (PEO); poly(γ-benzyl-L-glutamic acid) (PBLG); phosphatidylserine (PS); poly(isohexyl-cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); and combinations thereof.

[0163]

[0198] The bioactive agents disclosed herein can be suitable as pharmaceutical or pharmacological agents.

[0199] Any of the polymers disclosed herein may be suitable. In some cases, the polymer may include a polyoxazoline (POX) that includes a linear portion, a branched portion, or a combination thereof, and the polyoxazoline (POX) includes poly(2-oxazoline), poly(2-methyloxazoline), poly(2-ethyloxazoline), poly(2-propyloxazoline), poly(isopropyloxazoline), or a combination thereof. In some cases, the polyoxazoline is poly(2-ethyloxazoline).

[0164]

[0200] In some cases, the polyoxazoline may include a molar ratio of monomer to initiator ranging from 50:1 to 80:1.

[0201] The nanoaggregates may range in size from less than about 120 nm prior to lyophilization. In some cases, the nanoaggregates may range in size from about 50 nm to about 120 nm prior to lyophilization. In some cases, the nanoaggregates may have a weight ratio of polymer to bioactive agent ranging from about 2:1 to about 200:1.

[0165]

[0202] In some cases, in the method disclosed herein, the pharmaceutical composition can include two or more subsequent bioactive agents. In some cases, at least one of the two or more bioactive agents is paclitaxel. In some cases, at least one of the two or more bioactive agents is rapamycin. In some cases, the pharmaceutical composition can include paclitaxel and one or more additional bioactive agents disclosed herein that are different from paclitaxel. In some cases, the pharmaceutical composition can further include rapamycin and one or more subsequent bioactive agents selected from proteins, peptides, antibodies, antibody fragments, chemical compounds, small molecule drugs, one or more chemotherapeutic drugs, vaccines, and combinations thereof. In some cases, the one or more subsequent bioactive agents are selected from the group consisting of gemcitabine, taxanes, paclitaxel, docetaxel, cabazitaxel, larotaxel, mirataxel, ortataxel, tesetaxel, topoisomerase 1 (Top1) inhibitors, camptothecin derivatives, irinotecan (CPT-11), SN-38, topotecan, topoisomerase 2 (Top2) inhibitors, doxorubicin, etoposide, ciprofloxacin, platinum-based antineoplastic agents, agents), anti-programmed cell death protein (PD) 1 antibody, anti-PD ligand (PD-L) 1 antibody, anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen) antibody, anti-LAG3 (lymphocyte activation gene-3) antibody, anti-TIM-3 (T cell immunoglobulin and mucin domain-3) antibody, anti-CD19 antibody, anti-CD20 antibody, cytokines, interleukins, interferon alpha 2a, interferon alpha, granulocyte colony stimulating factor (G-CSF), neupo-gen or filgrastim, T cell receptor (TCR), chimeric antigen receptor or chimeric antigen T cell receptor (CAR-T), STING protein, STING agonist, STING activator, STING inhibitor, STING antagonist or combinations thereof, indoleamine 2,3-dioxygenase (IDO) inhibitor, indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, vaccine, and combinations thereof.In some cases, at least one of the two or more bioactive agents can include a STING-modulating molecule, such as the benzimidazole compounds disclosed in patent publications WO2017175156(A1) and WO2020156363, the pyridinylimidazole compounds disclosed in patent publications WO2019134705, WO2020010451, and US20200031825, or a combination.

[0166]

[0203] In some cases, in the methods disclosed herein, the pharmaceutical composition can include one or more additional bioactive agents selected from gemcitabine, taxanes, paclitaxel, temozolomide, platinum-based antineoplastic agents, daunorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine, methyl-CCNU, cisplatin, vinorelbine, capecitabine, and combinations thereof. In some cases, the additional bioactive agent can include 7-ethyl-10-hydroxycamptothecin (SN-38).

[0167]

[0204] In some cases, the nanoaggregates may be less than 150 nm in size prior to lyophilization. In some cases, the nanoaggregates may be less than 120 nm in size prior to lyophilization. In some cases, the nanoaggregates may be in a size range of about 50 nm to about 150 nm prior to lyophilization. In some cases, the size of the nanoaggregates or nanoparticles may be in a range of about 50 to about 100 nm prior to lyophilization. In some cases, the size of the nanoaggregates or nanoparticles may be in a range of about 50 to about 120 nm prior to lyophilization. The particle size may be measured by light scattering.

[0168]

[0205] In some cases, the nanoaggregates can have a weight ratio of polymer to rapamycin ranging from about 2:1 to about 20:1.

[0206] In some cases, the nanoaggregates can have a weight ratio of polymer to rapamycin ranging from about 5:1 to about 8:1.

[0169]

[0207] In some cases, the nanoaggregates may further comprise a targeting moiety comprising an antibody, an antigen-binding portion thereof, an antigen, a cell receptor, a cell receptor ligand, a ligand for a cell protein, a ligand for a membrane protein, a small molecule ligand, a lectin ligand, or a combination thereof.

[0170]

[0208] In some cases, the nanoaggregates may not include human serum albumin, organic solvents, detergents, or oils. In some cases, the nanoaggregates may not include human serum albumin, organic solvents, detergents, oils, or free acids. In some cases, the nanoaggregates may not include human serum albumin. In some cases, the nanoaggregates may not include organic solvents. In some cases, the nanoaggregates may not include detergents. In some cases, the nanoaggregates may not include oils. In some cases, the nanoaggregates may not include free acids. In some cases, the nanoaggregates may not include a substance selected from the group consisting of human serum albumin, organic solvents, detergents, oils, free acids, and combinations thereof.

[0171]

[0209] In some cases, the pharmaceutical composition may not include human serum albumin, organic solvent, detergent or oil. In some cases, the pharmaceutical composition may not include human serum albumin, organic solvent, detergent, oil or free acid. In some cases, the pharmaceutical composition may not include human serum albumin. In some cases, the pharmaceutical composition may not include an organic solvent. In some cases, the pharmaceutical composition may not include a detergent. In some cases, the pharmaceutical composition may not include an oil. In some cases, the pharmaceutical composition may not include a free acid. In some cases, the pharmaceutical composition may not include a substance selected from the group consisting of human serum albumin, organic solvent, detergent, oil, free acid and combinations thereof.

[0172]

[0210] In some cases of the methods disclosed herein, between 1% and 100% of the second end groups are free of primary amines. In some cases, between 1% and 100% of the second end groups are hydroxyl groups. All percentages are based on the total number of second end groups.

[0173]

[0211] In some cases, the pharmaceutical composition may have a pH value in the range of 3.0 to 6.9.

[0212] In some cases, a bioactive agent suitable for the present methods can include a compound having at least Formula (1)-Formula (29) (FIGS. 12A-12E), a pharma- ceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

[0174]

[0213] In some cases, the bioactive agent is a compound represented by the formula (1):

[0175] [ka]

[0176] or equation (4)

[0177] [ka]

[0178] The present invention can include compounds having the formula:

[0214] In some cases, the disease may be selected from one or more immune disorders, infectious diseases, cancer, and combinations thereof.

[0179]

[0215] In some cases, the immune disorder can include the above-mentioned immune deficiency disorders, overactive immune disorders, autoimmune diseases and other disorders or conditions involving abnormalities of the immune system.

[0216] In some cases, the method may further include administering to the subject one or more subsequent bioactive agents selected from a protein, a peptide, an antibody, a fragment of an antibody, a chemical compound, a small molecule drug, one or more chemotherapeutic drugs, a vaccine, and combinations thereof. In some cases, the one or more subsequent bioactive agents may be selected from gemcitabine, a taxane, paclitaxel, docetaxel, cabazitaxel, larotaxel, mirataxel, ortataxel, tesetaxel, a topoisomerase 1 (Top1) inhibitor, a camptothecin derivative, irinotecan (CPT-11), SN-38, topotecan, a topoisomerase 2 (Top2) inhibitor, doxorubicin, etoposide, ciprofloxacin, a platinum-based antineoplastic agent, a cyclophosphamide ... The bioactive agent may be selected from anti-PD1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 (cytotoxic T-lymphocyte-associated antigen) antibodies, anti-LAG3 (lymphocyte activation gene-3) antibodies, anti-TIM-3 (T-cell immunoglobulin and mucin domain-3) antibodies, anti-CD19 antibodies, anti-CD20 antibodies, cytokines, interleukins, interferon alpha 2a, interferon alpha, granulocyte colony stimulating factor (G-CSF), neupo-gen or filgrastim, T cell receptors (TCR), chimeric antigen receptors or chimeric antigen T cell receptors (CAR-T), vaccines, and combinations thereof. Any of the bioactive agents disclosed herein may be suitable.

[0180]

[0217] In some cases, each of the one or more subsequent bioactive agents may be administered to the subject before, simultaneously with, or after administration of the pharmaceutical composition. Each of the one or more subsequent bioactive agents may be administered independently to the subject. In some cases, the subsequent bioactive agent may include 7-ethyl-10-hydroxycamptothecin (SN-38).

