Polymer nano-aggregate pharmaceutical composition and application thereof

Abstract

The present disclosure relates to a pharmaceutical composition for treating or preventing a disease. The pharmaceutical composition may include a polymer-drug nanoaggregate having a polymer and at least one water insoluble or poorly water soluble bioactive agent. The polymer is water soluble and includes at least one first end group modified with H or a hydrophobic moiety and one second end group modified with a hydrophilic moiety, and may be a modified symmetrically or asymmetrically branched polymer. The present disclosure also relates to methods for treating or preventing diseases including one or more immune diseases, infectious diseases, and cancer using the pharmaceutical compositions disclosed herein. The pharmaceutical composition may be a vaccine or an adjuvant for a vaccine.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition which can be used to treat a disease in a patient in need thereof. The composition may include nanoaggregates formed from a water-soluble polymer and a water-insoluble or poorly water-soluble bioactive agent. Background Art

[0002] Synthetic polymers have been shown to have important applications as effective delivery vehicles or other types of excipients in pharmaceutical formulations.

[0003] Symmetrically branched polymers (SBPs), such as dendrimers, including starburst dendrimers (or dense star polymers) and combburst dendrigrafts (or supercomb branched polymers), are some examples. Those polymers generally have: (a) a well-defined core molecule, (b) at least two concentric dendritic layers (generations) with symmetrical (equal length) branches and branch attachment points, and (c) external surface groups, such as polyamidoamine (PAMAM)-based branched polymers and dendrimers described in U.S. Pat. Nos. 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 tectodendrimers, and other dendrimers, such as those described in "Dendritic Molecules," edited by Newkome et al., VCH Weinheim, 1996, "Dendrimers and Other Dendritic Polymers," edited by Frechet & Toroalia, John Wiley & Sons, Ltd., 2001; and U.S. Pat. No. 7,754,500.

[0004] Combburst dendrimers are constructed by a stepwise synthesis process with a core molecule and concentric layers with symmetrical branches. In contrast to dendrimers, combburst dendrimers or polymers are generated with monodisperse linear polymer building blocks (U.S. Pat. Nos. 5,773,527, 5,631,329, and 5,919,442). In addition, the branching pattern is different from that of dendrimers. For example, combburst dendrimers form branching junctions along the polymer backbone (chain branches), while starburst dendrimers are usually branched at the ends (terminal branches). Due to the living polymerization technology used, the molecular weight distribution (M) of these polymers (core and branches) is w / M n ) is usually very narrow. Therefore, the comb-on-graft dendritic grafts produced by the graft-on-graft process are clearly defined as M w / M n Closer to 1 than usual.

[0005] SBPs (e.g., dendrimers) are primarily produced by divergent or convergent synthetic methods through repeated protection and deprotection procedures. Since dendrimers utilize small molecules as building blocks for the core and branches, the molecular weight distribution of dendrimers is usually limited. In the case of lower generations, dendrimers of a single molecular weight are usually obtained. Dendrimers generally use small molecule monomers as building blocks, while dendrimer grafts use linear polymers as building blocks.

[0006] In addition to dendrimers and dendritic grafts, other SBPs may include symmetrical star-shaped or comb-shaped polymers, such as symmetrical star-shaped and comb-shaped polyethylene oxide (PEO), polyethylene glycol (PEG), polyethyleneimine (PEI), polypropyleneimine (PPI), polyoxazoline (POX), polymethyloxazoline (PMOX), polyethyloxazoline (PEOX), polypropyloxazoline (PPOX), polystyrene, polymethyl methacrylate (PMMA) or polydimethylsiloxane.

[0007] Asymmetric branched polymers (ABPs) can be of two different types: regular ABPs and random ABPs. Asymmetric branched dendrimers or regular ABPs (reg-ABPs) typically have a core, controlled and well-defined asymmetric (unequal length) branches and asymmetric branch junctions, as described in U.S. Patent Nos. 4,289,872; 4,360,646 and 4,410,688. On the other hand, random ABPs (ran-ABPs) have: a) no core, b) external and internal functional groups, c) random / variable branch lengths and patterns (i.e., terminal branches and chain branches), and d) unevenly distributed interior void space.

[0008] The synthesis and mechanism of random ABPs (such as those prepared from PEI) are reported in 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). Random ABPs, such as those prepared from POX, poly(2-oxazoline), poly(2-methyloxazoline) (PMOX), and poly(2-ethyloxazoline) (PEOX), are reported by Litt (J. Macromol. Sci. Chem. A9(5), 703-727 (1975)) and Warakomski (J. Polym. Sci. Polym. Chem. 28, 3551 (1990). The synthesis of random ABPs generally involves either a one-pot divergent process or a one-pot convergent process.

[0009] A polymer may also be a homopolymer or a copolymer. A copolymer is a polymer or polymer backbone formed by polymerization of different monomers or repeating units of different monomers. A homopolymer may refer to a polymer or polymer backbone composed of the same repeating units, i.e., a homopolymer is formed from the same monomers. A monomer may be a simple compound or a complex or collection of compounds, where the collection or complex is a repeating unit in a homopolymer.

[0010] Although branched polymers (including SBPs and ABPs) have been used for drug delivery, these attempts have mainly focused on chemically linking drugs to polymers, or physically encapsulating these drugs inside by unimolecular encapsulation (e.g., those described in U.S. Pat. Nos. 5,773,527; 5,631,329; 5,919,442; and 6,716,450). For example, dendrimers and dendritic grafts are considered to physically capture bioactive molecules using unimolecular encapsulation methods, such as those 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 supercomb branched polymers. Similarly, unimolecular encapsulation of various drugs using SBP to form "dendrimer cassettes" was reported in Tomalia et al., Angew. Chem. Int. Ed. Engl., 1990, 29, 138 and "Dendrimers and Other Dendritic Polymers", edited by Frechet & Tomalia, John Wiley & Sons, Ltd., 2001, pp. 387-424.

[0011] Branched core-shell polymers with hydrophobic core and hydrophilic shell can be used for capturing poorly water-soluble (poorly water soluble) drugs by molecular encapsulation. Random branching and hyperbranched core-shell structures with hydrophilic core and hydrophobic shell are also used for carrying drugs by unimolecular encapsulation and preformed (pre-formed) nano micelles (U.S. Patent number 6,716,450, and Liu et al., Biomaterials 2010,10,1334-1341). However, these unimolecular and preformed micellar structures are generated in the absence of drugs.

[0012] Observe block copolymers, such as miktoarm polymers (i.e. Y-shaped / AB 2 The branched block copolymers (A-type star polymers) and linear (A)-dendritic (B) block copolymers form stereocomplexes with paclitaxel (Nederberg et al., Biomacromolecules 2009, 10, 1460-1468 and Luo et al., Bioconjugate Chem. 2010, 21, 1216). These block copolymers are very similar to traditional lipid or AB-type linear block copolymers, which are well-known surfactants for generating micelles. However, such branched block copolymers are difficult to prepare and are therefore not suitable for large-scale production.

[0013] Water insoluble or poorly water soluble bioactive agents are difficult to formulate. Typically, multiple surfactants, detergents and other materials or complex high energy emulsification processes may be required. Large biomolecules (e.g., albumin) have been used in some formulations of water insoluble paclitaxel, such as Celgene and Bristol-Myers Squibb under their respective trademarks. However, the availability and large-scale production of such biomolecules faces major challenges.

[0014] Vaccines help the body recognize and destroy certain targets, such as cancer cells or microorganisms that cause infection. Adjuvants are often used to modify, enhance, or increase the potency or effectiveness of vaccines to provide better immunity against a specific disease. Aluminum-containing adjuvants have been used in vaccines since the 1930s. Adding small amounts of aluminum helps the body build stronger immunity against microorganisms. Monophosphoryl lipid A (MPL) (also known as "AS04") is used in vaccines in the United States. It has an immune-enhancing effect. MF59 is an adjuvant based on an oil-in-water emulsion that contains squalene, a naturally occurring oil found in many plant and animal cells, as well as in the human body. MF59 adjuvant has been used in Fluad, an influenza vaccine licensed for adults aged 65 years or older, in Europe since 1997 and in the United States since 2016. 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 soap bark tree (Quillaja saponaria Molina). AS01B is also a component of vaccines currently being tested in clinical trials, including malaria and HIV vaccines. CpG 1018 is a sequence containing a 22-mer CpG ODN with a modified phosphorothioate backbone that was recently developed for Adjuvant for the vaccine (registered trademark of Dynavax Technologies Corporation). It contains a synthetic oligodeoxynucleotide with a cytosine phosphate guanine (CpG) motif (CpG ODN) that is an agonist of TLR9 and mimics the activity of naturally occurring CpG motifs found in foreign DNA of the body (e.g., bacterial and viral DNA).

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

[0016] In some cases, the present invention relates to a pharmaceutical composition comprising: a nanoaggregate comprising a polymer and at least one water-insoluble or weakly water-soluble bioactive agent; and optionally a pharmaceutically suitable carrier; wherein the pharmaceutical composition is soluble in an aqueous solution to produce at least 1 mg / mL of the bioactive agent dissolved in the aqueous solution; wherein the polymer is water-soluble; and wherein the polymer comprises: a first polymer comprising at least one first terminal group modified with an H or hydrophobic portion and a second terminal group modified with a hydrophilic portion group), wherein the first end group comprises 1% to 99% H and 1% to 99% hydrophobic moiety, the hydrophobic moiety comprising a saturated or unsaturated aliphatic hydrocarbon, aromatic hydrocarbon, or a combination thereof having 1 to about 22 carbons; and the second end group comprises a group modified by an amine, amide, imine, imide, carboxyl, hydroxyl, ester, ether, acetate, phosphate, ketone, aldehyde, sulfonate, or a combination thereof; or a second polymer comprising one or more hydroxy dendrimers (HD); ethylene diamine-core poly(amidoamine)(PAMAM) hydroxyl-terminated generation-4,5,6,7,8,9,10 dendrimers, or a combination thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (poly ... acid), PLGA); poly(propylene oxide) (poly(propyleneoxide) (PPO); poly(caprolactone) (PCL); (PPO-PEO); poly (γ-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 (vinylamine) (PEI); poly (N-vinylpyrrolidone) (PVP); poly (L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly (hydroxybutyrate) (PHB); poly (ethylene oxide) (PEO); poly (L-glutamic acid-γ-benzyl ester) (PBLG); phosphatidylserine (PS); poly (isohexyl cyanoacrylate) (PIHCA); poly (allylamine hydrochloride) (PAH); poly (γ-propargyl) (PP); or a combination thereof.

[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.

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

[0019] In some cases, the pharmaceutical composition can be a prophylactic vaccine, a therapeutic vaccine, or a combination thereof, wherein the pharmaceutical composition further comprises at least one immunizing agent for stimulating an immune response in a subject in need thereof.

[0020] In some cases, the present invention relates 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.

[0021] In some cases, the present invention relates to a nanoaggregate comprising a polymer and at least one water-insoluble or weakly water-soluble bioactive agent; wherein the nanoaggregate is soluble in an aqueous solution to produce at least 1 mg / mL of the bioactive agent dissolved in the aqueous solution; wherein the polymer is water-soluble; wherein the bioactive agent comprises a drug based on natural or synthetic small molecules, an inorganic-based drug, a biological drug, a drug based on natural or synthetic macromolecules, a derivative thereof, or a combination thereof; and wherein the polymer comprises: a first polymer comprising at least one first end group modified with H or a hydrophobic portion and a second end group modified with a hydrophilic portion, wherein the first end group comprises 1% to 99% H and 1% to 99% hydrophobic portion, the hydrophobic portion comprising a saturated or unsaturated aliphatic hydrocarbon, an aromatic hydrocarbon, or a combination thereof having 1 to about 22 carbons, and the second end group comprises an amine, an amide, an imide, an imide, carboxyl, hydroxyl, ester, ether, acetate, phosphate, ketone, aldehyde, sulfonate, or a combination thereof; or a second polymer comprising one or more hydroxy dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 generation dendrimers or a combination thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); poly(caprolactone) (PCL); (PPO-PEO); poly (γ-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 (vinylamine) (PEI); poly (N-vinyl pyrrolidone) (PVP); poly (L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly (hydroxybutyrate) (PHB); poly (ethylene oxide) (PEO); poly (L-glutamic acid-γ-benzyl ester) (PBLG); phosphatidylserine (PS); poly (isohexyl cyanoacrylate) (PIHCA); poly (allylamine hydrochloride) (PAH); poly (γ-propargyl) (PP); or a combination thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1A-Figure 1D Examples of SBP include ( Figure 1A ) dendrimers, ( Figure 1B ) dendritic grafts, ( Figure 1C ) regular comb-branched polymers and ( Figure 1D ) Star-branched polymers. They all have a core, which is spherical or linear.

[0023] Figure 2A and Figure 2B Examples of chemical structures of symmetrically branched polypropyleneimine (PPI) dendrimers. Figure 2A : A dendrimer containing 4-PPI. Figure 2B : A dendrimer containing additional 8-PPI.

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

[0025] Figure 4A and Figure 4B Random ( Figure 4A ) and regularization ( Figure 4B ) Schematic example of an asymmetrically branched polymer (ABP).

[0026] Figure 5 Examples of chemical structures of randomly asymmetrically branched PEI homopolymers.

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

[0028] Fig. 7A and Figure 7B In branched polymers ( Fig. 7A )SBP and ( Figure 7B ) are illustrative schematic examples of drugs loaded in or at a surface domain or region of a hGH polypeptide. In this and other figures, R represents a surface group and the solid circles represent a bioactive agent, such as a drug of interest.

[0029] Figure 8 Schematic illustration of an example of a nanoparticle containing both a drug molecule (solid circles) and a branched polymer with surface groups (R).

[0030] Fig.9A and Fig. 9B In branched polymers ( Fig.9A )SBP and / or( Fig. 9B ) Schematic examples of water-insoluble or poorly water-soluble drugs loaded at the hydrophobic surface groups of ABP. In this figure and other figures, a thin wavy line represents a hydrophobic surface group.

[0031] Fig. 10A and Fig. 10B Various drug-containing nanoparticles SBP ( Fig. 10A ) and ABP( Fig. 10B ), the nanoparticle also carries at least one targeting group or part, such as an antibody, represented by "Y" in this figure and other figures.

[0032] Figure 11A-11C Example of light scattering (LS) measurement data of nanoaggregates. Fig.11A : The ratio of polymer A1 to rapamycin is 5:1. Fig. 11B : The ratio of polymer A1 to rapamycin is 7.5:1. Fig. 11C : The ratio of polymer B1 to rapamycin is 5:1.

[0033] Figures 12A-12D Examples of STING agonists are of the formula: Fig. 12A :Formula (1)-(6). Fig. 12B :Formula (7)-(12). Fig. 12C :Formula (13)-(18). Fig.12D :Formula (19)-(24). Fig.12E :Formula (25)-(29).

[0034] Figure 13A-13E Representative molecules of examples of biologically active agents. Fig.13A :SN-38,7-ethyl-10-hydroxycamptothecin. Fig. 13B : irinotecan, also known as CPT-11 under their respective trademarks, Campto, Fig. 13C : Camptothecin (CPT). Fig.13D : Topotecan, also known as Hycamtin. Fig.13E : Under their respective trademarks, SN-38ADC, Example of (hRS7-SN38ADC).

[0035] Fig.14A – Fig.14E Representative measurement data of nanoaggregate particles. Fig.14A : Example of nanoaggregates (Formulation 1). Fig. 14B : Another example of nanoaggregates (Formulation 2). Fig. 14C: Another example of nanoaggregates (Formulation 3). Fig. 14C : Another example of nanoaggregates (Formulation 3). Fig.14D : Another example of nanoaggregates (Formulation 4). Fig.14E : Another example of nanoaggregates (Formulation 5).