[0181]

[0218] The pharmaceutical composition may be administered to a subject by intravenous (IV) injection, subcutaneous (SC) injection, intramuscular (IM) injection, intradermal (ID) injection, or a combination thereof. A combination of intravenous (IV), subcutaneous (SC), intramuscular (IM) or intradermal (ID) injection may also be suitable.

[0182]

[0219] In some cases, the pharmaceutical composition can be a vaccine adjuvant. In some cases, the pharmaceutical composition is a prophylactic vaccine, a therapeutic vaccine, or a combination thereof, and the pharmaceutical composition further comprises at least one immunological agent that stimulates an immune response in a subject in need thereof. In some cases, the pharmaceutical composition is selected to treat or prevent at least one infectious disease selected from chickenpox (varicella), coronavirus, dengue fever, diphtheria, Ebola, influenza (influenza), hepatitis, Hib disease, HIV / AIDS, HPV (human papilloma virus), Japanese encephalitis, measles, meningococcal disease, empox, mumps, norovirus, pneumococcal disease, polio, rabies, respiratory syncytial virus (RSV), rotavirusHPV (human papilloma virus), Japanese encephalitis, measles, meningococcal disease, empox, mumps, norovirus, pneumococcal disease, polio, rabies, respiratory syncytial virus (RSV), rotavirus, rubella (german measles), shingles (shingles), tetanus (tetanus), whooping cough (pertussis), Zika fever, and combinations thereof.

[0183]

[0220] In some cases, the disease may be adenocarcinoma of the stomach or lower esophagus, AIDS-related Kaposi's sarcoma, ampullary carcinoma, angiosarcoma, B-cell lymphoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, cholangiocarcinoma, colon cancer, epithelial carcinoma, esophageal cancer, gastric cancer, genitourinary tract cancer, glioblastoma, head and neck cancer, head and neck squamous cell carcinoma (HNSCC), hematopoietic tissue cancer, testicular cancer, colon and rectal cancer, Hodgkin's lymphoma, Hodgkin's disease, hormone-refractory prostate cancer, kidney cancer, colorectal cancer, liver cancer, lymphoma, melanoma, metastatic breast cancer, metastatic pancreatic cancer, mycosis fungoides, myeloid leukemia, nasopharyngeal carcinoma, nervous system cancer, neuroblastoma, The disease may be one or more cancers, including non-small cell lung cancer (NSCLC), oral adenoid cystic carcinoma, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, renal cancer, sinonasal squamous cell carcinoma (SCC), skin cancer, small cell lung cancer (SCLC), squamous cell carcinoma of the head and neck, squamous cell carcinoma of the head and neck (SCCHN), stage IIB-IV melanoma, T-cell lymphoma, triple negative breast cancer (TNBC), upper GI adenocarcinoma, urothelial transitional cell carcinoma, or other cancers, or cancers including such cancers or neoplastic disorder diseases or disorders to be diagnosed or recognized. The disease may be any of the cancers disclosed above or hereafter. In some cases, the cancer may be a solid tumor. In some cases, the cancer may be one or more hematological cancers.

[0184]

[0221] In some cases, the disease may be one or more cancers including ampullary carcinoma, adrenal carcinoma, breast cancer, ovarian cancer, lung cancer, NSCLC (non-small cell lung cancer), cholangiocarcinoma, small cell lung cancer, bile duct carcinoma, bladder cancer, cervical cancer, soft tissue sarcoma, uterine sarcoma, colon cancer, gastric cancer, melanoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, head and neck cancer, oral adenoid cystic carcinoma, pancreatic cancer, paranasal squamous cell carcinoma (SCC), thyroid cancer, one or more metastatic cancers derived therefrom, or a combination thereof.

[0185]

[0222] In some cases, the one or more cancers are selected from thyroid cancer, recurrent ER(+) high grade ovarian cancer, ER(+) locally advanced or metastatic breast cancer, progressive neuroendocrine tumors, diffuse large B-cell lymphoma, progressive solid tumors, metastatic clear cell renal cancer, recurrent or refractory non-Hodgkin's lymphoma, chronic lymphocytic lymphoma, recurrent endometrial cancer, perivascular epithelioid cell tumor (PEComa), progressive unresectable or metastatic malignant perivascular epithelioid cell tumor, ovarian cancer, lung cancer, NSCLC (non-small cell lung cancer), small cell lung cancer, cholangiocarcinoma, bladder cancer, cervical cancer, soft tissue sarcoma, uterine sarcoma, colon cancer, gastric cancer, melanoma, head and neck cancer, pancreatic cancer, metastatic cancer derived from one or more thereof, and combinations thereof. In some cases, the one or more cancers can be progressive unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa).

[0186]

[0223] As used herein, the subsequent bioactive agent can have a molecular weight ranging from about 10-1,000,000 in one example, 100-500,000 in another example, 100-200,000 in yet another example, 500-200,000 in yet another example, 1,000-200,000 in yet another example, 5,000-200,000 in yet another example, 10,000-200,000 in yet another example, 15,000-200,000 in yet another example, 20,000-200,000 in yet another example, and 25,000-200,000 in yet another example. The bioactive agent can also have a molecular weight ranging from about 100-100,000 in one example, and from 100-75,000 in yet another example, and from 100-50,000 in yet another example, and from 100-30,000 in yet another example, and from 100-25,000 in yet another example.

[0187]

[0224] The subsequent bioactive agent may include a drug, a protein, a recombinant protein, an antibody, a Fab antibody fragment, other antibody fragments that bind to an antigen, an enzyme, a virus, a viral fragment, and combinations thereof. The subsequent bioactive agent may be selected from a peptide, a monoclonal antibody, a fragment of a monoclonal antibody, a polyclonal antibody, a fragment of a polyclonal antibody, a synthetic antibody, a fragment of a synthetic antibody, or a combination thereof. Subsequent bioactive agents include alemtuzumab, bevacizumab, cetuximab, ibritumomab, rituximab, trastuzumab, gemtuzumab, anti-PD1 antibodies (such as Keytruda or pembrolizumab, Opdivo or nivolumab, Bavencio or avelumab, Imfinzi or durvalumab, Tecentriq or atezolizumab), anti-PD-L1 antibodies, anti-CTLA-4 (cytotoxic T-lymphocyte-associated antigen, also known as CD152) antibodies, anti-LAG3 (lymphocyte activation gene-3) antibodies, anti-TIM-3 (T-cell immunoglobulin and mucin domain-3) antibodies, anti-CD19 antibodies, anti-CD20 antibodies (such as tositumomab), cytokines (such as interleukins, interferon alpha 2a, interferon alpha), granulocyte colony-stimulating factor (G-CSF) or neupogene (filgrass). The therapeutic agent may include, for example, antibodies or antigen-binding portions thereof, such as antibodies against STING (also known as thym), T cell receptors (TCR), chimeric antigen receptors or chimeric antigen T cell receptors (CAR-T), STING proteins, STING agonists, STING activators, STING inhibitors, STING antagonists, STING modulating molecules, indoleamine 2,3-dioxygenase (IDO) inhibitors, indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors, peptide hormones (such as insulin), glucagon, glucagon-like peptide-1, erythropoietin (EPO), thyroperoxidase (TPO), follicle stimulating hormone, etc., ligands for cell surface receptors, lectins, nucleic acids (such as siRNA's, ribozymes, antisense nucleic acids, naked nucleic acids, etc.), viruses, virus-like particles, etc. An example may include ecallantide.

[0188]

[0225] In some cases, the method can include administering to a subject an effective dose of a pharmaceutical composition comprising nanoaggregates comprising a polymer and a bioactive agent, and administering to the subject one or more subsequent bioactive agents before, simultaneously with, or after administration of the pharmaceutical composition. Any of the subsequent bioactive agents disclosed herein can be suitable. In some cases, the bioactive agent can be alemtuzumab, bevacizumab, cetuximab, ibritumomab, rituximab, trastuzumab, gemtuzumab, anti-PD1 antibodies (such as Keytruda or pembrolizumab, Opdivo or nivolumab, Bavencio or avelumab, Imfinzi or durvalumab, Tecentriq or atezolizumab), anti-PD-L1 antibodies, anti-CTLA-4 (cytotoxic T-lymphocyte-associated antigen, also known as CD152) antibodies, anti-LAG3 (lymphocyte activation gene-3) antibodies, anti-TIM-3 (T cell The antibody may be selected from immunoglobulin and mucin domain-3 antibodies, anti-CD19 antibodies, anti-CD20 antibodies (such as tositumomab), one or more cytokines, interferon alpha 2a, interferon alpha, granulocyte colony stimulating factor (G-CSF), neupogene (also known as filgrastim), T cell receptors (TCR), chimeric antigen receptors or chimeric antigen T cell receptors (CAR-T), nucleic acids (such as siRNA), ribozymes, antisense nucleic acids, naked nucleic acids, etc., viruses, virus-like particles, and combinations thereof. In some cases, the bioactive agent may be selected from alemtuzumab, bevacizumab, cetuximab, ibritumomab, rituximab, trastuzumab, gemtuzumab, Keytruda (pembrolizumab), Opdivo (nivolumab), Bavencio (avelumab), Imfinzi (durvalumab, tecentriq, or atezolizumab), an anti-PD-L1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG3 antibody, an anti-TIM-3 antibody, an anti-CD19 antibody, an anti-CD20 antibody, a T cell receptor (TCR), a chimeric antigen T cell receptor (CAR-T), and combinations thereof.

[0189]

[0226] The subsequent bioactive agent can include a vaccine. The vaccine can include an antigen, a toxin, a modified or neutralized toxin, including a natural or synthetic molecule that can induce an immune response in a biological system, such as in a human or animal. The vaccine can be attached to the polymer via a covalent bond, a non-covalent linking group, or a combination thereof. Commercially available vaccines and vaccines listed by the Centers for Disease Control and Prevention (CDC) can be suitable.

[0190]

[0227] The subsequent bioactive agents described herein may include any chemical or small molecule drug, chemotherapeutic drug, inorganic-based drug, biological or macromolecule-based drug, variants or derivatives thereof, and combinations thereof. Chemotherapy drugs listed by the National Cancer Institute of the National Institutes of Health (https: / / www.cancer.gov / about-cancer / treatment / drugs), or any future updates, may also be suitable.

[0191]

[0228] The subsequent bioactive composition may be administered intravenously (IV), intramuscularly (IM), subcutaneously (SC) or intradermal (ID) injection, orally, by inhalation, nasally, ophthalmically, e.g., using eye drops or ointments, transdermally, e.g., using a patch, or a combination thereof. Combinations of any of the foregoing routes of administration may also be suitable.

[0192]

[0229] The nanoaggregates disclosed herein can be nanocomposites, nanoparticles of one or more substances or components, such as polymer alone, polymer and bioactive agent, with at least one dimension of the physical mixture being in the nanometer range as defined herein. In the present disclosure, such mixtures can contain different nanoscale phases or domains formed between the bioactive agent and the branched homopolymer molecules in either the solid or liquid state. The nanocomposite can include a combination of bulk matrix (e.g., branched homopolymer and rapamycin) and nanodimensional phases, which can exhibit different properties due to differences in structure and chemistry (e.g., domains formed by the surface groups of rapamycin and the branched polymer, and domains formed by the interior of the branched polymer). The solubility of the domains / phases can be different, so that when the nanocomposite is dissolved in an aqueous solution, one of the phases can dissolve more quickly than the other phase or all of the other phases, and the composite nanoaggregates will gradually degrade, releasing the composite components in a stepwise and controlled manner, and in some cases one or more components will reform into a new form, such as a new nanoaggregate. The terms "nanocomposite," "nanoparticle," "nanoaggregate," "nanoaggregates," "aggregate," and "aggregates" are equivalent and are used interchangeably herein.

[0193]

[0230] The size of the nanoaggregates described herein, prior to lyophilization, ranges from about 10 to about 500 nm in diameter in one example, from about 30 to about 300 nm in diameter in another example, from 50 to 150 nm in yet another example, from 50 to 120 nm in yet another example, from 50 to 100 nm in yet another example, and from 70 to 90 nm in still another example. Nanoaggregates may exhibit size-related properties that are significantly different from those observed for microparticles.

[0194]

[0231] Applicants have discovered that when polymers synthesized using monomer to initiator molar ratios ranging from 50:1 to 80:1, such as 60:1, are mixed with rapamycin in a polymer to rapamycin weight ratio of 5:1 to 7:1, the nanoparticles formed are in the size range of 50 to 150 nm prior to lyophilization, which allows the particles to pass through a 0.22 μm filter with little difficulty.

[0195]

[0232] The nanoaggregates can have a filterability through a 0.22 μm filter in the range of 50 to 100 percent. 18 Polyoxazoline polymers having a range of monomer to initiator molar ratios may be suitable, such as polymers having a monomer to initiator molar ratio ranging from 50:1 to about 80:1, such as PEOXABP60, H / C18PEOXABP60, or combinations thereof disclosed herein.

[0196]

[0233] As disclosed above and hereinafter, the nanoaggregates can be coupled to targeting moieties or groups, including, but not limited to, antibodies (or antigen-binding portions thereof), antigens, cognate carbohydrates (e.g., sialic acid), cell surface receptor ligands, moieties that bind to cell surface receptors such as prostate specific membrane antigen (PSMA), moieties that bind to cell surface saccharides, extracellular matrix ligands, cytoplasmic receptor ligands, growth factors, cytokines, incretins, hormones, lectins, lectin targets (galactose, galactose derivatives, N-acetylgalactosamine, mannose, mannose derivatives, etc.), vitamins (folic acid, biotin, etc.), avidin, streptavidin, neutravidin, etc., to form conjugates such that the targeting group is incorporated into the nanocomposite particle of interest (Figures 10A-10B).

[0197]

[0234] In some cases, the bioactive agent can be dissolved in methanol or ethanol in various amounts up to 40 mg / mL. 17) modified random branched PEOX60 (monomer to initiator molar ratio = 60:1) (herein referred to as C 18 The PEOXABP60 can be prepared as taught in PCT Publication No. WO2014 / 123791, which is incorporated herein by reference in its entirety, and dissolved in methanol or ethanol at various concentrations up to 100 mg / mL. The two solutions can then be mixed in various volumes to form nanoaggregates, resulting in a final homopolymer to bioactive agent weight ratio in the mixture ranging from 2:1 to 20:1. The nanoaggregates can be rotary evaporated to dryness to form dried nanoaggregates. The dried nanoaggregates can then be redissolved or suspended in water or saline, then sterile filtered using a 0.22 μm filter, and lyophilized for 20 to 72 hours depending on the quantity to obtain lyophilized nanoaggregates or dry powder.

[0198]

[0235] In some cases, H / C 18 The polymer mixture PEOXABP60 may be suitable. Polymer Mixture H / C 18 PEOXABP60 can include a polymer having a second end group modified with -OH, NH2, or a combination thereof.

[0199]

[0236] The size of the nanoaggregates or nanoparticles as measured by light scattering may range from about 50 to about 150 nm, in one example, about 50 to about 100 nm, in another example, about 60 to about 100 nm, in yet another example, about 70 to about 100 nm, and in yet another example, about 70 to about 95 nm, before lyophilization. In some cases, the size of the nanoaggregates or nanoparticles as measured by light scattering may range from about 50 to about 100 nm before lyophilization. The pharmaceutical composition may include nanoaggregates having a size ranging from about 50 to about 150 nm in diameter after lyophilization. The size may be measured by reconstituting the dried nanoaggregates in saline, sodium bicarbonate solution, water, a buffer solution, or a combination thereof. The size of the nanoaggregates may be measured by reconstituting the dried nanoaggregates in a buffer solution, such as, in one example, phosphate buffered saline (PBS), in another example, a combination of PBS and saline (sodium chloride), and in a further example, a combination of saline and sodium bicarbonate.

[0200]

[0237] Pharmaceutical compositions comprising the nanoaggregates disclosed herein can be formulated to be compatible with the intended route of administration and can include one or more suitable carriers for pharmaceuticals. Examples of routes of administration include parenteral, e.g., intravenous (IV), intradermal (ID), subcutaneous (SC), oral (e.g., inhalation), transdermal (topical), transmucosal and rectal administration. Solutions or suspensions used for parenteral, intradermal or subcutaneous applications can include one or more suitable carriers for pharmaceuticals, such as sterile diluents, such as water for injection, saline, oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as EDTA; buffers, such as acetates, citrates or phosphates; and agents for adjusting tonicity, such as sodium chloride or dextrose. pH can be adjusted using acids or bases, such as HCl or NaOH. Parenteral preparations can be enclosed in glass or plastic ampoules, disposable syringes or multiple dose vials as articles of manufacture. The pharmaceutical compositions can be packaged in a container, pack, or dispenser together with instructions for administration.

[0201]

[0238] The pharmaceutical compositions may be suitable for injectable use, and may include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers may include physiological saline, bacteriostatic water, Cremophor EL® (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). The compositions are sterile and fluid to the extent that syringability exists. The compositions must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The pharmaceutical compositions may include one or more solvents or dispersion media, including, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid PEG, polysorbates, etc.), and suitable mixtures thereof. Suitable carriers for some pharmaceuticals may be used to maintain the proper fluidity of the composition, for example, by using a coating agent such as lecithin, by maintaining the required particle size in the case of dispersions, by using thickening agents, and by using surfactants. In addition, pharmaceutically suitable carriers can contain various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, etc., to prevent or inhibit the growth or action of microorganisms.Isotonizing agents, such as sugars, polyalcohols, or sodium chloride, such as mannitol, sorbitol, etc., can be included in the composition as pharmaceutically suitable carriers.Absorptive delaying agents, such as aluminum monostearate or gelatin, can also be used as pharmaceutically suitable carriers.

[0202]

[0239] In further embodiments, the pharmaceutical composition can include one or more suitable carriers for pharmaceuticals, such as controlled release formulations, including implants and microencapsulated delivery systems, that protect the compound from rapid excretion from the subject's body.Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid.The preparation method of such formulations is clear to those skilled in the art.These materials can also be commercially obtained, for example, from Alza Corporation and Nova Pharmaceuticals, Inc.