[0036] Fig.15 Representative SN-38 cytotoxicity data using the HCT-116 cell line. DETAILED DESCRIPTION

[0037] By reading the following specific embodiments, it will be easier for those of ordinary skill in the art to understand the features and advantages of the present invention. It should be understood that certain features of the present invention described above and below in the context of a separate embodiment may also be provided in combination in a single embodiment. On the contrary, for the sake of brevity, the various features of the present invention described in the context of a single embodiment may also be provided separately or in any combination or sub-combination. In addition, unless the context clearly specifies otherwise, references in the singular may also include plural forms (e.g., "a" and "an" may refer to one, or one or more).

[0038] Unless expressly stated otherwise, the use of numerical values ​​within the various ranges specified in this application are expressed as approximations, as if the minimum and maximum values ​​within the ranges were modified by the word "about". In this way, slight variations above and below the stated ranges can be used to achieve substantially the same results as the values ​​within the ranges. In addition, the disclosure of ranges is intended as a continuous range including every value between and including the minimum and maximum values ​​recited.

[0039] Drug solubility in the present disclosure is defined as <30 (soluble), 30-100 (poorly soluble), and >100 (insoluble) relative to the fraction of solvent required to dissolve a portion of the bioactive agent or drug. Water solubility is defined herein as <30 (water soluble), 30-100 (poorly soluble), and >100 (water insoluble) relative to the fraction of water required to dissolve a portion of the bioactive agent or drug.

[0040] For the purposes of this disclosure, despite the presence of branches of different lengths and the fact that the branches are present randomly, randomly branched PEI is considered a homopolymer because the branched polymer consists of a single monomer, ethyleneimine or aziridine repeating units. Due to the (AB) repeating units, polymers with a "(AB)-(AB)-(AB)..." structure can also be considered a homopolymer. Homopolymers can be linear or branched. In addition, one or more monomer or complex monomer components can be modified, substituted, derivatized, etc., for example, modified to carry functional groups. For the purposes of this disclosure, such molecules are homopolymers because the polymer backbone consists of a single type of simple monomer or complex monomer.

[0041] The term "polymer" refers to any polymer applicable to the present invention as defined above and below. In an example, the polymer may include polyoxazoline or modified polyoxazoline disclosed herein. In a further example, the polymer may include modified polyoxazoline, which may include one or more second end groups, such as -NH 2 , -NH, -NH 3 + , other basic groups, or combinations thereof, provided that 0.01% to 100% of the second end groups do not contain primary amines. In some cases, 0.01% to 100%, 0.1% to 100%, or 1% to 100% of the second end groups do not contain primary amines. In some cases, 1% to 100% of the second end groups may include hydroxyl groups. All percentages are based on the total number of second end groups.

[0042] The term "bioactive agent" refers to a molecule, compound, complex of one or more compounds or molecules, or a combination thereof that can provide biological activity in vivo, in vitro, or in combination thereof. Pharmaceutical compositions can include one or more bioactive agents, for example, pharmaceutically active agents (PAAs) or active pharmaceutical ingredients (APIs), and other biologically active or inert compounds, which can include emollients, bleaching agents, antiperspirants, drugs, moisturizers, fragrances, colorants, adjuvants, pigments, dyes, antioxidants, oils, fatty acids, lipids, inorganic salts, organic molecules, sunscreens, vitamins, drugs, keratolytic agents, UV blocking agents, tanning accelerators, decolorants, deodorants, perfumes, insect repellents, or a combination thereof. Some examples of bioactive agents are described in detail in the present disclosure.

[0043] The term "taxane" refers to paclitaxel, docetaxel, cabazitaxel, larotaxel, milataxel, ortataxel, tesetaxel, or a combination thereof. In some cases, paclitaxel may be preferred.

[0044] Throughout this disclosure, the term "rapamycin" is also referred to as "sirolimus" and is used interchangeably.

[0045] The term "mTOR" refers to the mammalian target of rapamycin, a protein kinase that regulates cell growth, survival, metabolism, and immunity. mTOR can assemble into several complexes, for example, mTOR complex 1 (mTORC1), mTOR complex 2 (mTORC2), and mTOR complex 3 (mTORC3). Activation of mTOR can promote tumor growth and metastasis. Inhibiting mTOR with one or more mTOR inhibitors can be used to treat cancer.

[0046] The term "mTOR inhibitor", "mTOR inhibitors", "inhibitor of mTOR" or "inhibitors of mTOR" refers to molecules that inhibit the activity of mTOR or the mTOR complex. Some examples of mTOR inhibitor drugs or molecules include everolimus, which can be used as and tablets / AFINITOR (Trademark of Novartis), (Pfizer); temsirolimus, available as (Pfizer); sirolimus (rapamycin), available as (Pfizer) and FYARRO TM(trademark of Aadi Bioscience, Inc.); zotarolimus; torin-1; torin-2; vistusertib; ridaforolimus (also known as AP23573 and MK-8669 or deforolimus); one or more dual PI3K-mTOR inhibitors (e.g., PKI-402, SPR965, PI-10 3, GNE477, WJD008, GSK2126458, etc.); one or more ATP competitive mTORC1 / 2 inhibitors (e.g., AZD-8055, OSI-027, INK128, WYE-132, Torin1, etc.); Apitolisib (GDC-0980 or RG7422), AZD8055, BGT226, CC-223, CH5132799, Chrysophanic acid Acid)(Chrysophanol), Dactolisib, ETP-46464, GDC-0349, Gedatolisib, GNE-493, GSK1059615, INK 128, KU-0063794, LY3023414, MHY1485, mTOR-IN-1, Omipalisib, OSI-027, Palomid 529, PF-04691502, PF-04979064, PI-103, PP121, QL-IX-55, SF1126, Tacrolimus, Torkinib, Vytorin, Voxtalisib, Voxtalisib, VS-5584, WAY-600, WYE-125132, WYE-354, WYE-687, XL388, derivatives thereof, or combinations thereof. Commercially available mTOR inhibitors, for example, those available from Adooq Biosciences may be suitable.

[0047] SN-38 (7-ethyl-10-hydroxycamptothecin) is a topoisomerase 1 ("Top 1" or "Top I" herein) inhibitor and a 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 agents has resulted in 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, and antibody-drug conjugates (ADCs) using SN-38 as a payload. Due to its low solubility and high toxicity, there are currently no approved SN-38 drug products for chemotherapy. Studies on polymer-conjugated SN-38 prepared by linking SN-38 to multi-arm polyethylene glycol via a glycine linker (Sapra, P., et al., Clin. Cancer Res., 14(6): 1888, 2008) and polymer micelle SN-38 (Carie, A; et al., J. Drug Delivery, Vol. 2011, p. 9, 2011, doi: 10.1155 / 2011 / 869027) have been reported. However, the synthesis and production of those are complicated.

[0048] In some cases, other topoisomerase inhibitors, e.g., topoisomerase II ("Top 2" or "Top II" herein) inhibitors, e.g., doxorubicin, etoposide, quinolones, fluoroquinolone, or a combination thereof, are also suitable for use in the pharmaceutical compositions, processes and methods disclosed herein. In some cases, quinolones targeting two essential bacterial Top 2 enzymes: DNA gyrase and DNA topoisomerase IV may be suitable. In some cases, the pharmaceutical composition may be suitable for use in the treatment of infectious diseases.

[0049] The terms "pharmaceutical suitable carrier, pharmaceuticallysuitable carriers" and "pharmaceutically suitable carrier, pharmaceutically suitable carriers" refer to one or more inactive ingredients in an approved drug product. Inactive ingredients listed in the "Inactive Ingredients in Approved Drug Products" database maintained and updated by the U.S. Food and Drug Administration (FDA) may be suitable. In some cases, a pharmaceutically suitable carrier may also be referred to as an excipient.

[0050] The term "subject" used in the present disclosure refers to an animal, a human being or a human patient. The term "animal" refers to wild animals, captured or zoo-raised animals, and domesticated animals, including livestock, farm animals, pets, experimental animals, such as horses, cattle, pigs, donkeys, mules, camels, goats, sheep, monkeys, rabbits, dogs, cats, mice, rats, etc. Warm-blooded animals are suitable. The term "human" refers to a human patient suffering from one or more diseases in need of treatment, a person suffering from one or more diseases unrelated to treatment, or a healthy person. In some cases, the subject can be a human patient or a healthy person.

[0051] The terms "antibody," "antibodies," or "fragment of an antibody" may include natural or synthetic antibodies that selectively bind to an antigen. The terms include polyclonal and monoclonal antibodies produced from animals, cells (including eukaryotic or prokaryotic cells), cell-free systems, or chemical synthesis. In addition to intact immunoglobulin molecules, the term "antibody" also includes fragments or polymers of those immunoglobulin molecules, as well as human or humanized versions of immunoglobulin molecules that selectively bind to a target antigen.

[0052] The term "aqueous solution" as used in the present disclosure refers to a solution comprising 80% to 100% water, the percentage being based on the total non-solid weight of the aqueous solution. The aqueous solution may further include additional components, such as salts, acids, bases, buffers, solvents, organic solvents, granules, emulsions, solids or non-solids, detergents, small molecules, macromolecules, other ingredients, or combinations thereof. The term "non-solid weight" refers to the weight of the solid content of the aqueous solution after drying (e.g., by removing all water or other liquids).

[0053] The term "infectious disease" refers to a disease caused by a harmful organism (pathogen), such as bacteria, viruses, fungi, protozoa, worms, parasites, prions, parts thereof, or combinations thereof. Infectious diseases can be spread from person to person through contact with animals, insects, or through contaminated food, water, or soil. Some examples of infectious diseases can include Chickenpox (Varicella), Coronavirus, Dengue, Diphtheria, Ebola, Influenza, Hepatitis, Hib Disease, HIV / AIDS, HPV (Human Papillomavirus), Japanese Encephalitis, Measles, Meningococcal Disease, Monkeypox, Mumps, Norovirus, Pneumococcal Disease, Polio, Rabies, Respiratory Syncytial Virus (RSV), Rotavirus, Rubella (German Measles), Herpes Zoster, Tetanus (Lockjaw), Whooping Cough (Pertussis), Zika, and other known diseases, or diseases that have not yet appeared or have not yet been identified.

[0054] The term "vaccine" refers to a substance or a group of substances that are intended to cause the immune system of a subject (e.g., a human or an animal) to respond to a microorganism (e.g., a bacterium, a virus, a fungus, a protozoan, a worm, a parasite, a prion, other harmful organisms (pathogens), or a tumor). Vaccines can help the body recognize and destroy microorganisms or cancer cells. In some cases, vaccines can include proteins from microorganisms or from cancer cells, nucleic acids encoding the proteins, toxins, nucleic acids, oligonucleotides; DNA; RNA; mRNA; siRNA; or a combination thereof. In some cases, vaccines can include modified proteins, nucleic acids encoding the modified proteins, toxins, nucleic acids, modified nucleic acids, oligonucleotides, or modified oligonucleotides; DNA; RNA; mRNA; siRNA; sgRNA; or a combination thereof that are intended to cause the immune system to respond to microorganisms or cancer cells. Modified or synthetic DNA, RNA, mRNA, siRNA, sgRNA, or a combination thereof may also be suitable.

[0055] The term "adjuvant" or "adjuvants" refers to drugs, substances, agents, or combinations thereof that are used to modify, enhance, or increase the potency or effectiveness of an immunogen (e.g., a vaccine) to provide better immunity against a specific antigen (e.g., a specific disease). Adjuvants may include one or more organic molecules; antigenic molecules that can mimic molecular patterns associated with specific pathogens, including liposomes, lipopolysaccharides, molecular cages for antigens, bacterial cell wall components, and endocytosed nucleic acids, such as RNA, double-stranded RNA (dsRNA), DNA, single-stranded DNA (ssDNA), DNA containing methylated or unmethylated CpG dinucleotides; inorganic compounds, such as potassium alum, aluminum hydroxide, aluminum phosphate, hydroxyapatite; oils, such as paraffin oil, propolis, peanut oil; bacterial products, such as inactivated bacteria; plant products, such as those from soybeans or other plants; cytokines, such as IL-1, IL-2, or IL-12; or combinations thereof.

[0056] The terms "isomer" and "isomers" refer to molecules that share the same chemical formula but whose atoms are connected in different ways or arranged in space in different ways, including structural isomers in which the atoms are bonded together in different orders, geometric isomers in which the atoms are bonded in the same order but with different configurations around the bonds, such as cis-isomers or trans-isomers, and enantiomers that have the same chemical structure but the three-dimensional arrangement of atoms around the asymmetric carbon is different so that they are mirror images of each other.

[0057] In some instances, the disclosure relates to a pharmaceutical composition comprising:

[0058] A nanoaggregate comprising a polymer and at least one water-insoluble or poorly water-soluble bioactive agent; and

[0059] Optionally, a pharmaceutically suitable carrier;

[0060] wherein the pharmaceutical composition is soluble in an aqueous solution to produce at least 1 mg / mL of the bioactive agent dissolved in the aqueous solution;

[0061] wherein the polymer is water soluble; and

[0062] Wherein the polymer may include:

[0063] 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, and wherein the first end group comprises 1% to 99% H and 1% to 99% hydrophobic moiety, the hydrophobic moiety may comprise a saturated or unsaturated aliphatic hydrocarbon, aromatic hydrocarbon, or a combination thereof having 1 to about 22 carbons, 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 a combination thereof; or

[0064] A second polymer comprising one or more hydroxy dendrimers (HD) (also known as hydroxy-terminated dendrimers); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxy-terminated-4, 5, 6, 7, 8, 9, 10 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); (PPO-PEO); poly(γ-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(vinylamine) (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-glutamate) (PBLG); phosphatidylserine (PS); poly(isohexyl cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP);

[0065] or a combination thereof.

[0066] 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 1% to 99% H and 1% to 99% hydrophobic moiety, wherein the hydrophobic moiety may include a saturated or unsaturated aliphatic hydrocarbon, aromatic hydrocarbon, or a combination thereof having 1 to about 22 carbons, and the second end group comprises a group modified with an amine, amide, imide, imide, carboxyl, hydroxyl, ester, ether, acetate, phosphate, ketone, aldehyde, sulfonate, or a combination thereof.

[0067] In some cases, the polymer can be composed 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, and wherein the first end group comprises 1% to 99% H and 1% to 99% hydrophobic moiety, the hydrophobic moiety may include a saturated or unsaturated aliphatic hydrocarbon, aromatic hydrocarbon, or a combination thereof having 1 to about 22 carbons, and the second end group comprises a group modified by an amine, amide, imide, imide, carboxyl, hydroxyl, ester, ether, acetate, phosphate, ketone, aldehyde, sulfonate, or a combination thereof. In some cases, the pharmaceutical composition may be free of a polymer selected from: one or more hydroxy dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 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); (PPO-PEO); poly (γ-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 (vinylamine) (PEI); poly (N-vinyl pyrrolidone) (PVP); poly (L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly (hydroxybutyrate) (PHB); poly (ethylene oxide) (PEO); poly (L-glutamic acid-γ-benzyl ester) (PBLG); phosphatidylserine (PS); poly (isohexyl cyanoacrylate) (PIHCA); poly (allylamine hydrochloride) (PAH); poly (γ-propargyl) (PP); and combinations thereof.