[0203]

[0240] Sterile solution for injection can be prepared by mixing the active compound with one or combination of the above-listed components in the required amount in suitable solvent, and then sterilize by filtration.Generally, dispersion is prepared by mixing active compound with a sterile vehicle that contains basic dispersion medium and other components required from above-listed.For the sterile powder for preparing sterile solution for injection, the preferred method of preparation is vacuum drying and freeze-drying, which obtains the powder of active ingredient and any additional desired components from the solution that has been previously sterilized and filtered.

[0204]

[0241] Oral compositions generally contain inert diluents or edible carriers.For the purpose of oral therapeutic administration, active compound can be mixed with excipients and used in the form of tablets, lozenges or capsules.Oral compositions can also be prepared using fluid carriers to produce syrup or liquid preparations or to be used as mouthwash, in which case the compound in the fluid carrier is orally administered, and then swished and expectorated or swallowed.

[0205]

[0242] Pharmaceutically compatible binder and / or adjuvant material can be included as part of composition.Tablet, pill, capsule, lozenge etc. can contain any of the following ingredients or compounds of similar nature: binder such as microcrystalline cellulose, tragacanth gum or gelatin, excipient such as starch or lactose; disintegrant such as alginic acid, primogel or corn starch; lubricant such as magnesium stearate or sterote; glidant such as colloidal silicon dioxide; sweetener such as sucrose or saccharin; or flavoring such as peppermint, methyl salicylate or orange flavoring.

[0206]

[0243] For administration by inhalation, the compounds are delivered in the form of, eg, an aerosol spray or mist from pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0207]

[0244] Systemic administration can also be by transmucosal or transdermal means.For transmucosal or transdermal administration, a penetrant suitable for the barrier to be permeated is used in the formulation.Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts and fusidic acid derivatives.Transmucosal administration can be achieved by using nasal sprays or suppositories.For transdermal administration, active compounds are formulated into ointments, salves, gels or creams generally known in the art.Another known penetrant is dimethylsulfoxide.

[0208]

[0245] The compounds can also be prepared in the form of suppositories (eg, with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0246] For ease of administration and uniformity of dosage, it may be advantageous to formulate oral or parenteral compositions in dosage unit form.Dosage unit form, as used herein, refers to a physically separate unit suitable as a unitary dosage for the subject to be treated.Each unit contains a predetermined amount of active compound calculated to produce a desired therapeutic endpoint.Dosage, such as preferred route of administration and dosage, can be obtained based on experimental data obtained from preclinical and clinical trials, practicing methods known in the art.Dosage and delivery form can be determined and depend on the characteristics of the bioactive agent, the polymer, the specific therapeutic effect to be achieved, the characteristics and condition of the recipient, etc.In the case of repeated administration over several days or longer, treatment can be continued until the desired endpoint is obtained, depending on the condition.

[0209]

[0247] In some cases, the present disclosure provides a nanoaggregate comprising a polymer and at least one water insoluble or poorly water soluble bioactive agent,

[0248] the nanoaggregates are soluble in an aqueous solution to yield at least 1 mg / mL of bioactive agent in the aqueous solution;

[0249] The polymer is water soluble;

[0250] The bioactive agent includes natural or synthetic small molecule based drugs, inorganic based drugs, biopharmaceuticals, natural or synthetic macromolecule based drugs, derivatives thereof, or combinations thereof;

[0251] The polymer

[0252] a first polymer comprising at least one first end group modified with H or a hydrophobic moiety, and a second end group modified with a hydrophilic moiety, wherein the first end group comprises in the range of 1%-99% H and in the range of 1%-99% hydrophobic moieties comprising saturated or unsaturated aliphatic hydrocarbons having 1 to about 22 carbons, aromatic hydrocarbons, or combinations thereof, and the second end group comprises a group modified with an amine, amide, imine, imide, carboxyl, hydroxyl, ester, ether, acetate, phosphate, ketone, aldehyde, sulfonate, or combinations thereof; or

[0253] one or more hydroxyl dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated generation 4, 5, 6, 7, 8, 9, 10 dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); Pluronics® (PPO-PEO); poly(gamma-L-glutamic acid) (PGA); poly(L-phenylalanine ethyl ester) (PAE); poly(L-lysine) (PLL); methyl-PEG (mPEG); poly a second polymer comprising: (aspartic acid) (PasP); poly(L-histidine) (PLH); poly(ethyleneamine) (PEI); poly(N-vinylpyrrolidone) (PVP); poly(L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly(hydroxybutyrate) (PHB); poly(ethylene oxide) (PEO); poly(γ-benzyl-L-glutamic acid) (PBLG); phosphatidylserine (PS); poly(isohexyl-cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); or a combination thereof. The present invention relates to nano-aggregates comprising:

[0210]

[0254] In some cases, between about 1% and 100% of the second end groups may not include a primary amine. In some cases, the nanoaggregates disclosed herein may include between 1% and 100% of the second end groups may include a hydroxyl group. All percentages are based on the total number of second end groups.

[0211]

[0255] In some cases, the nanoaggregates may be less than 150 nm in size prior to lyophilization. In some cases, the nanoaggregates may be less than 120 nm in size prior to lyophilization. In some cases, the nanoaggregates may be in the range of about 50 nm to about 120 nm in size prior to lyophilization.

[0212]

[0256] In some cases, the poly(2-ethyloxazoline) may include a molar ratio of monomer to initiator ranging from 50:1 to 80:1.

[0257] In some cases, the nanoaggregates can have a weight ratio of polymer to bioactive agent ranging from about 2:1 to about 200: 1. In some cases, the nanoaggregates can have a weight ratio of polymer to bioactive agent ranging from about 5:1 to about 8:1.

[0213]

[0258] In some cases, the nanoaggregates may further comprise a targeting moiety comprising an antibody, an antigen-binding portion thereof, an antigen, a cell receptor, a cell receptor ligand, a ligand for a cell protein, a ligand for a membrane protein, a small molecule ligand, a lectin ligand, or a combination thereof.

[0214]

[0259] The nanoaggregates may be free of human serum albumin, organic solvents, detergents, or oils.The nanoaggregates may be free of human serum albumin, organic solvents, detergents, oils, or free acids.

[0260] In some cases, the bioactive agent may include any one of the bioactive agents listed above and below. In some cases, the bioactive agent may include two or more of the bioactive agents listed above and below. In some cases, the bioactive agent may include natural or synthetic small molecule-based drugs, inorganic-based drugs, biopharmaceuticals, natural or synthetic macromolecule-based drugs, derivatives thereof, or combinations thereof. In some cases, the bioactive agent may include taxanes, paclitaxel, docetaxel, cabazitaxel, larotaxel, mirtaxel, ortataxel, tesetaxel, topoisomerase 1 (Top1) inhibitors, camptothecin derivatives, irinotecan (CPT-11), SN-38, topotecan, topoisomerase 2 (Top2) inhibitors, doxorubicin, etoposide, ciprofloxacin, mTOR inhibitors, at least one STING polypeptide or a portion thereof, a nucleic acid encoding a STING polypeptide or a portion thereof, The inhibitors may include STING inhibitors, STING activators, STING agonists, STING antagonists, STING modulating molecules, IDO inhibitors, IDO1 inhibitors, or combinations thereof, and mTOR inhibitors include everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, bistusertib, ridaforolimus, one or more dual PI3K-mTOR inhibitors, one or more ATP-competitive mTORC1 / 2 inhibitors, derivatives thereof, or combinations thereof.

[0215]

[0261] In some cases, the bioactive agent can include 7-ethyl-10-hydroxycamptothecin (SN-38).

[0262] In some cases, bioactive agents suitable for the nanoaggregates disclosed herein can include compounds having at least Formula (1)-Formula (29) (FIGS. 12A-12E), a pharma- ceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

[0216]

[0263] In some cases, the bioactive agent is a compound represented by the formula (1):

[0217] [ka]

[0218] or equation (4)

[0219] [ka]

[0220] The present invention can include compounds having the formula:

[0264] The present invention relates to the use of nanoaggregates comprising a polymer and at least one water-insoluble or poorly water-soluble bioactive agent, and optionally comprising a suitable carrier for the medicament, for the manufacture of a medicament for treating a disease, comprising:

[0265] the disease is selected from one or more of an immune disorder, an infectious disease, a cancer, and a combination thereof;

[0266] the nanoaggregates are soluble in aqueous solution to yield at least 1 mg / mL of bioactive agent in the aqueous solution;

[0267] The polymer is water soluble;

[0268] The bioactive agent includes natural or synthetic small molecule based drugs, inorganic based drugs, biopharmaceuticals, natural or synthetic macromolecule based drugs, derivatives thereof, or combinations thereof;

[0269] The polymer

[0270] a first polymer comprising at least one first end group modified with H or a hydrophobic moiety, and a second end group modified with a hydrophilic moiety, wherein the first end group comprises in the range of 1%-99% H and in the range of 1%-99% hydrophobic moieties comprising saturated or unsaturated aliphatic hydrocarbons having 1 to about 22 carbons, aromatic hydrocarbons, or combinations thereof, and the second end group comprises a group modified with an amine, amide, imine, imide, carboxyl, hydroxyl, ester, ether, acetate, phosphate, ketone, aldehyde, sulfonate, or combinations thereof; or

[0271] One or more hydroxyl dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated generation 4, 5, 6, 7, 8, 9, 10 dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); Pluronics® (PPO-PEO); poly(gamma-L-glutamic acid) (PGA); poly(L-phenylalanine ethyl ester) (PAE); poly(L-lysine) (PLL); methyl-PEG ( mPEG; poly(aspartic acid) (PasP); poly(L-histidine) (PLH); poly(ethyleneamine) (PEI); poly(N-vinylpyrrolidone) (PVP); poly(L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly(hydroxybutyrate) (PHB); poly(ethylene oxide) (PEO); poly(γ-benzyl-L-glutamic acid) (PBLG); phosphatidylserine (PS); poly(isohexyl-cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); or

[0272] a second polymer, including combinations thereof; Further targeting of use.

[0221]

[0273] In some cases, the polymer can include a first polymer disclosed herein.

[0274] In some cases, the polymer can be comprised of the first polymer disclosed herein.In some cases, the pharmaceutical composition can comprise one or more of hydroxyl dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated 4th, 5th, 6th, 7th, 8th, 9th, 10th generation dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); Pluronics® (PPO-PEO); poly(gamma-L-glutamic acid) (PGA); poly(L-phenylalanine ethyl ester) (PAE); poly(L-lysine) (PLL); methyl-PEG (mPEG); The polymer may not comprise a polymer selected from poly(aspartic acid) (PasP); poly(L-histidine) (PLH); poly(ethyleneamine) (PEI); poly(N-vinylpyrrolidone) (PVP); poly(L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly(hydroxybutyrate) (PHB); poly(ethylene oxide) (PEO); poly(γ-benzyl-L-glutamic acid) (PBLG); phosphatidylserine (PS); poly(isohexyl-cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); and combinations thereof.

[0222]

[0275] In some cases, between about 1% and 100% of the second end groups may not include a primary amine. In some cases, the nanoaggregates disclosed herein may include between 1% and 100% of the second end groups may include a hydroxyl group. All percentages are based on the total number of second end groups.

[0223]

[0276] In some cases, the polymer may be one or more of hydroxyl dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated generation 4, 5, 6, 7, 8, 9, 10 dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); Pluronics® (PPO-PEO); poly(gamma-L-glutamic acid) (PGA); poly(L-phenylalanine ethyl ester) (PAE); poly(L-lysine) (PLL); methyl-PEG (mPEG); poly(propylene oxide) (PPO ... The second polymer may include poly(aspartic acid) (PasP); poly(L-histidine) (PLH); poly(ethyleneamine) (PEI); poly(N-vinylpyrrolidone) (PVP); poly(L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropylmethylcellulose (HPMC); poly(hydroxybutyrate) (PHB); poly(ethylene oxide) (PEO); poly(γ-benzyl-L-glutamic acid) (PBLG); phosphatidylserine (PS); poly(isohexyl-cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); or a combination thereof.

[0224]

[0277] In some cases, the polymer comprises a first polymer and one or more of hydroxyl dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated generation 4, 5, 6, 7, 8, 9, 10 dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); Pluronics® (PPO-PEO); poly(gamma-L-glutamic acid) (PGA); poly(L-phenylalanine ethyl ester) (PAE); poly(L-lysine) (PLL); methyl-PEG (mPEG); poly(asparagine). and a second polymer comprising one or more subsequent polymers selected from poly(aminopropylamino)phenylamine) (PAsP); poly(L-histidine) (PLH); poly(ethyleneamine) (PEI); poly(N-vinylpyrrolidone) (PVP); poly(L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropylmethylcellulose (HPMC); poly(hydroxybutyrate) (PHB); poly(ethylene oxide) (PEO); poly(γ-benzyl-L-glutamic acid) (PBLG); phosphatidylserine (PS); poly(isohexyl-cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); and combinations thereof.

[0225]

[0278] In some cases, the bioactive agent may include any one of the bioactive agents listed above and below. In some cases, the bioactive agent may include two or more of the bioactive agents listed above and below. In some cases, the bioactive agent may include natural or synthetic small molecule-based drugs, inorganic-based drugs, biopharmaceuticals, natural or synthetic macromolecule-based drugs, derivatives thereof, or combinations thereof. In some cases, the bioactive agent may include taxanes, paclitaxel, docetaxel, cabazitaxel, larotaxel, mirtaxel, ortataxel, tesetaxel, topoisomerase 1 (Top1) inhibitors, camptothecin derivatives, irinotecan (CPT-11), SN-38, topotecan, topoisomerase 2 (Top2) inhibitors, doxorubicin, etoposide, ciprofloxacin, mTOR inhibitors, at least one STING polypeptide or a portion thereof, a nucleic acid encoding a STING polypeptide or a portion thereof, The bioactive agent may include a STING inhibitor, a STING activator, a STING agonist, a STING antagonist, a STING modulating molecule, an IDO inhibitor, an IDO1 inhibitor, or a combination thereof, and the mTOR inhibitor includes everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, bistusertib, ridaforolimus, one or more dual PI3K-mTOR inhibitors, one or more ATP-competitive mTORC1 / 2 inhibitors, derivatives thereof, or combinations thereof. In some cases, the bioactive agent may include 7-ethyl-10-hydroxycamptothecin (SN-38).

[0226]

[0279] The bioactive agent can include a compound having at least Formula (1)-Formula (29) (FIGS. 12A-12E), a pharma- ceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

[0227]

[0280] In some cases, the bioactive agent is a compound represented by the formula (1):

[0228] [ka]

[0229] or equation (4)

[0230] [ka]

[0231] The present invention can include compounds having the formula:

[0281] In some cases, the disease can include one or more immune disorders, infectious diseases, cancer, and combinations thereof.

[0232]

[0282] In some cases, the polymer can include a polyoxazoline (POX) that includes a linear portion, a branched portion, or a combination thereof, and the polyoxazoline (POX) includes a poly(2-oxazoline), a poly(2-methyloxazoline), a poly(2-ethyloxazoline), a poly(2-propyloxazoline), a poly(isopropyloxazoline), or a combination thereof.

[0233]

[0283] Applicants have unexpectedly discovered that improved nanoaggregate formation can be realized when a polymer includes a particular amount of first end groups that include H. Applicants have further discovered that manufacturing process improvements such as shorter production cycle times, less mixing energy, and other benefits can be realized when a polymer includes a particular amount of first end groups that include H, as disclosed herein.

[0234]

[0284] The present disclosure will now be illustrated in the following non-limiting examples. EXAMPLES

[0235]

[0285] The present invention is further defined in the following examples. It should be understood that these examples show preferred embodiments of the present invention, but are given by way of illustration only. From the above discussion and these examples, those skilled in the art can ascertain the essential features of the present invention, and can make various changes and modifications to the present invention, and adapt the present invention to various uses and conditions, without departing from the spirit and scope thereof. Materials and Measurements polymer

[0286] Hydrocarbon (CH3(CH2)) with a monomer to initiator molar ratio of 60:1 17 )-modified random branched PEOX polymer (referred to herein as "C 18 PEOXABP60) is an initiator (CH3(CH2) 17 )-Br as previously described in PCT Publication No. WO2014 / 123791, which is incorporated herein by reference.

[0236]

[0287] Another hydrocarbon-modified randomly branched PEOX polymer with a monomer to initiator molar ratio of 60:1 was prepared as above using initiator (CH3(CH2)5)-Br.

[0237]

[0288] Another hydrocarbon-modified randomly branched PEOX polymer with a monomer to initiator molar ratio of 60:1 was synthesized using the initiator (CH3(CH2) 11 )-Br was used as above.

[0238]

[0289] Another hydrocarbon-modified randomly branched PEOX polymer with a monomer to initiator molar ratio of 60:1 was prepared as described above using methyl tosylate as the initiator.

[0290] A hydrogen-modified randomly branched PEOX polymer having a monomer to initiator molar ratio of 60:1 (herein "H-PEOXABP60") was prepared as described above using p-toluenesulfonic acid as the initiator.

[0239]

[0291] Another hydrogen-modified randomly branched PEOX polymer with a monomer to initiator molar ratio of 60:1 was prepared as described above using trifluoroacetic acid as the initiator.

[0292] The hydrogen-modified randomly branched PEOX polymers having a monomer to initiator molar ratio of 60:1 are collectively referred to as "H-PEOXABP60."

[0240]

[0293] Table 1 shows the H(H-PEOXABP60) and C 18 Hydrocarbons (C 18 Some non-limiting examples of polymers with various first termini modified with PEOXABP60 are shown. 18 The presence of the hydrocarbon-modified first end group was determined by HPLC. H vs. C 18 The molar ratios of hydrocarbons and the percent H are given.