[0068] In some cases, the polymer may include a second polymer comprising one or more hydroxy dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 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); (PPO-PEO); poly (γ-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 (vinylamine) (PEI); poly (N-vinyl pyrrolidone) (PVP); poly (L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly (hydroxybutyrate) (PHB); poly (ethylene oxide) (PEO); poly (L-glutamic acid-γ-benzyl ester) (PBLG); phosphatidylserine (PS); poly (isohexyl cyanoacrylate) (PIHCA); poly (allylamine hydrochloride) (PAH); poly (γ-propargyl) (PP); or a combination thereof.

[0069] In some cases, the polymer may be composed of: one or more hydroxy dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 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); (PPO-PEO); poly (γ-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 (vinylamine) (PEI); poly (N-vinylpyrrolidone) (PVP); poly (L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); polyhydroxybutyrate (PHB); poly (ethylene oxide) (PEO); poly (L-glutamic acid-γ-benzyl ester) (PBLG); phosphatidylserine (PS); poly (isohexyl cyanoacrylate) (PIHCA); poly (allylamine hydrochloride) (PAH); poly (γ-propargyl) (PP); and combinations thereof. In some cases, the polymer may include only the polymers listed above, and exclude the above-mentioned polymer including at least one first end group modified with H or a hydrophobic moiety and a second end group modified with a hydrophilic moiety.

[0070] In some cases, the polymer may include a first polymer and one or more subsequent polymers (also referred to as "second polymers") selected from one or more hydroxy dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 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); (PPO-PEO); poly (γ-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 (vinylamine) (PEI); poly (N-vinyl pyrrolidone) (PVP); poly (L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly (hydroxybutyrate) (PHB); poly (ethylene oxide) (PEO); poly (L-glutamic acid-γ-benzyl ester) (PBLG); phosphatidylserine (PS); poly (isohexyl cyanoacrylate) (PIHCA); poly (allylamine hydrochloride) (PAH); poly (γ-propargyl) (PP); and combinations thereof.

[0071] In some cases, polymer can include polyoxazoline (POX), it includes linear part, branched part or its combination, and wherein said polyoxazoline (POX) can include poly-(2-methyloxazoline), poly-(2-ethyloxazoline) and poly-(2-propyloxazoline), or its combination.In some cases, polyoxazoline can be poly-(2-ethyloxazoline).

[0072] In some cases, the polyoxazoline can include a molar ratio of monomer to initiator in a range of 50:1 to 80:1.

[0073] In some cases, 1% to 100% of the second end groups do not contain primary amines. In some cases, in the pharmaceutical compositions disclosed herein, 1% to 100% of the second end groups may include hydroxyl groups. All percentages are based on the total number of second end groups.

[0074] In some cases, the first end group comprises 1% to 99% H and 1% to 99% hydrophobic moiety, 1% to 90% H and 10% to 99% hydrophobic moiety, 1% to 85% H and 15% to 99% hydrophobic moiety, 1% to 80% H and 20% to 99% hydrophobic moiety, 1% to 75% H and 25% to 99% hydrophobic moiety, 1% to 70% H and 30% to 99% hydrophobic moiety, 1% to 65% H and 35% to 99% hydrophobic moiety, 1% to 60% H and 40% to 99% hydrophobic moiety, 1% to 55% H and 45% to 99% hydrophobic moiety, 1% to 50% H and 65% to 99% hydrophobic moiety, 1% to 45% H and Ranges from 55% to 99% hydrophobic moieties, from 1% to 40% H and 60% to 99% hydrophobic moieties, from 1% to 35% H and 65% to 99% hydrophobic moieties, from 1% to 30% H and 70% to 99% hydrophobic moieties, from 1% to 25% H and 75% to 99% hydrophobic moieties, from 1% to 20% H and 80% to 99% hydrophobic moieties, from 1% to 15% H and 85% to 99% hydrophobic moieties, from 1% to 10% H and 90% to 99% hydrophobic moieties, from 1% to 5% H and 95% to 99% hydrophobic moieties, and from 1% to 99% hydrophobic moieties, including all percentages within the stated ranges, the percentages being based on the total number of first end groups in the polymer. In some cases, the first end group includes 1% to 50% H and 50% to 99% hydrophobic moieties, 1% to 40% H and 60% to 99% hydrophobic moieties, 1% to 30% H and 70% to 99% hydrophobic moieties, 1% to 20% H and 80% to 99% hydrophobic moieties, 1% to 10% H and 90% to 99% hydrophobic moieties, 1% to 5% H and 95% to 99% hydrophobic moieties, or 1% to 2% H and 98% to 99% hydrophobic moieties, including all percentages within the range, the percentages are based on the total number of first end groups in the polymer. In some cases, the percentages are based on the moles of first end groups in the polymer.

[0075] Alternatively, the polymer can be described using a ratio of H to hydrocarbon groups ("hydrocarbons"), such as H:hydrocarbons = 0.01:1 to 100: 1. In some cases, the first end group includes a ratio of H to hydrophobic moieties in the range of 0.01:1 to 100:1, including all ratios within the range. In some cases, the first end group comprises a ratio of H: hydrophobic moiety 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, 95:1 to 100:1, including all ratios within the ranges. 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, 95:1 to 10:1, including all ratios within the ranges. In some cases, the first end group includes a ratio of H to 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, 95:1 to 5:1, including all ratios within the range. In some cases, the first end group includes a ratio of H: hydrophobic moiety 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 ratios about those ratios. The ratio can be based on the molar ratio of H to the hydrocarbon group.

[0076] Percentages and ratios can be easily converted using conventional methods, for example, a ratio of 0.01:1 can be converted to approximately 1%, 0.2:1 can be converted to approximately 17%, 0.5:1 can be converted to approximately 33%, 1:1 can be converted to approximately 50%, 1.5:1 can be converted to approximately 60%, 2:1 can be converted to approximately 67%, 5:1 can be converted to approximately 83%, 10:1 can be converted to approximately 90%, 20:1 can be converted to approximately 95%, and 100:1 can be converted to approximately 99%.

[0077] The percentage or ratio of the hydrogen-modified first end group and the hydrocarbon-modified first end group can be measured using HPLC known to those skilled in the art.

[0078] In the pharmaceutical compositions disclosed herein, the first end group may include H or a hydrophobic portion, which may include a saturated or unsaturated aliphatic hydrocarbon, an aromatic hydrocarbon, or a combination thereof having 1 to about 22 carbons, and the second end group may include a group modified by an amine, an amide, an imine, an imide, a carboxyl group, a hydroxyl group, an ester, an ether, an acetate, a phosphate, a ketone, an aldehyde, a sulfonate, or a combination thereof.

[0079] In one example, the first end group may include hydrogen (H), in one example, a hydrocarbon having 2 to 22 carbons, in another example, 4 to 22 carbons, in yet another example, 6 to 22 carbons, in yet another example, 7 to 22 carbons, in yet another example, 8 to 22 carbons, in yet another example, 10 to 22 carbons, in yet another example, 12 to 22 carbons, in yet another example, 14 to 22 carbons, in yet another example, 16 to 22 carbons, and in a further example, 18 to 22 carbons. In a specific example, the first end group may include 18 carbons, for example, (CH 3 (CH 2 ) 17 )-group. In some cases, the first end group may include a hydrocarbon having 7 to 22 carbons. In some cases, the first end group may include H. In some cases, the first end group may include 1% to 99% H and 1% to 99% of a hydrophobic portion, the hydrophobic portion may include a saturated or unsaturated aliphatic hydrocarbon, an aromatic hydrocarbon, or a combination thereof having 1 to about 22 carbons. The first end group may be modified by selecting a variety of initiators. In some cases, p-toluenesulfonic acid, trifluoroacetic acid, methyl toluenesulfonate, HCl, HBr, HI, H-Br, hydrocarbon-Br, such as C 1 To C 22 -Br, or a combination thereof may be used as an initiator. The polymers prepared herein may be mixed together in a predetermined ratio.

[0080] Initiator can include hydrophobic electrophilic molecules, including hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons or combinations thereof, and halide functional groups, such as alkyl halides, aralkyl halides, acyl halides or combinations thereof. The example of such compounds can include monofunctional initiators, such as hydrocarbons containing 1 to about 22 carbons with saturated or unsaturated chemical bonds, such as methyl iodide / bromide / chloride, ethyl iodide / bromide / chloride, 1-iodine / bromine / chlorobutane, 1-iodine / bromine / chlorohexane, 1-iodine / bromine / chlorododecane, 1-iodine / bromine / chlorooctadecane, benzyl iodide / bromide / chloride etc. Other initiators can include allyl bromide / chloride. Acyl halides can also be used, such as acyl bromides / acyl chlorides, benzoyl bromides / chlorides and compounds containing tosyl, such as p-toluenesulfonic acid (p-toluenesulfonic acid), methyl toluenesulfonate (methyl tosylate) and other toluenesulfonic acid esters. Any one or more initiators can be used in combination. In some cases, the initiator can also include a hydrophilic portion including a proton / H-containing molecule, such as p-toluenesulfonic acid, trifluoroacetic acid, methyl toluenesulfonate, HCl, HBr, HI, or a combination thereof.

[0081] During the polymerization process, an initiator may be used to start the polymerization. When used, various molar ratios of monomer to initiator may be used to obtain a particular polymer. A particular polymer may have different properties, such as molecular weight, size of branching, and other properties, including those unexpectedly discovered by the applicant as disclosed herein. In some cases, a suitable molar ratio of monomer to initiator may be from 20:1 to 100:1, including any and all ratios within the range, for example, 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, including 20; 1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 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 etc., this means to use the mol ratio of the monomer in the above-mentioned scope and initiator to prepare selected polymer.In some cases, poly-oxazoline disclosed herein can be included in the mol ratio of the monomer in the scope of 50:1 to 80:1 and initiator, this means that the mol ratio (comprising any and all ratios in the described scope) of the monomer in the scope of 50:1 to 80:1 and initiator can be used for producing selected polymer.

[0082] The polymers can be prepared using the monomers and initiators described herein and in earlier PCT publication WO 2014 / 123791, the entire contents of which are incorporated herein by reference.

[0083] A hydrogen-modified randomly branched PEOX polymer having a certain monomer to initiator molar ratio in the range of 20:1 to 100:1 can be prepared as described above using an initiator selected from a hydrophilic portion including a proton / H containing molecule, such as p-toluenesulfonic acid, trifluoroacetic acid, methyl toluenesulfonate, HCl, HBr, HI, or a combination thereof.

[0084] The hydrocarbon C having a molar ratio of monomer to initiator in the range of 20:1 to 100:1 can be prepared using an initiator as described above. 1 to (CH 3 (CH 2 ) 21 )-modified randomly branched PEOX polymer, the initiator is selected from CH 3 -Br, (CH 3 (CH 2 ))-Br, (CH 3 (CH 2 ) 2 )-Br, (CH 3 (CH 2 ) 3 )-Br, (CH 3 (CH 2 ) 4 )-Br, (CH 3 (CH 2 ) 5 )-Br, (CH 3 (CH 2 ) 6 )-Br, (CH 3 (CH 2 ) 7 )-Br, (CH 3 (CH 2 ) 8 )-Br, (CH 3 (CH 2 ) 9 )-Br, (CH 3 (CH 2 ) 10 )-Br, (CH 3 (CH 2 ) 12 )-Br, (CH 3 (CH 2 ) 12 )-Br, (CH 3 (CH 2 ) 13 )-Br, (CH 3 (CH 2 ) 14 )-Br, (CH3 (CH 2 ) 15 )-Br, (CH 3 (CH 2 ) 16 )-Br, (CH 3 (CH 2 ) 17 )-Br, (CH 3 (CH 2 ) 18 )-Br, (CH 3 (CH 2 ) 19 )-Br, (CH 3 (CH 2 ) 20 )-Br and (CH 3 (CH 2 ) 21 )-Br. Mixtures of initiators may also be suitable.

[0085] In some cases, the randomly branched PEOX polymer modified with hydrogen and the hydrocarbon C prepared above can be prepared by mixing in a predetermined ratio. 1 to (CH 3 (CH 2 ) 21 )-modified randomly branched PEOX polymers to prepare hydrocarbon mixtures (e.g., C 1 to (CH 3 (CH 2 ) 21 In some cases, the polymer may include 1% to 99% hydrocarbons, such as C 1 to (CH 3 (CH 2 ) 21 )-modified first end groups, and 1% to 99% H-modified first end groups.

[0086] In some cases, the first end group may include H and C in a ratio ranging from 0.01:1 to 100:1. 1 To C 22 The hydrophobic part of the hydrocarbon (e.g. (CH 3 (CH 2 ) 17 In some cases, the first end group may include H and C in a ratio ranging from 0.1:1 to 5:1. 1 To C 22 The hydrophobic part of the hydrocarbon (e.g. (CH 3 (CH 2 ) 17 )-).

[0087] Including hydrocarbon CH 3 (CH 2 ) 17 A polymer having a mixture of a )-modified first terminal and a H-modified first terminal may be referred to as a "H / C 18 Polymers with specific initiator molar ratios (e.g., 60:1, 70:1, 80:1, etc.) can be referred to as "H / C 18 PEOXABP60", "H / C 18 PEOXABP70","H / C 18 PEOXABP80” etc.

[0088] The polymers disclosed above and below may be suitable and may include linear polymers, branched polymers, symmetrically branched polymers, asymmetrically branched polymers, dendritic polymers, dendritic graft polymers, comb-branched polymers, star-branched polymers, or combinations thereof. The polymers are water soluble. In an example, the polymers may be dissolved in water to produce, for example, a 12% by weight or higher aqueous solution.

[0089] The second end group can include ammonia, ammonia derivatives, ethylenediamine (EDA), ethylenediamine derivatives, piperazine, piperazine derivatives, 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 a group modified by its combination. In another example, the second end group can include a group modified by ethylenediamine (EDA), ethylenediamine derivatives or a group modified by its combination. Any derivative of ethylenediamine disclosed herein is suitable. The polymer can have a reaction challenge molar ratio (reaction challenge molar ratio) of polyoxazoline reactive chain ends (reactive chain end) and EDA in the range of 1:1 to 1:100. In one example, the polymer can have the reaction excitation mol ratio of the reactive chain ends of polyoxazoline and EDA in the range of 1:1 to 1:100, 1:2 to 1:100 in another example, 1:2 to 1:50 in another example, 1:2 to 1:40 in another example, 1:2 to 1:30 in a further example, 1:2 to 1:20 in another example, 1:2 to 1:15 in another example, and 1:5 to 1:15 in a further example. In a further example, polymer can have the reaction excitation mol ratio of the reactive chain ends of polyoxazoline and EDA of about 1:10. The polyoxazoline modified by EDA disclosed herein can provide the functional group that the polymer charge as disclosed herein has pH dependency variation. In some cases, pharmaceutical composition disclosed herein can include polymer, and the polymer can have the mol ratio of the reactive chain ends of polyoxazoline and EDA of about 1:10. In some cases, 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%, 1% to 2% of the second end groups may include EDA-modified groups. In some cases, 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%, 1% to 2% of the second end groups may include primary amines.

[0090] In some cases, the second end group can include a group modified by an amine, amide, imine, imide, carboxyl, hydroxyl, ester, ether, acetate, phosphate, ketone, aldehyde, sulfonate, or a combination thereof, provided that 0.01% to 100%, 0.1% to 100%, 1% to 100%, 5% to 100%, 10% to 100%, 15% to 100%, 20% to 100%, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 90% to 100%, 95% to 100%, 99% to 100% of the second end groups may 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 contain primary amines. In some cases, about 50% to 100% of the second end groups may not contain primary amines. In some cases, about 75% to 100% of the second end groups may not contain primary amines. In some cases, about 90% to 100% of the second end groups may not contain primary amines.

[0091] In some cases, 100% of the second end groups of the polymer may include a hydroxyl-modified group. In some cases, as disclosed herein, CH 3 (CH 2 ) 17 In some cases, the initiator is selected from hydrophilic part (it comprises the molecule containing proton / H), for example tosic acid, trifluoroacetic acid, methyl toluenesulfonate, HCl, HBr, HI or its combination, and the initiator can be used as the initiator for the polymerization of 2-ethyl oxazoline by the cationic ring-opening process, to generate randomly branched polymers, and then, for example, the randomly branched polymers are dissolved in water, to produce the second end modified by hydroxyl.In some cases, about 100% second end group can include hydroxyl.In some cases, about 100% second end group can not contain primary amine.

[0092] In some cases, the pharmaceutical composition may have a pH value in the range of about 3.0 to about 10.0, and wherein 1% to 100% of the second end groups do not contain 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 wherein about 100% of the second end groups do not contain 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 include hydroxyl groups, the percentage being based on the total number of second end groups.

[0093] Polymer H / C having a hydroxyl group as the second terminal group 18 PEOXABP can be referred to as H / C 18 PEOXABP-OH. Polymers with specific initiator molar ratios (e.g., 60:1, 70:1, 80:1, etc.) can be referred to as "H / C 18 PEOXABP60-OH", "H / C 18 PEOXABP70-OH","H / C 18 PEOXABP80-OH" etc. Polymers having an amine group as a second end group H / C 18 PEOXABP can be referred to as H / C 18 PEOXABP-NH 2 Polymers with specific initiator molar ratios (e.g., 60:1, 70:1, 80:1, etc.) can be referred to as "H / C 18 PEOXABP60-NH 2 ”, “H / C 18 PEOXABP70-NH 2 ”, “H / C 18 PEOXABP80-NH 2 ", etc. In some cases, mixtures of the polymers disclosed herein may be suitable.

[0094] Without wishing to be bound by a particular theory or mechanism, the applicant believes that certain levels of primary amines may interact with certain bioactive agents (e.g., rapamycin) and lead to degradation of the bioactive agent. The applicant has discovered that polymers that do not contain primary amines or have various percentages of primary amines on the second end group can be used to modulate the properties of a certain bioactive agent (e.g., rapamycin), such as stability or degradation, providing an additional approach to optimizing the formulation of a pharmaceutical composition.

[0095] In any of the pharmaceutical compositions disclosed above and below, the polymer may include a polyoxazoline (POX) comprising a linear portion, a branched portion, or a combination thereof. In one example, the polymer may include a plurality of linear portions linked together, in another example, one or more linear portions are linked to one or more branched portions, in yet another example, one or more branched portions are linked together, for example, Figure 1A-Figure 10B Each linear portion can independently have various lengths, various modifications, or combinations thereof. Each branched portion can independently have various lengths, numbers of branches, various modifications, or combinations thereof.

[0096] Polyoxazoline (POX) can include poly-(2-oxazoline), poly-(2-substituted oxazoline), it includes poly-(2-methyloxazoline), poly-(2-ethyloxazoline), poly-(2-propyloxazoline), poly-(isopropyloxazoline) (PiPOX), or its combination. In an example, POX can include poly-(2-methyloxazoline) (PMOX), in another example, include poly-(2-ethyloxazoline) (PEOX), in another example, include poly-(2-propyloxazoline) (PPOX), in another example, include poly-(isopropyloxazoline) (PiPOX), or in further example, include the combination of two or more poly-(2-substituted oxazoline), wherein the two or more poly-(2-substituted oxazoline) can be the repeating unit in the polyoxazoline polymer, also referred to as composite monomer. Polyoxazoline (POX) is hydrophilic. The polyoxazoline (POX) may not contain monomers with hydrophobic side chains, whether simple monomers or complex monomers, such as monomers with 4 or more carbons (C 4 and above).

[0097] Figure 1A-Figure 1D and Figure 2A-2B Some examples of symmetrically branched polymers (SBPs) with symmetrical branches are schematically depicted in , where all homopolymers of interest have one core and present symmetrical branching junctions consisting of terminal branches or chain branches throughout the homopolymer. The functional groups are primarily present on the exterior of the polymer.

[0098] Modified SBPs can be obtained, for example, by chemically attaching functional groups to, for example, symmetrically branched PAMAM or PPI dendrimers (commercially available from Aldrich), polyether dendrimers, polyester dendrimers, comb-branched / star-branched polymers, for example, those containing PEO, PEG, PMOX or PEOX, polystyrene, and comb-branched dendritic grafts, for example, those containing PEOX, PMOX or PEI. Synthetic procedures for preparing such SBPs / dendrimers are known and described above and below.

[0099] In some cases, the higher branching density of SBP can make the polymer compact at the molecular level with well-defined internal void space, which makes such molecules suitable as carriers for water-insoluble or poorly water-soluble drugs, such as rapamycin, which is entrapped or encapsulated therein.

[0100] Surface modification can enhance the performance and use of the resulting modified SBP. For example, a water-insoluble SBP can be rendered water-soluble by appropriate modification, while an SBP with a high charge density can be modified to carry very low or no charge on or on the polymer surface. On the other hand, a water-soluble SBP can be modified with hydrophobic surface groups to enhance the ability to dissolve water-insoluble or weakly water-soluble drugs on or in its surface. Modification can occur at any position of the polymer, for example, at the end, side chain, backbone residue, etc.

[0101] In one embodiment of the present disclosure, SBPs (e.g., symmetrically branched PEI dendrimers, PPI dendrimers, PAMAM dendrimers, or symmetrically branched PEI dendritic grafts) can be modified by using different kinds of, for example, primary amine groups, for example, by Michael addition or by adding acrylates to the amine groups of the homopolymers. Thus, for example, by Michael addition, methyl acrylate can be introduced to the primary and / or secondary amino groups of PEI, PPI, and polylysine (PLL) homopolymers. The ester groups can then be further derivatized, for example, by an amidation reaction. Thus, such an amidation reaction using, for example, ethylenediamine (EDA) can achieve the addition of amino groups at the ends of the newly formed branches. Other modifications of the homopolymers can be made using known chemicals, for example, as provided 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 and include any molecular entity including reactive EDA, substituted EDA, or other members of the polyethyleneamine family, such as diethylenetriamine, triethylenetetramine, tetraethylenepentamine, pentaethylenehexamine, etc., including polyethyleneamine, tetramethylethylenediamine, etc. Amidation reactions using, for example, ethylenediamine (EDA) can also modify the polymer charge density at the ends of the newly formed branches. As disclosed herein, the charge of polymers having such amidation groups can have a pH-dependent change, resulting in a pH-dependent change in polymer charge density.

[0102] In certain embodiments, the modification may include a portion that contributes to or enhances the hydrophobicity of a polymer or portion thereof. For example, a hydrophobic functional group, such as an aliphatic chain comprising a hydrocarbon chain of 1 to about 22 carbons (which may be saturated or unsaturated, linear, cyclic or branched, an aromatic structure (e.g., containing one or more aromatic rings, which may be fused rings), or a combination thereof, may be used as a modifier and added to the polymer by implementing the chemical methods provided herein as taught herein. By such addition, a modified SBP, such as a modified PEI, PPI, PAMAM dendrimer, or PEI dendrimer graft may be formed. An example of a PAMAM modified PPI dendrimer is Figure 3 As shown. As an extension of SBP (such as PPI and PEI), the modified SBP thus obtained is also symmetrically branched. Depending on the solvent environment (i.e. pH or polarity), the surface functional groups can carry different charges and / or charge densities, and / or hydrophobic groups. Then, the molecular shape and surface functional group positions (i.e. surface functional group backfolding) can be further adjusted based on these characteristic properties.

[0103] In another embodiment of the present disclosure, any of a variety of synthetic procedures can be used to prepare modified SBP, such as a synthetic scheme known to be easy to react with a suitable site on a homopolymer. In addition, any of a variety of reagents can be used in the selected synthetic scheme to achieve any of the various modifications or additions to the homopolymer backbone. Therefore, for example, in the case of the Michael addition reaction of the above-mentioned amine, any of the additions of various substituents can be used, for example, in the alkylation stage, for example, using any of a variety of acrylate reagents, for example, acrylates including hydrocarbon substituents, for example, including saturated or unsaturated hydrocarbons of 1 to about 22 carbons, which can be substituted, aliphatic, aromatic, cyclic, saturated at one or more bonds, or a combination thereof. Therefore, 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, etc., and mixtures thereof. Similarly, in the amidation stage in the examples illustrated above, any of a variety of amines can be used. For example, EDA, monoethanolamine, tris(hydroxymethyl)aminomethane, alkylamines, allylamines, or any amino-modified polymer, including those comprising PEG, PEO, perfluoropolymers, polystyrene, polyethylene, polydimethylsiloxane, polyacrylates, polymethylmethacrylate, etc., and mixtures thereof, may be used.

[0104] This synthetic strategy not only allows for the symmetrical growth of the molecule (where more branches with different chemical compositions can be introduced), but also allows for the addition of multiple functional groups to the exterior of the polymer structure. The precursor homopolymer can be modified successively using the same or different synthetic methods until the desired SBP with the appropriate molecular weight and functional groups is obtained. In addition, the hydrophobic and hydrophilic properties and charge density of such polymers can be customized to suit specific application requirements using suitable monomers and suitable modification reactions used to construct the homopolymer.

[0105] In another embodiment of the present disclosure, if a divergent synthesis method is used, the chain ends of symmetrical star-branched or comb-branched homopolymers (e.g., poly(2-oxazoline) or poly(2-substituted oxazolines), including, for example, poly(2-methyloxazoline), poly(2-ethyloxazoline), poly(2-propyloxazoline), and poly(2-butyloxazoline, etc.), PEI, PEO / ethylene glycol, polyvinylpyrrolidone (PVP), polyphosphate, polyvinyl alcohol (PVA) or polystyrene chain ends) can be modified using another small molecule or polymer to generate various functional groups at the ends of the homopolymer chains, including primary, secondary or tertiary amines, carboxylates, hydroxyls, aliphatics (e.g., hydrocarbon chains), aromatics, fluoroalkyls, aryls, PEGs, PEOs, acetates, amides and / or esters. Alternatively, if a convergent synthesis approach is employed, various initiators can be used to introduce the same type of functional groups at the chain ends ("Dendritic Molecules," Newkome et al., eds., VCH, Weinheim, 1996; "Dendrimers and Other Dendritic Polymers," Frechet & Tomalia, eds., John Wiley & Sons, Ltd., 2001; and J. Macromol. Sci. Chem. A9(5), pp. 703-727 (1975)).

[0106] Some examples of asymmetrically branched polymers (ABPs) having asymmetrical branches are described in Figure 4A-4BSchematically depicted in , some of the target polymers lack a core and present asymmetric branch junctions consisting of chain branches and terminal branches throughout the homopolymer. Junctional groups are typically present both externally and internally. However, when larger functional groups (e.g., larger hydrophobic or hydrophilic groups) are used, the functional groups may typically be preferentially and possibly necessarily attached to the exterior of the ABP, for example, possibly due to steric effects. Therefore, such surface-modified branched polymers (MBPs) can be used to solubilize water-insoluble or weakly water-soluble drugs or to form nanoaggregates therewith.

[0107] For example, functional groups can be chemically attached to a regular ABP such as polylysine (e.g., branched PLL), a random ABP such as PEI (available from Aldrich, Polysciences, or BASF under the trade name Modified ABPs can be obtained by using polyoxazolines (commercially available) or polyoxazolines, which can be prepared according to the procedure of Litt (J. Macromol. Sci. Chem. A9 (5), pp. 703-727 (1975)). Other ABPs can include, but are not limited to, polyacrylamide, polyphosphate, PVP, PVA, etc. Random asymmetric branched PEI can be prepared mainly by cationic ring-opening polymerization of ring-strained cyclicimine monomers (e.g., aziridine (ethyleneimine) and azetidine (propyleneimine)), with Lewis or Bronsted acid as initiator (Dernier et al., "Ethylenediamine and Other Aziridines," Academic Press, New York, (1969); and Pell, J. Chem. Soc. 71 (1959)). Since many methods are essentially one-pot processes, large amounts of random ABPs can be easily produced.

[0108] The synthetic methods for preparing ABPs generally generate various branching junctions within the macromolecule. In other words, the terminal and chain branching junctions are mixed and distributed throughout the molecular structure. Compared with dendritic polymers and dendritic grafts, random ABPs can have a lower branching density and a more open molecular structure. Although the branching pattern is random, the average ratio of primary, secondary, and tertiary amine groups can be relatively consistent with a ratio of about 1:2:1, such as described in: Dick et al., J. Macromol. Sci. Chem., A4 (6), 1301-1314 (1970) and Lukovkin, Eur. Polym. J. 9, 559 (1973). In one example, the polymers disclosed herein can include primary, secondary, and tertiary amine groups in a ratio of about 1:2:1.

[0109] The presence of branching junctions can make random ABPs (e.g., asymmetrically branched PEI) form macromolecules with possible spherical, ovoid, or similar configurations. In the spherical structure, there are pockets of various sizes formed by incomplete branching junctions inside the macromolecule. Unlike dendritic polymers and dendritic grafts, whose internal pockets are always located around the central core of the molecule, the pockets of random ABPs are unevenly distributed throughout the molecule. Therefore, random ABPs have both external functional groups and unevenly distributed internal functional groups, which can further react with various molecules to form new macromolecular structures-a kind of modified random ABP.

[0110] Although there is a core, the functional groups of regular ABPs can also be distributed on the outside and inside, which is very similar to random ABPs. One such homopolymer is PLL, which can be prepared as described in the following documents: U.S. Patent Nos. 4,289,872; 4,360,646 and 4,410,688, the entire contents of each of which are incorporated by reference. As taught herein and known in the art, such homopolymers can also be modified in a manner similar to random ABPs.

[0111] In one embodiment of the present disclosure, an ABP (e.g., a randomly asymmetrically branched PEI or a regularly asymmetrically branched PLL) is modified by, for example, adding acrylates to the amine groups of a polymer (e.g., PEI and PLL homopolymers) using different types of primary and / or secondary amines, for example, by Michael addition. The ester groups can then be further derivatized, for example, by an amidation reaction. Thus, for example, such an amidation reaction using, for example, EDA can produce the addition of amino groups at the ends of the newly formed branches. Other modifications of the polymer can be made using known chemistries, for example, as provided in the above-mentioned "Poly (amines) and Poly (ammonium salts)". By such additions, a modified ABP, such as a modified PEI or PLL homopolymer, is formed. As an extension of an ABP (e.g., PEI and PLL), the resulting modified ABP is also asymmetrically branched. Depending on the solvent environment (i.e., pH or polarity), the surface functional groups can carry different charges and charge densities. The molecular shape and functional group positions (i.e., functional group inverse folding) can then be further adjusted based on these characteristic properties.