[0241] [Table 1]

[0242]

[0294] To generate nanoaggregates, a molar ratio of initiator = 60:1 was used with a hydrocarbon (CH3(CH2) 17 )-modified first termini and H-modified first termini (referred to herein as "H / C 18 PEOXABP60) was used.

[0243]

[0295] H / C 18 H / C with a value of about 0.3 18 A polymer, PEOXABP60, was terminated with a hydroxyl group as the second end group in water (referred to herein as "Polymer A1"). The aqueous solution of the polymer had a pH value in the range of 3.0-6.9. If necessary, the aqueous solution of the polymer can be adjusted to have a pH value in the range of 5.6-7.5 or 3.0-10 using HCl or NaOH.

[0244]

[0296] H / C 18 H / C has a value of about 0.4 18A polymer, PEOXABP60, was terminated with a hydroxyl group as the second end group in water (referred to herein as "Polymer A2"). An aqueous solution of the polymer can be adjusted to have a pH value in the range of 3.0-6.9. Another aqueous solution of the polymer can be adjusted to have a pH value in the range of 7.0-10 or 5.6-7.5 using HCl or NaOH.

[0245]

[0297] H / C 18 H / C is about 0.7 18 A polymer, PEOXABP60, was terminated with a hydroxyl group as the second end group in water (referred to herein as "Polymer A3"). The aqueous solutions of the polymer had pH values ​​ranging from 3.0 to 6.9. The aqueous solutions of the polymer could be adjusted to have pH values ​​ranging from 7.0 to 10 or 5.6 to 7.5 using HCl or NaOH, as necessary.

[0246]

[0298] H / C with a hydroxyl group as the second end group 18 All PEOXABP60 polymers are H / C 18 It can be referred to as PEOXABP60-OH.

[0299] H / C 18 H / C is about 0.7 18 The PEOXABP60 polymer was terminated with EDA having a molar ratio of polyoxazoline reactive chain end to EDA of about 1:10 to produce a polymer having a second end group comprising a primary amine modified group (referred to herein as "Polymer B1"). An aqueous solution of the polymer had a pH value in the range of 7.0 to 10. Another aqueous solution of the polymer can be adjusted to have a pH value in the range of 8.9 to 9.7 using HCl or NaOH. Another aqueous solution of the polymer can be adjusted to have a pH value in the range of 3.0 to 6.9.

[0247]

[0300] H / C 18 H / C has a value of about 0.4 18The PEOXABP60 polymer was terminated with EDA having a molar ratio of polyoxazoline reactive chain end to EDA of about 1:10 to produce a polymer having a second end group containing a primary amine modified group (referred to herein as "Polymer B2"). Aqueous solutions of the polymer can be adjusted to have a pH value in the range of 7.0 to 10. Separate aqueous solutions of the polymer can be adjusted to have a pH value in the range of 3.0 to 10 or 5.6 to 7.5 using HCl or NaOH.

[0248]

[0301] H / C 18 H / C with a value of about 0.3 18 The PEOXABP60 polymer was terminated with EDA having a molar ratio of polyoxazoline reactive chain end to EDA of about 1:10 to produce a polymer having a second end group containing a primary amine modified group (referred to herein as "Polymer B3"). Aqueous solutions of the polymer can be adjusted to have a pH value in the range of 7.0 to 10. Separate aqueous solutions of the polymer can be adjusted to have a pH value in the range of 3.0 to 10 or 5.6 to 7.5 using HCl or NaOH.

[0249]

[0302] H / C with -NH2 group as the second terminal group 18 All PEOXABP60 polymers are H / C 18 It can be referred to as PEOXABP60-NH2. Nanoparticle measurements

[0303] The sizes of the various polymers, polymer-only nanoaggregates, and drug-derived polymer-drug nanoaggregates were measured by dynamic light scattering (DLS) method using a Malvern Zetasizer Nano-ZS Zen3600 particle size analyzer (Malvern Panalytical Inc., Westborough, MA01581, USA).

[0250] Examples 1-2 H / C 18 PEOXABP60-A (Polymer A1) Polymer: Nanoparticles with Rapamycin

[0304] H / C 18 PEOXABP60-A (polymer A1) (750 mg) and rapamycin (150 mg) were dissolved in 5 mL of methanol for approximately 20 min. Then, the methanol was removed using a rotary evaporator to generate dry nanoaggregates. The dry powder of nanoaggregates was reconstituted in water to generate nanoaggregate aqueous solutions containing 3.5 mg / mL or 5 mg / mL of rapamycin (weight ratio of polymer:rapamycin = 5:1). An example of light scattering (LS) measurement data is shown in Figure 11A. The nanoaggregates ranged in size from 100 to approximately 106 nm.

[0251]

[0305] H / C 18 PEOXABP60-A (polymer A1) (750 mg) and rapamycin (100 mg) were dissolved in 5 mL of methanol and processed according to the process described above to produce nanoaggregate aqueous solutions containing 3.5 mg / mL or 5 mg / mL of rapamycin with a weight ratio of polymer:rapamycin = 7.5:1. An example of LS measurement data is shown in Figure 11B. The nanoaggregates ranged in size from 100 to approximately 102 nm.

[0252]

[0306] The aqueous nanoaggregate solutions were each passed through a 0.8 μm filter followed by a 0.22 μm filter. Aliquots of the filtrate, i.e., sterile nanoaggregates, were lyophilized for 24 hours depending on the amount used to produce lyophilized nanoaggregates. The vials were stoppered and the ready-to-use white powders were stored at room temperature.

[0253] Example 3 H / C 18 PEOXABP60-NH2 (Polymer B1) Polymer: Nanoparticles with Rapamycin

[0307] H / C 18PEOXABP60-NH2 (polymer B1) (750 mg) and rapamycin (150 mg) were dissolved in 5 mL of methanol and processed according to the process described above to produce a nanoaggregate aqueous solution containing 5 mg / mL of rapamycin with a weight ratio of polymer:rapamycin = 5:1. An example of LS measurement data is shown in Figure 11C. The nanoaggregates in the final product, i.e. after lyophilization, ranged in size from 91 to approximately 112 nm.

[0254]

[0308] The aqueous nanoaggregate solution was passed through a 0.8 μm filter followed by a 0.22 μm filter. The filtrate, i.e., sterile nanoaggregates, was aliquoted and lyophilized for 24 hours depending on the amount used to produce lyophilized nanoaggregates. The vials were stoppered and the ready-to-use white powder was stored at room temperature.

[0255] Example 4 Rapamycin stability assay

[0309] The stability of the nanoaggregates prepared in Examples 1-3 with respect to degradation products and impurities of rapamycin was measured by HPLC at room temperature for periods ranging from 0 to 147 hours.

[0256]

[0310] The nanoaggregates prepared in Examples 1 to 3 had good stability over the measurement period. Example 5 H / C 18 PEOXABP60-A (Polymer A1) Polymer: Nanoparticles having the formula (1)

[0311] Polymer A1 (100 mg) having an H / C18 of about 0.3 prepared above is mixed with a compound of formula (1) (2 mg) in 1 mL of water and treated according to the method described above to produce a nanoaggregate aqueous solution containing 2 mg / mL of formula (1) with a weight ratio of polymer:formula (1) = 50:1.

[0257] Example 6 H / C 18 PEOXABP60-A (Polymer A3) Polymer: Nanoparticles having the formula (1)

[0312] Polymer A3 (500 mg) having an H / C18 of about 0.7 prepared above is mixed with a compound of formula (1) (10 mg) in 5 mL of water and treated according to the method described above to produce a nanoaggregate aqueous solution containing 2 mg / mL of formula (1) with a weight ratio of polymer:formula (1) = 50:1.

[0258] Example 7 H / C ratio of 3:1 to 10:1 18 PEOXABP60-NH2 (Polymer B3) Nanoparticles with a polymer:paclitaxel ratio

[0313] In a general procedure, paclitaxel was dissolved in methanol to a concentration of up to 40 mg / mL. Polymer B3 was dissolved separately in methanol to a concentration of up to 100 mg / mL. The two solutions were then mixed in various volumes, resulting in a final weight ratio of polymer to paclitaxel in the mixture ranging from 3:1 to 10:1. The mixture was then lyophilized.

[0259]

[0314] The diameter of the aggregate size measured by light scattering was in the range of about 70 nm to 90 nm before freeze-drying and 120 to 140 nm after freeze-drying.

[0315] Alternatively, both paclitaxel and polymer B3 can be dissolved in common solvents such as acetone, methanol or ethanol, then added dropwise to water with stirring or sonication, and then sterile filtered through a 0.22 μm filter. The final product can then be produced by lyophilization, and the aggregate size can be measured by light scattering.

[0260]

[0316] Other taxane-derived aggregates or nanoparticles can be similarly prepared using a variety of hydrophobically surface-modified branched polymers such as C4, C6, C12 or C22 hydrocarbon-modified randomly branched PEOX, PEI and PPI polymers: C4, C6, C12, C18 and C22 hydrocarbon-modified PAMAM, PEI and PPI dendrimers and dendrigrafts; and C4, C6, C12, C18 and C22 hydrocarbon-modified branched PLL / polymers.