[0112] In another embodiment, any of a variety of synthetic schemes can be used to prepare the modified ABP, for example, a synthetic scheme known to readily react with suitable sites on a homopolymer. In addition, any of a variety of reagents can be used in the selected synthetic scheme to achieve any of a variety of modifications or additions to the polymer backbone. Thus, for example, in the case of the Michael addition reaction of the amine described above, the addition of any of a variety of substituents can be used in the alkylation stage, as provided above, for example, using an acrylate, which can include a saturated or unsaturated hydrocarbon, such as a hydrocarbon comprising 1 carbon to about 22 carbons, which can be aliphatic, branched, saturated, aromatic, cyclic, or a combination thereof. In one example, the hydrocarbon can have 2 to 22 carbons, in another example, 4 to 22 carbons, in yet another example, 6 to 22 carbons, in yet another example, 7 to 22 carbons, in yet another example, 8 to 22 carbons, in yet another example, 10 to 22 carbons, in yet another example, 12 to 22 carbons, in yet another example, 14 to 22 carbons, in yet another example, 16 to 22 carbons, in a further example, 18 to 22 carbons, and in yet another example, 20 to 22 carbons. In a specific example, the first end group can include 18 carbons, such as (CH 3 (CH 2 ) 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, etc., and mixtures thereof. Similarly, in the amidation stage in the examples exemplified above, any of the various amines can be used in the methods provided herein and known in the art. For example, EDA, monoethanolamine, tris(hydroxymethyl)aminomethane, alkylamine, allylamine or any amino-modified polymer can be used, including PEG, perfluoropolymers, polystyrene, polyethylene, polydimethylsiloxane, polyacrylate, polymethyl methacrylate, etc., and mixtures thereof. In addition, hydrophobic groups (including aliphatic (e.g., C 1 to about C 22 The attachment of modified ABPs to the modified ABPs may be achieved by reactions such as epoxidation, amidation, Michael addition (including the use of -SH or -NH 2 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. In addition, the hydrophobic and hydrophilic properties as well as the charge density of such homopolymers can be tailored to suit specific application requirements using suitable monomers used to construct the homopolymers and suitable modification reactions. An example of a modified ABP is Figure 5 A modified hyperbranched PEI such as Fig. 6A shown.

[0113] In another embodiment of the present disclosure, the focus of random ABP (e.g., POX) (merged from various reactive chain ends during convergent synthesis) can be capped 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 esters. Alternatively, various initiators can be used to introduce the same type of functional groups at the surface groups where polymerization begins during convergent synthesis (J. Macromol. Sci. Chem. A9 (5), pp. 703-727 (1975)).

[0114] Alkyl surface-modified randomly branched poly(2-ethyloxazoline) with primary amine groups at the focal point of the branched polymer can be prepared using the Litt and Warakomski procedure described above. 3 (CH 2 ) 17 -Br can be used as an initiator for the polymerization of 2-ethyloxazoline via a cationic ring-opening process to generate randomly branched polymers, which are then quenched with N-ten-butyloxycarbonylpiperazine (N-Boc-piperazine) or EDA. End-capping with a large excess of EDA can allow the hydrophobically modified branched poly(2-ethyloxazoline) polymers to be functionalized with primary amine groups at the focal point ( Figure 6B ). Alternatively, the N-Boc-piperazine-terminated hydrophobically modified branched poly(2-ethyloxazoline) polymer can also be deprotected to generate free amino groups at the focal point. In some cases, the polymer can include a modified branched poly(2-ethyloxazoline) functionalized with a primary, secondary or tertiary amine, carboxylate, hydroxyl, alkyl, fluoroalkyl, aryl, PEG, acetate, amide or ester group at the focal point of the polymer, wherein two or more reactive chain ends are combined during convergent synthesis.

[0115] In some cases, the alkyl surface-modified randomly branched poly(2-ethyloxazoline) can have hydroxyl groups at the focal point of the branched polymer. For example, the focal point of the polymer can be dissolved in water (e.g., containing, for example, 1N Na 2 CO 3 ) can be hydrolyzed to, for example, hydroxyl groups.

[0116] In some cases, the focal point of a polymer described herein can include a second end group modified with a hydrophilic moiety.

[0117] The introduction of primary amine groups into hydrophobically modified branched poly(2-oxazoline) homopolymers can enhance drug solubility and generate bioactive agent-induced nanoaggregates (e.g. Figure 7A-7B , Figure 8 , Figure 9A-9B Primary amine groups also allow for the attachment of various targeting groups (e.g., antibodies, antigen-binding portions thereof, antigens, or members of binding pairs) to, for example, hydrophobically modified branched poly(2-oxazoline) polymers ( Figure 10A-10B). This may be particularly useful before mixing the polymer and the bioactive agent (e.g., rapamycin). Such nanoaggregates or nanoparticles containing such targeting groups and modifications thereof can provide targeting capabilities on the nanoaggregates with the bioactive agent (e.g., rapamycin) and enable the release of the bioactive agent preferentially or only at the desired therapeutic location. As described above, when the polymer is used to mix with rapamycin to produce the pharmaceutical composition of the present disclosure, it is preferred that the polymer has 1% to 100% of the second end groups without primary amines.

[0118] As disclosed herein, modified branched polymers (MBPs) (e.g., hydrophobically modified homopolymers, including SBPs, ABPs, or combinations thereof) can be used to generate encapsulating polymers or nanocapsules for dissolving the water-insoluble bioactive agent rapamycin. In an organic solvent environment, the hydrophilic or amphiphilic interior can be poly(2-oxazoline), poly(2-substituted oxazolines), wherein the poly(2-substituted oxazolines) can include poly(2-methyloxazoline), poly(2-ethyloxazoline), poly(2-propyloxazoline), poly(isopropyloxazoline) (PiPOX), or combinations thereof, PEG, PEO, polyphosphonates, etc. The hydrophobic exterior can include aliphatic hydrocarbons (e.g., from C 1 to about C 22 ), aromatic hydrocarbons, polyethylene polymers, polystyrene polymers, perfluoropolymers, polydimethylsiloxanes, polyacrylates, polymethyl methacrylates, etc. In an aqueous environment, the situation is just the opposite. In drug-induced nanoaggregates in an aqueous environment, drug molecules (such as rapamycin or other water-insoluble bioactive agents) can associate with the hydrophobic groups / domains of MBP ( Figure 9A-9B ). The branching density (e.g., from low generation (e.g., star-shaped and comb-shaped homopolymers) to high generation dendrimers and dendritic grafts), and the amount of hydrophobic surface group coverage of the branched homopolymer (e.g., 0% to 100% coverage) can significantly affect homopolymer solubility, which in turn affects the ability to dissolve or adsorb / absorb rapamycin. For example, an increase in branching density and hydrophobe coverage will make the homopolymer more compatible with, for example, rapamycin.

[0119] In further examples, ABPs and SBPs having about 0.1 to about 30% or more surface hydrophobic components by weight are effective in dissolving or dispersing weakly water-soluble or water-insoluble compounds (e.g., rapamycin). In addition, the branched homopolymers used (e.g., POX, PMOX, PEOX, PPOX, PEO / PEG, polyacrylamide, polyphosphate, PVP, and PVA) are soluble in water and various organic solvents, thereby promoting the formation of nanoparticles or nanoaggregates containing, for example, rapamycin. Good water solubility and good hydrophobic drug miscibility in aqueous solution (with or without other organic solvents) make such homopolymers useful for improving the solubility of weakly water-soluble bioactive agents. For example, by reducing the formulation steps, processing time, and the need to use complex and expensive equipment currently used in the pharmaceutical industry, the target homopolymers simplify the manufacturing process and reduce production costs. If additional branching density is required, the SBP or ABP can first be modified using additional groups described herein and then, for example, connected to additional hydrophobic functional groups to enhance the solubility of, for example, rapamycin.

[0120] In one example, the polymer is configured to have an effective branching density, the amount of hydrophobic groups at the polymer surface, or a combination thereof, for encapsulating a water-insoluble bioactive agent (e.g., rapamycin) to form water-soluble nanoaggregates. The effective branching density, the amount of hydrophobic groups at the polymer surface, or a combination thereof can be altered as described above and below.

[0121] In one example, the polymer may have a hydrophobic group (including aliphatic (e.g., C 1 to about C 22 The POX polymer may be a homopolymer of a repeating unit comprising a single monomer or a repeating unit comprising two or more monomers in each repeating unit.

[0122] In some cases, the polymer may comprise an asymmetrically branched polymer (ABP) or a dendritic asymmetrically branched polymer, such as an asymmetrically branched PEOX formed from an initiator and monomers in the ratios disclosed herein. In some cases, the polymer may comprise a randomly branched poly(2-ethyloxazoline) having one or more first end groups (e.g., a hydrophobic moiety disclosed herein) and a second end group located at the focal point of the branched polymer, such as by using, for example, Figure 6B The chain transfer polymerization illustrated herein converges on the synthesis of a reactive linear PEOX polymer to form a modified randomly branched PEOX.

[0123] In some cases, the polymers may have different first end groups and different second end groups. Some examples are Figure 6C As shown: polymer (1) to polymer (4) have -OH as the second terminal group, polymer (5) to polymer (8) have -NH 2 As the second terminal group, polymers (1) and (5) have H as the first terminal group, and polymers (2) and (6) have -CH 3 As the first terminal group, polymers (3) and (7) have C 12 As the first terminal group, polymers (4) and (8) have C 18 As the first end group.Polyoxazoline (POX) polymer can be a linear polymer, a branched polymer or a polymer with a combination of one or more linear parts and one or more branched parts.Polyoxazoline (POX) can include poly-(2-methyloxazoline), poly-(2-ethyloxazoline), poly-(2-propyloxazoline), poly-(isopropyloxazoline) (PiPOX), or a combination thereof.Although the above text describes the specific first end group and the second end group, other first and second groups disclosed herein can be suitable.In some cases, the second end group can include a group modified by amine, amides, imines, imide, carboxyl, hydroxyl, ester, ether, acetate, phosphate, ketone, aldehyde, sulfonate or a combination thereof.The first end group and the second end group can be modified according to methods and processes well known to those skilled in the art.If desired, one or more reagents well known to those skilled in the art, joints or intermediates can be used.

[0124] In any of the pharmaceutical compositions disclosed above and below, the polyoxazoline may comprise a molar ratio of monomer to initiator in the range of 50:1 to 80:1.

[0125] The pharmaceutical composition may 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 (e.g., those comprising PEO, PEG, PMOX or PEOX, polystyrene), and comb-branched dendritic grafts (e.g., those comprising PEOX, PMOX, PEI, polylysine (e.g., branched PLL), polyacrylamide, polyphosphate, PVP, PVA, or a combination thereof). Random asymmetrically branched PEI can be prepared primarily by cationic ring-opening polymerization of cyclic imine monomers with ring strain (e.g., aziridine (ethyleneimine) and azetidine (propyleneimine), or a combination thereof). Additional polymers can simply be mixed with the nanoaggregates disclosed herein. In one example, the nanoaggregates can be mixed with one or more additional polymers after they are formed.

[0126] As used herein, the pharmaceutical compositions, processes, methods and uses disclosed herein throughout this disclosure, the term "biologically active agent" refers to a substance that may be, as disclosed herein, a drug based on a natural or synthetic small molecule, an inorganic-based drug, a biopharmaceutical, a drug based on a natural or synthetic macromolecule, a modification and / or derivative thereof, or a combination thereof. The biologically active agent may include a drug based on a natural or synthetic small molecule, an inorganic-based drug, a biopharmaceutical, a drug based on a natural or synthetic macromolecule, a modification and / or derivative thereof, or a combination thereof, wherein at least one of the drugs is poorly water soluble or water insoluble. The drug of interest may be a small molecule, a salt thereof, in which the molecule is modified to be water insoluble or poorly water soluble, or may be a biomolecule modified to be water insoluble or poorly water soluble, particularly when the water insoluble or poorly water soluble form of the drug has improved properties, such as improved bioavailability, lower toxicity, better pharmacokinetics, or a combination thereof. Suitable examples may include drugs that are poorly soluble or insoluble in water, or drugs that have been modified to be water insoluble or poorly soluble in water to have improved properties. Bioactive agents may include growth agents, AIDS adjunct agents, alcohol abuse products (e.g., agents used to treat dependence or withdrawal), Alzheimer's disease therapeutics, amyotrophic lateral sclerosis therapeutics, analgesics, anesthetics, anticonvulsants, antidiabetics, antidotes, antifibrotic therapeutics, antihistamines, antioxidants (e.g., dyes and pigments, such as astaxanthin), anti-infectives (e.g., antibiotics, antivirals, antifungals, amebicides, anthelmintics, antimalarials, antileprosy drugs, etc.), antitumor drugs, antiparkinsonian drugs, antirheumatic drugs, appetite stimulants, biological response modifiers, biological preparations, blood regulators (e.g., anticoagulants, colony stimulating factors, hemostatics, plasma volume expanders, thrombin inhibitors, etc.), bone metabolism regulators, cardioprotective agents, cardiovascular drugs (e.g., adrenergic blockers, adrenergic stimulants, angiotensin converting enzyme (ACE) inhibitors, antiarrhythmic drugs, antilipidemic drugs, calcium channel blockers, diuretics, pressors, etc.), central nervous system (CNS) stimulants, cholinesterase inhibitors, contraceptives, fertility treatment drugs, ovulation stimulants, cystic fibrosis management agents (management agents), detoxifying agents, diagnostic agents, dietary supplements, dopamine receptor agonists, endometriosis treatments, enzymes, erectile dysfunction treatments, foot care products, gastrointestinal (GI) treatments (e.g., antacids, antidiarrheals, antiemetics, antiflatulence, bowel emptying drugs, digestive enzymes, histamine receptor agonists, laxatives, proton pump inhibitors, prostaglandins, etc.), Gaucher'sDisease treatments, gout treatments, homeopathic medicines, skin treatments, vitamins, nutrients, hormones, hypercalcemia treatments, hypocalcemia treatments, immunomodulators, immunosuppressants, L-carnitine deficiency treatments, mast cell stabilizers, migraine treatments, motion sickness treatments (e.g., benadryl and phenergan), decongestants, antihistamines, cough suppressants, multiple sclerosis treatments, muscle relaxants, nasal treatments (e.g., anti-inflammatory drugs), smoking cessation aids cessationaid), appetite suppressants, nucleoside analogs, obesity treatment agents, ophthalmic products (e.g., antibiotics, antiglaucoma agents, artificial tears, lubricants, etc.), sexual aids, osteoporosis treatment agents, ear products (e.g., anti-infectives and cerumenolytics), minerals, oxytocin, parasympathetic blockers, parasympathomimetics, patent ductus arteriosus drugs, phosphate binders, porphyria drugs, prostaglandins, psychotherapeutics, contrast media, respiratory drugs (e.g., anti-inflammatory drugs, antitussives, bronchodilators, decongestants, expectorants, leukotriene antagonists, surfactants, etc.), salt substitutes, sedatives, hypnotics, skin and mucosal treatments (e.g., acne treatments), anorectal treatments (e.g., hemorrhoid treatments and enemas), antiperspirants, antipruritics, antipsoriatics, antiseborrheic agents, burn treatments, cleansers, depigmenting agents, emollients, hair growth retardants, hair growth stimulants, keratolytics, hair problem treatments, mouth and throat problem treatments, photosensitizers, wart treatments, wound care treatments, or a combination thereof. Biologically active agents may also include over-the-counter drugs and products (e.g., deodorants), Tourette syndrome drugs, tremor treatments, urinary tract drugs (e.g., acidifiers, alkalizers), antispasmodics, benign prostatic hyperplasia treatments, calcium oxalate stone preventives, enuresis treatments, vaginal products (e.g., anti-infectives, hormones, etc.), vasodilators, vertigo treatments, Wilson's disease treatments, etc.

[0127] Further examples of bioactive agents may include unmodified or other forms of the drug that may be modified, for example, into salts, ionized forms, or hydrophilic forms that may be modified to remove such functional groups, modifications, etc. to produce poorly water soluble or water insoluble bioactive agents. If the pharmaceutical composition comprises two or more bioactive agents, at least one of the bioactive agents may be modified or has been modified to be water insoluble or poorly water soluble. Examples of such bioactive agents may 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, triethanolamine salicylate, nalbuphine hydrochloride, mefenamic acid, butorphanol tartrate, choline salicylate, butalbital, phenyltoloxamine citrate, diphenhydramine citrate, methoxythiazine, cinnamedrine hydrochloride, hydrochloride), meprobamate, etc.); anesthetics (e.g., cyclopropane, enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, propofol, etc.); antiasthmatics (e.g., azelastine, ketotifen, traxanox, amlexanox, sodium cromoglycate, ibudilast, montelukast, nedocromil, oxamol, pranlukast, serotonin, supelalast toluene, thiamide, zafirlukast, zileuton, beclomethasone, budesonide, dexamethasone, flunisolide, triamcinolone acetonide, etc.); antibiotics (e.g., neomycin, streptomycin, chloramphenicol, cephalosporin, ampicillin, penicillin, tetracycline, etc.); quinolones, fluoroquinolones, antidepressants (e.g., nefopam, oxypredine, hydrochloride Doxepin, amoxapine, trazodone hydrochloride, amitriptyline hydrochloride, maprotiline hydrochloride, phenelzine sulfate, desipramine hydrochloride, nortriptyline hydrochloride, phenylcypromine sulfate, fluoxetine hydrochloride, doxepin hydrochloride, imipramine hydrochloride, imipramine pamoate, nortriptyline, amitriptyline hydrochloride, isocarboxazid, trimipramine maleate, protriptyline hydrochloride, etc.); antidiabetic drugs (such as biguanides, hormones, sulfonylurea derivatives, etc.); antifungal drugs (such as griseofulvin, ketoconazole, amphotericin B, nystatin, candidiasis, etc.); antihypertensive drugs (such as propranolol, propafenone, oxprenolol, nifedipine, reserpine, trimethaphan camsylate), phenoxybenzamine hydrochloride, pargyline hydrochloride, deserpidine, diazoxide, guanethidine monosulfate, minoxidil, rescinnamine, sodium nitroprusside, Rauvolfiaserpentina, Rauvolfiaserpentina mixed base, phentolamine mesylate, reserpine, etc.);Anti-inflammatory drugs (e.g., nonsteroidal compounds, such as indomethacin, naproxen, ibuprofen, ramifenazone, piroxicam, etc.; steroidal compounds, such as cortisone, dexamethasone, fluazacort, hydrocortisone, prednisolone, prednisone, etc.); antineoplastic drugs (e.g., doxorubicin, cyclophosphamide, dactinomycin, bleomycin, daunorubicin, doxorubicin, epirubicin, gemcitabine, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (a β-chloronitrosourea (BCNU) compound), 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.); antianxiety drugs (e.g. lorazepam, buspirone hydrochloride, prazepam, chlordiazepoxide hydrochloride, oxazepam, clorazepate potassium dipotassium), diazepam, hydroxyzine pamoate, hydroxyzine hydrochloride, alprazolam, droperidol, halazepam, chlormezazone, dantrolene, etc.); immunosuppressants (e.g. cyclosporine, azathioprine, mizoribine, FK506 (tacrolimus), rapamycin (sirolimus), etc.); anti-migraine drugs (e.g. ergotamine tartrate, propranolol hydrochloride, isometheptene galactoate, etc.); mucate, dichloralphenazone, etc.); sedatives / hypnotics (e.g., barbiturates (e.g., pentobarbital, sodium pentobarbital, sodium secobarbital, etc.) or benzodiazepines (e.g., flurazepam hydrochloride, triazolam, tomazepam, midazolam hydrochloride, etc.); antianginal drugs (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.); tetranitrate, 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, mexiletine hydrochloride, disopyramide phosphate, procainamide hydrochloride, quinidine sulfate, quinidine gluconate, quinidine polygalacturonate, flecainide acetate, tocamide hydrochloride) hydrochloride, lidocaine hydrochloride, etc.); antiarthritis drugs (such as phenylbutazone, sulindac, penicillamine, salsalate, piroxicam, azathioprine, indomethacin, meclofenamic acid sodium, gold sodium thiomalate, ketoprofen, auranofin, aurothioglucose, tolmetin sodium, etc.); antigout drugs (such as colchicine, allopurinol, etc.); anticoagulants (such as heparin, heparin sodium, warfarin sodium, etc.); thrombolytic drugs (such as urokinase, streptokinase, altoplase, etc.); antifibrinolytic drugs (such as ammonia hexanoic acid); blood activators (e.g., pentoxifylline); antiplatelet agents (e.g., aspirin, empirin, ascriptin, etc.); anticonvulsants (e.g., valproic acid, divalproex sodium, phenytoin, phenytoin sodium, clonazepam, primidone, phenobarbital, phenobarbital sodium, carbamazepine, amobarbital sodium, methsuximide, metharbital, mephenytoin, phensuximide, methyphenytoin, ethotoin, phenylacetylurea, secobarbital sodium sodium), clorazepate, trimethadione, etc.); anti-parkinsonian 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, diphenylpyralidone hydrochloride, phenindamine tartrate, azatadine maleate, tripeliramine hydrochloride, dexchlorpheniramine maleate, maleate), medimethazine hydrochloride, isobutrazol tartrate, etc.); agents that can be used for calcium regulation (e.g., calcitonin, parathyroid hormone, etc.); antibacterial drugs (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, polymyxin E sodium mesylate, colistin sulfate, etc.); antiviral drugs (e.g., interferon gamma, zidovudine, amantadine hydrochloride, ribavirin, acyclovir, etc.);Antimicrobial drugs (such as cephalosporins (such as cefazolin sodium, cephradine, cefaclor, cefpirin sodium, ceftizoxime sodium, cefoperazone sodium, cefotetan disodium, cefuroxime axetil, ceftriaxone sodium, cefotaxime sodium, cefadroxil monohydrate, ceftazidime, cephalexin, ceftriaxone sodium, cefonic acid sodium, cefuroxime hydrochloride monohydrate, cefmandolin sodium, cefoxitin sodium, cefonic acid sodium, cefuroxime sodium, cefuroxime sodium, cefuroxime sodium, cefuroxime sodium, etc.), penicillins (such as ampicillin, amoxicillin, benzathine penicillin G, cyclacillin, ampicillin sodium, penicillin GK, penicillin VK, piperacillin sodium, oxacillin sodium, baclofen hydrochloride The invention relates to the treatment of inflammatory inflammatory diseases such as inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, and inflammatory bowel disease. The invention relates to the treatment of inflammatory inflammatory diseases such as inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, sulfate), albuterol, bitolterol, isoproterenol mesylate hydrochloride, terbutaline sulfate, epinephrine bitartrate, orproterenol sulfate, epinephrine, epinephrine bitartrate); anticholinergics (e.g. ipratropium bromide); xanthines (e.g. aminophylline, diprophylline, orproterenol sulfate, aminophylline); mast cell stabilizers (e.g. sodium cromoglycate); 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, orproterenol sulfate, salbutamol, flunisolide, etc.);Hormones (e.g. androgens (e.g. danazol, testosterone cypionate, fluoxymesterone, ethyltostosterone, testosterone enanthate, methyltestosterone, fluoxymesterone, testosterone cypionate, etc.), estrogens (e.g. estradiol, estrone sulfate piperazine (estropipate), conjugated estrogens, etc.), progestins (e.g. medroxyprogesterone acetate, norethisterone 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, hydroxyflurane, hydrocortisone, hydrocortisone cypionate, prednisolone, fludrocortisone acetate, paramethasone acetate, prednisolone tert-butyl acetate (prednisolone tebulate), prednisolone acetate, prednisolone sodium phosphate, hydrocortisone sodium succinate, etc.), thyroid hormones (e.g., levothyroxine sodium); etc.); hypoglycemic drugs (e.g., human insulin, purified bovine insulin, purified porcine insulin, glyburide, chlorpropamide, glipizide, tolbutamide, tolazamide, etc.); lipid-lowering drugs (e.g., clofibrate, dextrothyroxine sodium, probucol, lovastatin, niacin, etc.); proteins (e.g., DNA enzymes, alginase, superoxide dismutase, lipase, etc.); nucleic acids (e.g., sense nucleic acids or antisense nucleic acids encoding any therapeutically useful protein (including any protein described herein), etc.); drugs that can be used for erythropoiesis (e.g., erythropoietin); anti-ulcer or anti-retroviral Flow agents (e.g., famotidine, cimetidine, ranitidine hydrochloride, etc.); antinauseants or antiemetics (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, halogenated nitrosoureas, anthracyclines, ellipticine, etc.; STING inhibitors such as C-176, C-170, and C-171; interferon gene stimulator (STING) activators such as 3',3'-cGAMP (3',3'-cyclic GMP-AMP, cyclic GMP-AMP, cGAMP); STING agonists such as SR-717 lithium, α-mangostin or diABZI;STING agonist (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, 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, Navoximod, Indoximod, NLG802 (indoximod prodrug) or LY3381916; and combinations thereof. ;

[0128] In some cases, the bioactive agent may comprise any one of the bioactive agents listed above and below. In some cases, the bioactive agent may comprise two or more of the bioactive agents listed above and below.

[0129] In some cases, in any pharmaceutical composition disclosed herein, the bioactive agent may include a drug based on natural or synthetic small molecules, an inorganic-based drug, a biological drug, a drug based on natural or synthetic macromolecules, a derivative thereof, or a combination thereof.

[0130] In some cases, the bioactive agent may comprise an immunoglobulin, such as IgG, IgM, or one or more molecules disclosed and prepared according to the processes and methods described in US Pat. No. 10,688,048, which is hereby incorporated by reference in its entirety.

[0131] In some cases, the bioactive agent may include a taxane, paclitaxel, docetaxel, cabazitaxel, larotaxel, milatataxel, ortataxel, tesetaxel, topoisomerase 1 (Top 1) inhibitors, camptothecin derivatives, irinotecan (CPT-11), SN-38, topotecan, topoisomerase 2 (Top 2) inhibitors, doxorubicin, etoposide, ciprofloxaxin, mammalian target of rapamycin (mTOR) inhibitors, at least one STING polypeptide or a portion thereof, a nucleic acid encoding the STING polypeptide or a portion thereof, a STING inhibitor, a STING activator, a STING agonist, a STING antagonist, a STING regulatory molecule, an IDO inhibitor, an IDO1 inhibitor, or a combination thereof, wherein the mTOR inhibitor comprises everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, veltusertib, defostiolimus, one or more dual phosphopinositide 3-kinase (PI3K)-mTOR inhibitors, one or more ATP-competitive mTORC1 / 2 inhibitors, derivatives thereof, or a combination thereof.

[0132] In some cases, the bioactive agent may include 7-ethyl-10-hydroxycamptothecin (SN-38). In some cases, the bioactive agent may include 7-ethyl-10-hydroxycamptothecin (SN-38), irinotecan (also known as Camptosar, Campto, Onivyde, CPT-11), camptothecin (CPT), topotecan, or a combination thereof.

[0133] In some cases, the biologically active agent may comprise at least one STING polypeptide or a portion thereof, a nucleic acid encoding the STING polypeptide or a portion thereof, a STING inhibitor, a STING activator, a STING agonist, a STING antagonist, a STING modulator, an IDO inhibitor, an IDO1 inhibitor, or a combination thereof. The biologically active agent may comprise RNA, mRNA, siRNA, a single guide RNA (sgRNA), DNA, an oligonucleotide, or a combination thereof, each of which encodes one of the above-mentioned STING polypeptides or portions thereof, STING inhibitors, STING activators, STING agonists, STING antagonists, STING modulators, IDO inhibitors, or IDO1 inhibitors.

[0134] In some cases, the bioactive agent may 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 may include one or more IDO or IDO1 inhibitors. Any STING protein, STING agonist, STING activator, STING inhibitor, STING antagonist, IDO inhibitor or IDO1 inhibitor disclosed herein or found thereafter may be suitable. In some cases, the bioactive agent may include a STING regulatory molecule, such as a benzimidazole compound disclosed in patent publications WO2017175156A1 and WO2020156363 by Liu et al. (Cell Research, 1-19, 2022), a pyridyl imidazole compound disclosed in patent publications WO2019134705, WO2020010451 and US20200031825, or a combination thereof.

[0135] In some cases, the bioactive agent may include one or more STING agonists. In some cases, the STING agonist may include one or more compounds having formula (1)-(29): Figure 12A-12E ),

[0136]

[0137]

[0138]

[0139]

[0140]

[0141] Its corresponding salts, solvates, prodrugs, isomers, or combinations thereof.

[0142] In some cases, the bioactive agent may comprise a compound having the formula:

[0143] Formula (1)

[0144]

[0145] Formula (4)

[0146]

[0147] A pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

[0148] In some cases, the bioactive agent may include a topoisomerase 1 (Top 1) inhibitor, a camptothecin derivative, irinotecan (CPT-11), SN-38, topotecan, a topoisomerase 2 (Top2) inhibitor, doxorubicin, etoposide, ciprofloxacin, or a combination thereof. SN-38 (7-ethyl-10-hydroxycamptothecin) having the chemical structure Fig.13A ) is a topoisomerase 1 (Top1) inhibitor. Throughout this disclosure, the terms "7-ethyl-10-hydroxycamptothecin" and "SN-38" are used interchangeably. Irinotecan ( Fig. 13B ) (also known as Campto, )CPT-11 ((S)-(+)-7-ethyl-10-hydroxycamptothecin-10-[1,4'-bipiperidinyl]-1'-carboxylate monohydrochloride) is a water-soluble camptothecin analog and a prodrug of SN-38. Irinotecan can be converted into SN-38 by metabolism in the body (Chabot GG. Clinic alpharmacokinetics of irinotecan, Clin. Pharmacokonet. 1997, 33(4), 245-259). Camptothecin (CPT) ( Fig. 13C ) is a pentacyclic monoterpene alkaloid naturally occurring in the bark and stems of Camptotheca acuminata. Topotecan (also known as Hycamtin) ( Fig.13D ) is also a water-soluble camptothecin derivative, and both intravenous and oral forms have been approved. Examples of SN-38 antibody-drug conjugates (ADCs) (SN-38ADCs) may include those under their respective trademarks. (hRS7-SN38ADC)( Fig.13E ).

[0149] In some cases, nano-aggregates are water-soluble and may include polymers and at least one water-insoluble or weakly water-soluble bioactive agent. The pharmaceutical composition comprising nano-aggregates is soluble in an aqueous solution to produce at least 1 mg / mL of a bioactive agent dissolved in the aqueous solution. In some cases, the pharmaceutical composition comprising nano-aggregates is soluble in an aqueous solution to produce at least 2 mg / mL of a bioactive agent disclosed herein or a combination thereof dissolved in the aqueous solution. In some cases, the pharmaceutical composition comprising nano-aggregates is soluble in an aqueous solution to produce 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 a bioactive agent disclosed herein or a combination thereof dissolved in the aqueous solution.

[0150] Any polymer disclosed herein can be suitable.In some instances, polymer can include poly-oxazoline (POX), it comprises linear part, branched part or its combination, and wherein poly-oxazoline (POX) includes poly-(2-oxazoline), poly-(2-methyloxazoline), poly-(2-ethyloxazoline), poly-(2-propyloxazoline), poly-(isopropyloxazoline) (PiPOX) or its combination.In some instances, poly-oxazoline can be poly-(2-ethyloxazoline).