[0261] Example 8 H / C 18 PEOXABP60-NH2 (Polymer B3) Nanoparticles with a polymer:paclitaxel ratio of 7:1

[0317] H / C 18 PEOXABP60-NH2 (polymer B3) (700 mg) was dissolved in 9.33 mL of methanol to give a 75 mg / mL solution. A 15 mg / mL solution of paclitaxel was also prepared by dissolving 100 mg in 6.67 mL of methanol. The above two solutions were mixed for 20 minutes resulting in a solution containing 6.25 mg of paclitaxel and 43.75 mg of polymer per mL, giving a solution with a polymer:drug ratio of 7:1. The mixture was placed on a rotary evaporator to remove the methanol and dry. The resulting solid was redissolved in 33.3 mL of water with stirring to give a final paclitaxel concentration of 3 mg / mL. The solution preparation was passed through a 0.8 μm filter and then a 0.22 μm filter. The filtrate was lyophilized. The vial was stoppered and the ready-to-use white powder was stored at room temperature.

[0262] Examples 9 to 11 H / C 18 PEOXABP60-A (Polymer A2) Polymer: Nanoparticles with (SN-38 / Irinotecan)

[0318] H / C 18 PEOXABP60-A (polymer A2) (981 mg) and SN-38 (149 mg) and irinotecan (97 mg) were dissolved in 70 mL of solvent (THF:methanol, 6:1, v / v) under stirring at 50° C. for about 20 min. The organic solvent was then removed using a rotary evaporator to produce dry nanoaggregates. The dry nanoaggregate powder was reconstituted in 5% glucose to produce a nanoaggregate aqueous solution containing 2 mg / mL of total API (weight ratio of polymer:(SN-38 / irinotecan)=4:1 with a molar ratio of SN-38 / irinotecan=2.5 / 1). An example of LS measurement data is shown in FIG. 14A (formulation 1). The nanoaggregates were about 110 nm in size.

[0263]

[0319] H / C18 PEOXABP60-A (polymer A2) (60 mg) and SN-38 (11.4 mg) and irinotecan (12.2 mg) were dissolved in 7 mL of solvent (THF:methanol, 6:1, v / v) under stirring at 50° C. for about 20 min. The organic solvent was then removed using a rotary evaporator to produce dry nanoaggregates. The dry nanoaggregate powder was reconstituted in 5% glucose to produce a nanoaggregate aqueous solution containing 2 mg / mL of total API (weight ratio of polymer:(SN-38 / irinotecan)=2.6:1 with a molar ratio of SN-38 / irinotecan=1.5 / 1). An example of LS measurement data is shown in FIG. 14B (formulation 2). The nanoaggregates were about 110 nm in size.

[0264]

[0320] H / C 18 PEOXABP60-A (polymer A2) (60 mg) and SN-38 (11.4 mg) and irinotecan (3.6 mg) were dissolved in 7 mL of solvent (THF:methanol, 6:1, v / v) under stirring at 50° C. for about 20 min. The organic solvent was then removed using a rotary evaporator to produce dry nanoaggregates. The dry nanoaggregate powder was reconstituted in 5% glucose to produce a nanoaggregate aqueous solution containing 2 mg / mL of total API (weight ratio of polymer:(SN-38 / irinotecan)=4:1 with a molar ratio of SN-38 / irinotecan=5 / 1). An example of LS measurement data is shown in FIG. 14C (formulation 3). The nanoaggregates were about 120 nm in size.

[0265]

[0321] H / C 18PEOXABP60-A (Polymer A1) (5.25 g) and SN-38 (1.16 g) and irinotecan (1.84 g) were dissolved in 600 mL of solvent (THF:methanol, 6:1, v / v) under stirring at 50° C. for about 30 min. The organic solvent was then removed using a rotary evaporator to produce dry nanoaggregates. The dry nanoaggregate powder was reconstituted in 5% glucose to produce a nanoaggregate aqueous solution containing 2 mg / mL of total API (weight ratio of polymer:(SN-38 / irinotecan)=1.75:1 with a molar ratio of SN-38 / irinotecan=1 / 1). An example of LS measurement data is shown in FIG. 14D (Formulation 4). The nanoaggregates were about 94 nm in size. H / C 18 PEOXABP60-B (Polymer B1) Polymer: Nanoparticles with (SN-38 / Irinotecan)

[0322] H / C 18 PEOXABP60-B (polymer B1) (5.25 g) and SN-38 (1.83 g) and irinotecan (1.17 g) were dissolved in 600 mL of solvent (THF:methanol, 6:1, v / v) under stirring at 50° C. for about 30 min. The organic solvent was then removed using a rotary evaporator to produce dry nanoaggregates. The dry nanoaggregate powder was reconstituted in 5% glucose to produce a nanoaggregate aqueous solution containing 2 mg / mL of total API (weight ratio of polymer:(SN-38 / irinotecan)=1.75:1 with a molar ratio of SN-38 / irinotecan=2.5 / 1). An example of LS measurement data is shown in FIG. 14E (formulation 3). The nanoaggregates were about 108 nm in size.

[0266]

[0323] The aqueous nanoaggregate solution was passed through a 0.8 μm filter followed by a 0.2 μm filter. An aliquot of the filtrate, i.e., sterile nanoaggregates, was lyophilized for 24-100 hours depending on the amount used to produce lyophilized nanoaggregates. The vials were stoppered and the ready-to-use white powder was stored at room temperature.

[0267] Example 12 Maximum tolerated dose (MTD) study in mice

[0324] Severe combined immunodeficiency (SCID) mice were injected with various amounts of irinotecan / CPT-11, nano SN-38 produced in Examples 10-12 until the MTD was reached.

[0268] Example 13 Cell-based cytotoxicity assays

[0325] The cytotoxicity of SN-38 was tested against the HCT-116 cell line using a standard in vitro cytotoxicity assay. Cell viability was assessed using the Promega Cell Titer96 Aqueous One kit. Overall, nanoformulated SN-38 was approximately 250-fold more cytotoxic than irinotecan, with an EC50 median effective concentration (EC60) of approximately 0.13 μM against HCT-116 cells. 50 ), whereas irinotecan showed an EC of approximately 32.6 μM. 50 (Figure 15). Nano SN-38: Polymer:SN-38=4:1 as produced in the above example; SN-38 / Irinotecan mixture: Physical mixture of SN-38 and Irinotecan in 4:1 molar ratio dissolved in DMSO; SN-38 control: SN-38 dissolved in DMSO (dimethyl sulfoxide); and Irinotecan control: Irinotecan dissolved in water were tested on cells. Representative measurement data are shown in Figure 15 and Table 2.

[0269] [Table 2]

[0270] Example 14 H / C 18 PEOXABP60-A (Polymer A1) Polymer: Nanoparticles having the formula (1)

[0326] Polymer A1 (200 mg) with H / C18 of about 0.4 prepared as above was dissolved in water to make a 100 mg / g solution. To this polymer solution, compound of formula (1) (8 mg) was added and the mixture was treated according to the method described above to produce an aqueous solution of nanoaggregates containing 2 mg / mL of formula (1) with a weight ratio of polymer:formula (1) = 25:1. The solution was filtered through a 0.8 μm filter, then a 0.22 μm filter, and then lyophilized for 20-100 hours to obtain a lyophilized powder (power). The vial was stoppered and the ready-to-use white powder was stored at room temperature.

[0271]

[0327] Polymer A1 (400 mg) with H / C18 of about 0.4 prepared as above was dissolved in water to make a 100 mg / g solution. To this polymer solution, compound of formula (1) (8 mg) was added and the mixture was treated according to the method described above to produce an aqueous solution of nanoaggregates containing 2 mg / mL of formula (1) with a weight ratio of polymer:formula (1) = 50:1. The solution was filtered through a 0.8 μm filter and then a 0.22 μm filter, and then lyophilized for 20-100 hours to obtain a lyophilized powder. The vial was stoppered and the ready-to-use white powder was stored at room temperature. H / C 18 PEOXABP60-A (Polymer A2) Polymer: Nanoparticles having the formula (1)

[0328] Polymer A2 (400 mg) with H / C18 of about 0.4 prepared as above was dissolved in water to make a 100 mg / g solution. To this polymer solution, compound of formula (1) (8 mg) was added and the mixture was treated according to the method described above to produce an aqueous solution of nanoaggregates containing 2 mg / mL of formula (1) with a weight ratio of polymer:formula (1) = 50:1. The solution was filtered through a 0.8 μm filter, then a 0.22 μm filter, and then lyophilized for 20-100 hours to obtain a lyophilized powder. The vial was stoppered and the ready-to-use white powder was stored at room temperature.

[0272]

[0329] Polymer A3 (400 mg) with H / C18 of about 0.7 prepared as above was dissolved in water to make a 100 mg / g solution. To this polymer solution, compound of formula (1) (8 mg) was added and the mixture was treated according to the method described above to produce an aqueous solution of nanoaggregates containing 2 mg / mL of formula (1) with a weight ratio of polymer:formula (1) = 50:1. The solution was filtered through a 0.8 μm filter and then a 0.22 μm filter, and then lyophilized for 20-100 hours to obtain a lyophilized powder. The vial was stoppered and the ready-to-use white powder was stored at room temperature.