[0151] As used throughout the present disclosure, the size of the nanoaggregate before lyophilization may be less than 150nm. In some cases, the size of the nanoaggregate before lyophilization may be less than 120nm. "Less than" means that the size may be less than the defined size (nm) and may be about 0nm, i.e., the nanoaggregate solution may be a clear solution without measurable particles or aggregates. For example, "less than 150nm" refers to within the range of 0nm to 150nm, and "less than 120nm" refers to within the range of 0nm to 120nm. In some cases, the size of the nanoaggregate or nanoparticle before lyophilization may be from about 0.01nm to about 100nm. In some cases, the size of the nanoaggregate or nanoparticle before lyophilization may be from about 0.01nm to about 120nm. In some cases, the size of the nanoaggregate or nanoparticle before lyophilization may be from about 0.01nm to about 150nm. In some cases, the size of the nanoaggregate or nanoparticle before lyophilization may be from about 50 to about 100nm. In some cases, the size of the nanoaggregates or nanoparticles before lyophilization can be about 50 to about 120 nm. Particle size can be measured by light scattering.

[0152] In some cases, the pharmaceutical compositions of the present disclosure (wherein the nanoaggregates may further comprise a targeting moiety) comprise an antibody, an antigen binding portion thereof, an antigen, a cell receptor, a cell receptor ligand, a ligand of a cell protein, a ligand of a membrane protein, a small molecule ligand, a lectin ligand, or a combination thereof.

[0153] In some cases, the nanoaggregates may be free of human serum albumin, organic solvents, detergents, or oils. In some cases, the nanoaggregates may be free of human serum albumin, organic solvents, detergents, oils, or free acids. In some cases, the nanoaggregates may be free of human serum albumin. In some cases, the nanoaggregates may be free of organic solvents. In some cases, the nanoaggregates may be free of detergents. In some cases, the nanoaggregates may be free of oils. In some cases, the nanoaggregates may be free of free acids. In some cases, the nanoaggregates may be free of substances selected from human serum albumin, organic solvents, detergents, oils, free acids, and combinations thereof.

[0154] In some cases, the pharmaceutical composition may be free of human serum albumin, organic solvents, detergents, or oils. In some cases, the pharmaceutical composition may be free of human serum albumin, organic solvents, detergents, oils, or free acids. In some cases, the pharmaceutical composition may be free of human serum albumin. In some cases, the pharmaceutical composition may be free of organic solvents. In some cases, the pharmaceutical composition may be free of detergents. In some cases, the pharmaceutical composition may be free of oils. In some cases, the pharmaceutical composition may be free of free acids. In some cases, the pharmaceutical composition may be free of substances selected from human serum albumin, organic solvents, detergents, oils, free acids, and combinations thereof.

[0155] In some cases, the bioactive agent may include one or more STING agonists. In some cases, the bioactive agent may include at least a compound having formula (1) to formula (29), a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof ( Figure 12A-12E ).

[0156] In some cases, the bioactive agent may comprise a compound having the formula:

[0157] Formula (1)

[0158]

[0159] Formula (4)

[0160]

[0161] A pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

[0162] The pharmaceutical composition of the present disclosure may be a drug for treating or preventing a disease selected from one or more immune diseases, infectious diseases, cancers, and combinations thereof. Immune diseases may include immunodeficiency diseases, overactive immune diseases, autoimmune diseases, and other diseases or symptoms with abnormal immune systems. In some cases, immune diseases may be various autoinflammatory, autoimmune, and degenerative diseases, such as those associated with the STING (interferon gene stimulator) signaling pathway or the IDO pathway. In some cases, immune diseases may be associated with inflammation, cell stress, and tissue damage mediated by STING in infections. In some cases, the pharmaceutical composition of the present disclosure may be a drug for cancer immunotherapy based on immune checkpoint blockade. In some cases, the pharmaceutical composition of the present disclosure may include STING protein, STING agonist, STING activator, STING inhibitor, STING antagonist, IDO inhibitor, IDO1 inhibitor, or a combination thereof. In some cases, the pharmaceutical composition of the present disclosure may include one or more STING inhibitors. In some cases, the pharmaceutical composition of the present disclosure may include one or more STING activators.

[0163] The terms "cancer" and "cancers" as used herein and throughout this disclosure refer to cancer or tumors, which may include malignant tumors and benign tumors, such as solid tumors and cancers of the blood, such as leukemia. Malignant tumors can spread into or invade nearby tissues. In addition, as these tumors grow, some cancer cells can break away and move to distant parts of the body through the blood or lymphatic system, forming new tumors (metastases) away from the original tumor (primary cancer). Cancer may include primary cancer or metastases. The pharmaceutical compositions disclosed herein may be cancer therapeutic drugs for treating one or more cancers. In some cases, the term "cancer" as used herein may include one or more cancers selected from acoustic neuroma, acute lymphoblastic leukemia (adults), acute lymphoblastic leukemia (children), acute myeloid leukemia, adenocarcinoma, anal cancer, anemia and neutropenia (low red and white blood cell counts), 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), bile duct cancer, biliary track cancer, bladder cancer, bladder cancer. carcinoma), 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, bronchial cancer, 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 carcinoma, colorectal cancer (CRC), diffuse large B-cell lymphoma, ependymoma, esophageal cancer, gallbladder and bile duct cancer, gastric cancer (gastriccancer), germ cell tumor, 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 lymphoma, kidney cancer, leukemia, liver cancer, lung cancer, lung cancer (early and locally advanced non-small cell lung cancer (NSCLC)), lung cancer (metastatic non-small cell lung cancer), lung cancer NSCLC (non-small cell lung cancer), lung cancer (small cell lung cancer), lymphoid malignancies, malignant pleural mesothelioma, medullary carcinoma, medullary thyroid cancer, Medulloblastoma, melanoma, meningioma, multiple myeloma, mycosis fungoides / Sezary syndrome, myelodysplastic syndrome, myeloproliferative neoplasms, neuroblastoma, neuroendocrine tumors (advanced), neuroendocrine tumors, oligodendroglioma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, papillary thyroid cancer, peripheral T-cell lymphoma, perivascular epithelioid cell (PEC) tumor (PEComa), perivascular epithelioid cell tumor (advanced unresectable or metastatic malignancy), pheochromocytoma, pineal tumor, primary cutaneous lymphoma (Primary Cutaneous Lymphomas), Prostate Cancer, Prostate Cancer (Advanced), Prostate Cancer (Early), Rectal Cancer, Recurrent Endometrial Cancer, Recurrent ER(+) High-Grade Ovarian Cancer, Recurrent or Refractory Non-Hodgkin Lymphoma, Kidney Cancer (Metastatic Clear Cell), Renal Cell Carcinoma, Retinoblastoma with Brain Metastasis, Schwannoma, Craniopharyogioma, Sebaceous Gland Carcinoma, Seminomas, Soft Tissue Sarcomas, Squamous Cell Carcinomas, Squamous Cell Skin Cancers, Stomach Cancer, Sweat Gland Carcinomas, Systemic Mastocytosis, Testicular Tumors, Thyroid Cancer, Uterine Cancer, Uterine Sarcomas, Waldenstrom's Macroglobulinemia ( Macroglobulinemia) and combinations thereof.

[0164] In some cases, one or more cancers can be selected from any of the above-mentioned cancers.In some cases, one or more cancers can be selected from thyroid cancer, recurrent ER (+) high-grade ovarian cancer, ER (+) locally advanced or metastatic breast cancer, advanced neuroendocrine tumors, diffuse large B-cell lymphomas, advanced solid tumors, metastatic clear cell renal carcinoma, recurrent or refractory non-Hodgkin lymphoma, chronic lymphocytic lymphoma, recurrent endometrial cancer, perivascular epithelial cell tumor (PEComa), late unresectable or metastatic malignant perivascular epithelial cell tumor, ovarian cancer, lung cancer, NSCLC (non-small cell lung cancer), small cell lung cancer, biliary cancer, bladder cancer, cervical cancer, soft tissue sarcoma, uterine sarcoma, colon cancer, gastric cancer, melanoma, head and neck cancer, pancreatic cancer, one or more metastatic cancers produced therefrom, and combinations thereof.In some cases, one or more cancers can be late unresectable or metastatic malignant perivascular epithelial cell tumor (PEComa).

[0165] The pharmaceutical composition of the present disclosure may be a medicament for treating or preventing one or more of the diseases disclosed herein.

[0166] In some cases, the pharmaceutical composition may include two or more bioactive agents, wherein 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 may include paclitaxel and one or more additional bioactive agents disclosed herein that are different from paclitaxel. In some cases, the pharmaceutical composition may include rapamycin and one or more additional bioactive agents selected from gemcitabine, paclitaxel, docetaxel, cabazitaxel, larotaxel, milatataxel, ortataxel, tesetaxel, temozolomide, platinum-based antineoplastic agents, daunorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (bischloroethyl nitrosourea, also known as BCNU or BiCNU), methyl-CCNU, cisplatin, vinorelbine, capecitabine, and combinations thereof. In some cases, the pharmaceutical composition may include two or more bioactive agents in nanoaggregates. In some cases, the pharmaceutical composition may include at least one water-insoluble or poorly water-soluble bioactive agent, such as rapamycin, and one or more additional bioactive agents (which may be contained in the nanoaggregates or not contained in the nanoaggregates) in the nanoaggregates. The pharmaceutical composition may comprise a nanoaggregate comprising a polymer and two or more bioactive agents that are each water-insoluble or weakly water-soluble. The pharmaceutical composition may comprise a nanoaggregate comprising a polymer and at least one water-insoluble or weakly water-soluble bioactive agent, and one or more additional bioactive agents that are each water-soluble. In one example, the pharmaceutical composition may comprise a nanoaggregate comprising rapamycin, a taxane, and gemcitabine, in another example a nanoaggregate comprising rapamycin and a taxane, and in yet another example a nanoaggregate comprising rapamycin and temozolomide.

[0167] The term "combination thereof" used for the combinations of bioactive agents disclosed above refers to a combination of two or more bioactive agents, wherein such combination does not have an unwanted effect, such as an unwanted interaction between or among the bioactive agents. It should be understood that some combinations of bioactive agents may be inappropriate, or may be undesirable, such as those with unwanted interactions. For example, a combination of theophylline and ciprofloxacin or warfarin and diflunisal may be inappropriate. Thus these combinations or any combination determined to be inappropriate by appropriate guidelines or regulations are excluded.

[0168] The pharmaceutical composition of the present invention disclosed herein may include 1 mg / mL to 10 mg / mL of rapamycin dissolved in an aqueous solution, which does not contain human serum albumin, organic solvents, detergents, or oils. The pharmaceutical composition of the present invention disclosed herein may include 1 mg / mL to 10 mg / mL of rapamycin dissolved in an aqueous solution, which does not contain human serum albumin, organic solvents, detergents, oils, or free acids. Rapamycin itself is insoluble in water. In one example, the pharmaceutical composition of the present invention may include 1 mg / mL to 10 mg / mL of rapamycin dissolved in an aqueous solution, 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 another example, 3 mg / mL to 10 mg / mL in another example, 3 mg / mL to 6 mg / mL in another example, or 3 mg / mL to 5 mg / mL in another example, which does not contain human serum albumin, organic solvents, detergents, oils, or free acids.

[0169] As described above, the size of the nano aggregates before freeze drying may be less than 150nm. In some cases, the size of the nano aggregates before freeze drying may be less than 120nm. In some cases, the size of the nano aggregates before freeze drying may be in the range of about 0.01nm or about 0nm to about 150nm. The size of the nano aggregates before freeze drying may be in the range of about 50nm to about 150nm. In some cases, the size of the nano aggregates or nanoparticles before freeze drying may be about 50 to about 100nm. In some cases, the size of the nano aggregates or nanoparticles before freeze drying may be about 50 to about 120nm. In another example, the size of the nano aggregates before freeze drying may be in the range of about 70 to 90nm. The particle size may be measured by light scattering.

[0170] In any of the pharmaceutical compositions disclosed above and below, the nanoaggregates may have a weight ratio of polymer to bioactive agent in the range of about 2:1 to about 200:1. The nanoaggregates may have a weight ratio of polymer to bioactive agent in the range of about 2:1 to about 200:1 in one example, about 2:1 to about 150:1 in another example, about 2:1 to about 120:1 in yet another example, about 2:1 to about 100:1 in yet another example, about 2:1 to about 80:1 in yet another example, about 2:1 to about 60:1 in yet another example, about 2:1 to about 40:1 in yet another example, about 2:1 to about 30:1 in yet another example, and about 2:1 to about 40:1 in yet another example. In one example, about 2:1 to about 20:1, in another example, about 2:1 to about 15:1, in another example, about 2:1 to about 10:1, in another example, about 2:1 to about 8:1, in another example, about 5:1 to about 10:1, in another example, about 5:1 to about 8:1, in another example, 5:1, in another example, about 6:1 to about 8:1, in another example, 6:1, in another example, 7:1, in another example, 7.5:1, and in another example, 8:1. When the pharmaceutical composition comprises two or more bioactive agents, the ratio of the polymer to the bioactive agent can be based on the total weight of the polymer and the bioactive agent.

[0171] In some cases, the pharmaceutical composition of interest may be an adjuvant for a vaccine.

[0172] In some cases, the pharmaceutical composition may be a prophylactic vaccine, a therapeutic vaccine, or a combination thereof, wherein the pharmaceutical composition may further comprise at least one immunizing agent for stimulating an immune response in a subject in need thereof. The immunizing agent may comprise an inactive microbe selected from bacteria, viruses, fungi, protozoa, worms, parasites, prions, parts thereof, or a combination thereof; a toxin, a nucleic acid encoding a toxin; a protein; a nucleic acid encoding a protein; an oligonucleic acid; a DNA; an RNA; an mRNA; an siRNA; an sgRNA; a fragment thereof; or a combination thereof.

[0173] In some cases, the pharmaceutical composition can be formulated to treat or prevent at least one infectious disease. In some cases, the pharmaceutical composition can be formulated to treat or prevent at least one infectious disease selected from chickenpox, coronavirus, dengue fever, diphtheria, Ebola, influenza, hepatitis, Hib disease, HIV / AIDS, human papillomavirus (HPV), Japanese encephalitis, measles, meningococcal disease, monkeypox, mumps, norovirus, pneumococcal disease, poliomyelitis, rabies, respiratory syncytial virus (RSV), rotavirus, rubella (German measles), herpes zoster, tetanus, pertussis, Zika, and combinations thereof.

[0174] 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 can be measured in an aqueous solution of the pharmaceutical composition.

[0175] In some cases, a pharmaceutical composition may comprise one or more bioactive agents disclosed herein, derivatives thereof, or combinations thereof, wherein 1% to 100% of the second end groups do not contain primary amines, and wherein 1% to 100% of the second end groups comprise hydroxyl groups.

[0176] In some cases, the pharmaceutical composition may include an mTOR inhibitor comprising everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, veltorinostat, rifolimus, a derivative thereof, or a combination thereof, wherein 1% to 100% of the second end groups do not contain a primary amine, and wherein 1% to 100% of the second end groups contain a hydroxyl group.

[0177] In some cases, the pharmaceutical composition may include an mTOR inhibitor comprising everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, veltorinostat, rifolimus, a derivative thereof, or a combination thereof, wherein 50% to 100% of the second end groups do not contain a primary amine, and wherein 50% to 100% of the second end groups contain a hydroxyl group.

[0178] In some cases, the pharmaceutical composition may include an mTOR inhibitor comprising everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, veltorinostat, rifolimus, a derivative thereof, or a combination thereof, wherein 80% to 100% of the second end groups do not contain a primary amine, and wherein 80% to 100% of the second end groups comprise a hydroxyl group.