[0273] Example 15

[0330] Polymer B3 (400 mg) with H / C18 of about 0.3 prepared as above was dissolved in water to make a 100 mg / g solution. To this polymer solution, compound of formula (1) (8 mg) was added and the mixture was treated according to the method described above to produce an aqueous solution of nanoaggregates containing 2 mg / mL of formula (1) with a weight ratio of polymer:formula (1) = 50:1. The solution was filtered through a 0.8 μm filter and then a 0.22 μm filter, and then lyophilized for 20-100 hours to obtain a lyophilized powder. The vial was stoppered and the ready-to-use white powder was stored at room temperature.

[0274]

[0331] Polymer B3 (200 mg) with H / C18 of about 0.3 prepared as above was dissolved in water to make a 100 mg / g solution. To this polymer solution, compound of formula (1) (8 mg) was added and the mixture was treated according to the method described above to produce an aqueous solution of nanoaggregates containing 2 mg / mL of formula (1) with a weight ratio of polymer:formula (1) = 25:1. The solution was filtered through a 0.8 μm filter and then a 0.22 μm filter, and then lyophilized for 20-100 hours to obtain a lyophilized powder. The vial was stoppered and the ready-to-use white powder was stored at room temperature.

Claims

1. A nanoaggregate comprising a polymer and at least one bioactive agent that is water-insoluble or poorly water-soluble, The nanoaggregates are soluble in the aqueous solution such that at least 1 mg / mL of the bioactive agent is produced in the aqueous solution. The aforementioned polymer is water-soluble, The aforementioned polymer A first polymer comprising at least one first terminal group modified with H or a hydrophobic moiety, and a second terminal group modified with a hydrophilic moiety, wherein the first terminal group comprises the 1% to 99% hydrophobic moiety comprising 1% to 99% H and saturated or unsaturated aliphatic hydrocarbons, aromatic hydrocarbons, or combinations thereof having 1 to about 22 carbon atoms, and the second terminal group comprises a group modified with amines, amides, imines, imides, carboxyls, hydroxyls, esters, ethers, acetates, phosphates, ketones, aldehydes, sulfonates, or combinations thereof, or One or more hydroxyl dendrimers (HD); ethylenediamine-coapoly(amideamine) (PAMAM) hydroxyl-terminated 4th, 5th, 6th, 7th, 8th, 9th, and 10th generation dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic acid-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); Pluronics® (PPO-PEO); poly(γ-L-glutamic acid) (PGA); poly(L-phenylalanine ethyl ester) (PAE); poly(L-lysine) (PLL); methyl-PEG (mPEG) A second polymer comprising: poly(aspartic acid) (PasP); poly(L-histidine) (PLH); poly(ethyleneamine) (PEI); poly(N-vinylpyrrolidone) (PVP); poly(L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly(hydroxybutyrate) (PHB); poly(ethylene oxide) (PEO); poly(γ-benzyl-L-glutamic acid) (PBLG); phosphatidylserine (PS); poly(isohexyl cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); or those combinations Nanoaggregates containing these materials.

2. The nanoaggregate according to claim 1, wherein the polymer comprises polyoxazoline (POX), linear POX, branched POX, poly(2-methyloxazoline), poly(2-ethyloxazoline), poly(2-propyloxazoline), poly(isopropyloxazoline), or a combination thereof.

3. The polymer comprises polyoxazoline, The nanoaggregate according to claim 1, wherein the polyoxazoline comprises a monomer-to-initiator molar ratio in the range of 50:1 to 80:

1.

4. The second terminal group contains no primary amine in 1% to 100% of the above, The nanoaggregate according to claim 1, wherein hydroxyl groups are contained in 1% to 100% of the second terminal groups.

5. The nanoaggregate according to claim 1, wherein the nanoaggregate comprises a weight ratio of the polymer to the bioactive agent in the range of about 2:1 to about 200:

1.

6. The nanoaggregate according to claim 1, further comprising a target-directing moiety containing an antibody, an antigen-binding moiety thereof, an antigen, a cell receptor, a cell receptor ligand, a ligand for a cell protein, a ligand for a membrane protein, a small molecule ligand, a lectin ligand, or a combination thereof.

7. The nanoaggregates according to claim 1, wherein the nanoaggregates do not contain human serum albumin, organic solvents, detergents, or oils, and the bioactive agent comprises natural or synthetic low-molecular-weight drugs, inorganic-based drugs, biopharmaceuticals, natural or synthetic macromolecular-weight drugs, derivatives thereof, or combinations thereof.

8. The aforementioned biological activators include taxanes, paclitaxel, docetaxel, cabazitaxel, larotaxel, mirataxel, ortataxel, tesetaxel, topoisomerase 1 (Top1) inhibitors, camptothecin derivatives, irinotecan (CPT-11), SN-38, topotecan, topoisomerase 2 (Top2) inhibitors, doxorubicin, etoposide, ciprofloxaxine, mTOR inhibitors, at least one interferon gene stimulating factor (STING) polypeptide or a part thereof, nucleic acids encoding the STING polypeptide or a part thereof, STING inhibitors, The nanoaggregate according to claim 1, comprising a STING activator, a STING agonist, a STING antagonist, a STING modulate molecule, an indoleamine-2,3-dioxygenase (IDO) inhibitor, an IDO1 inhibitor, or a combination thereof, wherein the mTOR inhibitor comprises everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, bistucertib, ridafololimus, one or more dual PI3K-mTOR inhibitors, one or more ATP-competitive mTORC1 / 2 inhibitors, derivatives thereof, or a combination thereof.

9. The nanoaggregate according to claim 1, wherein the bioactive agent comprises at least one compound of formula (1) to formula (29). 【Chemistry 1-1】 [Chemistry 1-2] [Chemistry 1-3] [Chemistry 1-4] [Chemistry 1-5]

10. The aforementioned biological agent is given by formula (1) 【Chemistry 2】 or equation (4) 【Transformation 3】 The nanoaggregate according to claim 1, comprising a compound having the following properties.

11. A pharmaceutical composition comprising the nanoaggregates described in Claim 1, and which may also comprise a suitable carrier for pharmaceutical use, A pharmaceutical composition that is soluble in an aqueous solution such that at least 1 mg / mL of the bioactive agent is produced in the aqueous solution, and which does not contain human serum albumin, organic solvents, detergents, or oils.

12. The pharmaceutical composition according to claim 11, wherein the bioactive agent comprises a natural or synthetic low-molecular-weight drug, an inorganic-based drug, a biopharmaceutical, a natural or synthetic macro-molecular-weight drug, derivatives thereof, or a combination thereof.

13. The aforementioned biological activators include taxanes, paclitaxel, docetaxel, cabazitaxel, larotaxel, mirataxel, ortataxel, tesetaxel, topoisomerase 1 (Top1) inhibitors, camptothecin derivatives, irinotecan (CPT-11), SN-38, topotecan, topoisomerase 2 (Top2) inhibitors, doxorubicin, etoposide, ciprofloxaxine, mTOR inhibitors, at least one STING polypeptide or a part thereof, nucleic acids encoding the STING polypeptide or a part thereof, and STING inhibitors. The pharmaceutical composition according to claim 11, comprising a drug, a STING activator, a STING agonist, a STING antagonist, a STING modulate molecule, an IDO inhibitor, an IDO1 inhibitor, or a combination thereof, wherein the mTOR inhibitor comprises everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, bistucertib, ridafololimus, one or more dual PI3K-mTOR inhibitors, one or more ATP-competitive mTORC1 / 2 inhibitors, derivatives thereof, or a combination thereof.

14. Further comprising at least one immunotherapy agent that stimulates an immune response, The pharmaceutical composition according to claim 11, wherein the immunosuppressant comprises an inactive microorganism selected from bacteria, viruses, fungi, protozoa, insects, parasites, prions, some or a combination thereof; a toxin; a nucleic acid encoding the toxin; a protein; a nucleic acid encoding the protein; an oligonucleotide; DNA; RNA; mRNA; siRNA; sgRNA; fragments thereof; or a combination thereof.

15. A pharmaceutical composition comprising the nanoaggregates described in claim 1 for use in treating one or more diseases selected from immunodeficiency, infection, cancer, and combinations thereof, A pharmaceutical composition wherein the nanoaggregates generate at least 1 mg / mL of the bioactive agent in an aqueous solution.

16. The pharmaceutical composition according to claim 15, wherein the infectious disease includes varicella (chickenpox), coronavirus, dengue fever, diphtheria, Ebola, influenza, hepatitis, Hib disease, HIV / AIDS, HPV (human papillomavirus) disorder, Japanese encephalitis, measles, meningococcal disease, mpox, mumps, norovirus disorder, pneumococcal disease, polio, rabies, respiratory rash virus (RSV) disorder, rotavirus disorder, rubella (German measles), herpes zoster, tetanus, pertussis, Zika fever, and combinations thereof.

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