[0179] In some cases, the pharmaceutical composition may include an mTOR inhibitor comprising everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, veltorinostat, rifolimus, a derivative thereof, or a combination thereof, wherein 90% to 100% of the second end groups do not contain a primary amine, and wherein 90% to 100% of the second end groups comprise a hydroxyl group.

[0180] In some cases, the pharmaceutical composition may further comprise one or more subsequent biologically active agents selected from proteins, peptides, antibodies, fragments of antibodies, compounds, small molecule drugs, one or more chemotherapeutic drugs, and combinations thereof.

[0181] The pharmaceutical compositions disclosed above and below may further comprise an additional bioactive agent that is formulated without a polymer, particularly a polymer disclosed herein. The phrase "an additional bioactive agent formulated without a polymer" refers to a bioactive agent formulation comprising a bioactive agent and without a polymer disclosed herein, wherein the additional bioactive agent may 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 specific example, the additional taxane does not contain a polyoxazoline (POX) polymer disclosed herein. In some cases, in one example, the pharmaceutical composition may comprise an additional taxane formulated with human serum albumin, in another example, with ethanol or In one embodiment, the taxane is formulated with polyethoxylated castor oil, in another embodiment, a taxane modified with an acid, ammonium, alkyl or aryl group, in another embodiment, a taxane formulated in a lipid, in another embodiment, a taxane formulated in a cationic lipid, and in another embodiment, a combination thereof. Commercially available taxane formulations (e.g., available from Celgene under the respective trademarks) include taxanes formulated with polyethoxylated castor oil, in yet another embodiment, taxanes modified with an acid, ammonium, alkyl or aryl group, in yet another embodiment, taxanes formulated in a lipid, in yet another embodiment, a taxane formulated in a cationic lipid, and in another embodiment, a combination thereof. and 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 comprises Taxol, and in yet another embodiment comprises a combination of Abraxane and Taxol.

[0182] The term "soluble in aqueous solution" means that the solution contains no detectable particles or has a particle size that can be filtered through a 0.22 μm filter (filtration rating (R f ) in the range of 50% to 100%. As used throughout this disclosure, the term "0.22 μm filter" refers to a filter device having a filtration pore size of 0.22 μm. The term "0.8 μm filter" refers to a filter device having a filtration pore size of 0.8 μm.

[0183] In any of the pharmaceutical compositions disclosed above and below, the nanoaggregates may have a filtration rate through a 0.22 μm filter in the range of 50% to 100%. The filtration rate may be expressed as R f , and are defined in detail later in this disclosure.

[0184] In embodiments, the nanoaggregates may have a filtration rate of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more, or between 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95-100%, 50-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95 ... or any ratio that must be 50% or higher.

[0185] The nanoaggregates may be filtered through a 0.22 μm filter prior to lyophilization to produce sterilized nanoaggregates, wherein the nanoaggregates may have a filtration rate (R) through a 0.22 μm filter in the range of 50% to 100%. f ). In another example, the pharmaceutical composition can be filtered through a 0.22 μm filter to produce a filtered pharmaceutical composition. Briefly, a sample of polymer-drug nanoaggregates 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 having a predetermined filtration surface area (e.g., a 25 mm diameter sterile syringe filter device having a 0.22 μm filtration pore size) at a predetermined initial volume V 0 Filter the sample. The volume V through the filter can be obtained p The filtration rate R of the sample can be calculated according to the formula f :

[0186] R f =V p / V 0 .

[0187] Filtration rate R f It can be expressed as a percentage or fraction of a predetermined filtration surface area. In some cases, as disclosed herein, a standard sterile filter with a diameter of 25 mm can be used. Filtration rate R fIt can be expressed as a percentage or fraction of using a 25 mm diameter sterile filter with a predetermined filtration surface area. Filtration rates measured with filters of different sizes can be converted or normalized with reference to a standard 25 mm diameter filter. Percentages are used in the present disclosure. In embodiments of the method, the nanoaggregates may have a filtration rate of at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more; or between 50-100%, 60-100%, 70-100%, 80-100%, 90-100%, 55-100%, 65-100%, 75-100%, 85-100%, 95-100% or any ratio that must be 50% or higher.

[0188] 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 pharmaceutically suitable carriers. In some cases, 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, pharmaceutical compositions disclosed herein can be formulated for intravenous (IV), intradermal (ID), subcutaneous (SC), transdermal (topical) transmucosal administration. In some cases, pharmaceutical compositions disclosed herein can be formulated for oral administration, such as tablets, capsules, oral sprays, solutions or suspensions. In some cases, pharmaceutical compositions disclosed herein can be formulated for nasal administration, such as nasal sprays. Pharmaceutically suitable carriers disclosed herein can be suitable.

[0189] In some cases, the pharmaceutical composition can be prepared by a method that can include the following steps:

[0190] (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;

[0191] (2) removing the organic solvent from the nanoaggregates to form dried nanoaggregates;

[0192] (3) dissolving the dried nanoaggregates in water, saline or PBS to form an aqueous solution of nanoaggregates; and

[0193] (4) freeze-drying the aqueous solution of nanoaggregates to form freeze-dried nanoaggregates;

[0194] wherein the polymer is water soluble and comprises at least one first end group modified with an H or hydrophobic moiety and a second end group modified with a hydrophilic moiety; and

[0195] wherein the first end group comprises 1% to 99% H and 1% to 99% hydrophobic moieties, wherein the hydrophobic moieties may include saturated or unsaturated aliphatic hydrocarbons, aromatic hydrocarbons, or combinations thereof having 1 to about 22 carbons, and the second end group comprises groups modified by amines, amides, imides, imides, carboxyls, hydroxyls, esters, ethers, acetates, phosphates, ketones, aldehydes, sulfonates, or combinations thereof.

[0196] The aqueous nanoaggregate solution may be filtered through a 0.22 μm filter prior to lyophilization to produce sterile nanoaggregates.

[0197] In some cases, the nanoaggregates can be produced by dissolving the polymer and the bioactive agent together in a nanoaggregate solution containing an organic solvent to form nanoaggregates. Any organic solvent or mixture thereof may be suitable. In some cases, the organic solvent may include acetic acid, acetone, acetonitrile, benzene, 1-butanol, 2-butanol, 2-butanone, tert-butanol, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, diethylene glycol, ethyl ether, diglyme (diethylene glycol, dimethyl ether), 1,2-dimethoxyethane (1,2-dimethoxy-,ethane), dimethoxyethane (DME, also known as glyme), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, ethanol, Ethyl acetate, ethylene glycol, glycerol, heptane, hexamethylphosphoramide (HMPA), hexamethylphosphoroustriamide (HMPT), hexane, methanol, methyl tert-butyl ether (MTBE), dichloromethane, N-methyl-2-pyrrolidone (NMP), nitromethane, pentane, petroleum ether (ligroin or ligroine), 1-propanol, 2-propanol, pyridine, tetrahydrofuran (THF), toluene, triethylamine, o-xylene, m-xylene, p-xylene, or a combination thereof.

[0198] In some cases, nanoaggregates can be produced by the following steps: 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 nanoaggregates; wherein 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.

[0199] In some cases, nanoaggregates can be produced by the following steps: 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 comprising a second organic solvent to form a bioactive agent solution; and mixing the polymer solution and the bioactive agent solution to form nanoaggregates; wherein the first organic solvent and the second organic solvent can be the same or different; and wherein the second organic solvent is an organic solvent miscible with water. The first solvent can be selected from an aqueous solution (e.g., water, saline, a buffer (e.g., 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 organic solvents miscible with water, 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.

[0200] 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 acid or base to reach the desired pH range. Acids (e.g., HCl or other acids) may be suitable. Bases (e.g., NaOH or other bases) may be suitable.

[0201] As described above, the nano-aggregates of the pharmaceutical composition produced by the method of the present invention may be free of human serum albumin, organic solvents, detergents, or oils. The nano-aggregates of the pharmaceutical composition produced by the method of the present invention may be free of human serum albumin, organic solvents, detergents, oils, or free acids. As described above, in another example, the pharmaceutical composition produced by the method of the present invention may be free of human serum albumin, organic solvents, detergents, oils, or free acids.

[0202] The method disclosed above and below also further comprises mixing into the pharmaceutical composition an additional bioactive agent that is formulated without polymer. In some cases, a chemical or small molecule drug, a chemotherapeutic drug, an inorganic-based drug, a biopharmaceutical, or a macromolecular-based drug, a modified substance or derivative thereof, and a combination thereof (independently or in combination thereof) that is formulated without the above-mentioned polymer may be suitable.

[0203] In some cases, the present disclosure further relates to a method for treating or preventing a disease in a subject in need thereof, which method may include administering to the subject an effective dose of a pharmaceutical composition comprising:

[0204] Nanoaggregates comprising a polymer and at least one water-insoluble or poorly water-soluble bioactive agent; and

[0205] Optionally, a pharmaceutically suitable carrier;

[0206] wherein the pharmaceutical composition is soluble in an aqueous solution to produce at least 1 mg / mL of the bioactive agent dissolved in the aqueous solution;

[0207] wherein the polymer is water soluble; and

[0208] The polymers may include:

[0209] 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 1% to 99% H and 1% to 99% hydrophobic moiety, wherein the hydrophobic moiety comprises a saturated or unsaturated aliphatic hydrocarbon having 1 to about 22 carbons, an aromatic hydrocarbon, or a combination 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 a combination thereof; or

[0210] a second polymer comprising one or more hydroxy dendrimers (HD), ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 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), (PPO-PEO), poly(γ-L-glutamic acid) (PGA), poly(L-phenylalanine ethyl ester) (PAE), poly(L-lysine) (PLL), methyl PEG (mPEG), polyaspartic acid (PasP), poly(L-histidine) (PLH), poly(vinylamine) (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-glutamate) (PBLG), phosphatidylserine (PS), poly(isohexyl cyanoacrylate) (PIHCA), poly(allylamine hydrochloride) (PAH), poly(γ-propargyl) (PP); or

[0211] Its combination.

[0212] In some cases, the polymer can include a first polymer as disclosed herein.

[0213] In some cases, the polymer may be composed of a first polymer as disclosed herein. In some cases, the pharmaceutical composition may be free of a polymer selected from: one or more hydroxy dendrimers (HD), ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 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), (PPO-PEO), poly (γ-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 (vinylamine) (PEI), poly (N-vinyl pyrrolidone) (PVP), poly (L-leucine) (PLLeu), deoxycholic acid (DOCA), hydroxypropyl methylcellulose (HPMC), poly (hydroxybutyrate) (PHB), poly (ethylene oxide) (PEO), poly (γ-benzyl L-glutamate) (PBLG), phosphatidylserine (PS), poly (isohexyl cyanoacrylate) (PIHCA), poly (allylamine hydrochloride) (PAH), poly (γ-propargyl) (PP), and combinations thereof.

[0214] In some cases, the polymer may include a second polymer comprising one or more hydroxy dendrimers (HD), ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 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), (PPO-PEO), poly (γ-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 (vinylamine) (PEI), poly (N-vinyl pyrrolidone) (PVP), poly (L-leucine) (PLLeu), deoxycholic acid (DOCA), hydroxypropyl methylcellulose (HPMC), poly (hydroxybutyrate) (PHB), poly (ethylene oxide) (PEO), poly (γ-benzyl L-glutamate) (PBLG), phosphatidylserine (PS), poly (isohexyl cyanoacrylate) (PIHCA), poly (allylamine hydrochloride) (PAH), poly (γ-propargyl) (PP), or a combination thereof.

[0215] In some cases, the polymer may include a first polymer and one or more subsequent polymers (also referred to as "second polymers") selected from one or more hydroxy dendrimers (HD), ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 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), (PPO-PEO), poly (γ-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 (vinylamine) (PEI), poly (N-vinyl pyrrolidone) (PVP), poly (L-leucine) (PLLeu), deoxycholic acid (DOCA), hydroxypropyl methylcellulose (HPMC), poly (hydroxybutyrate) (PHB), poly (ethylene oxide) (PEO), poly (γ-benzyl L-glutamate) (PBLG), phosphatidylserine (PS), poly (isohexyl cyanoacrylate) (PIHCA), poly (allylamine hydrochloride) (PAH), poly (γ-propargyl) (PP), and combinations thereof.

[0216] The bioactive agents disclosed herein may be suitable for use as drugs or pharmacological agents.

[0217] Any polymer disclosed herein can be suitable.In some cases, polymer can include poly-oxazoline (POX), it comprises linear part, branched part or its combination, and wherein poly-oxazoline (POX) includes poly-(2-oxazoline), poly-(2-methyloxazoline), poly-(2-ethyloxazoline), poly-(2-propyloxazoline), poly-(isopropyloxazoline) or its combination.In some cases, poly-oxazoline is poly-(2-ethyloxazoline).

[0218] In some cases, the polyoxazoline may include a molar ratio of monomer to initiator in a range of 50:1 to 80:1.

[0219] The size of the nanoaggregates before lyophilization may be in the range of less than about 120 nm. In some cases, the size of the nanoaggregates before lyophilization may be in the range of about 50 nm to about 120 nm. In some cases, the nanoaggregates may have a weight ratio of polymer to bioactive agent in the range of about 2:1 to about 200:1.

[0220] In some cases, the method disclosed herein, the pharmaceutical composition may 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 may include paclitaxel and one or more additional bioactive agents disclosed herein that are different from paclitaxel. In some cases, the pharmaceutical composition may include rapamycin and one or more subsequent bioactive agents, the bioactive agent being selected from proteins, peptides, antibodies, fragments of antibodies, compounds, small molecule drugs, one or more chemotherapeutic drugs, vaccines, and combinations thereof. In some cases, one or more subsequent bioactive agents may be selected from gemcitabine, taxanes, paclitaxel, docetaxel, cabazitaxel, larotaxel, milatataxel, ortataxel, tesetaxel, topoisomerase 1 (Top 1) inhibitors, camptothecin derivatives, irinotecan (CPT-11), SN-38, topotecan, topoisomerase 2 (Top 2) Inhibitors, doxorubicin, etoposide, ciprofloxacin, platinum-based anti-tumor drugs, antibodies against programmed cell death protein (PD) 1, antibodies against PD ligand (PD-L) 1, antibodies against CTLA-4 (cytotoxic T lymphocyte-associated antigen), antibodies against LAG3 (lymphocyte activation gene-3), antibodies against TIM-3 (T cell immunoglobulin and mucin domain-3), antibodies against CD19, antibodies against CD20, cytokines, interleukins, interferon α2a, interferon α, Granulocyte colony stimulating factor (G-CSF), Neupogen 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 a combination thereof, indoleamine 2,3-dioxygenase (IDO) inhibitor, indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, vaccine and a combination thereof. In some cases, at least one of the two or more bioactive agents may include a STING regulatory molecule, such as a benzimidazole compound disclosed in patent publications WO2017175156A1 and WO2020156363, a pyridyl imidazole compound disclosed in patent publications WO2019134705, WO2020010451 and US20200031825, or a combination thereof.

[0221] In some cases, the method disclosed herein, the pharmaceutical composition may include one or more additional bioactive agents selected from gemcitabine, taxane, 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 may include 7-ethyl-10-hydroxycamptothecin (SN-38).

[0222] In some cases, the size of the nano aggregates may be less than 150nm before freeze drying. In some cases, the size of the nano aggregates may be less than 120nm before freeze drying. In some cases, the size of the nano aggregates may be within the range of about 50nm to about 150nm before freeze drying. In some cases, the size of the nano aggregates or nanoparticles may be about 50 to about 100nm before freeze drying. In some cases, the size of the nano aggregates or nanoparticles may be about 50 to about 120nm before freeze drying. The particle size can be measured by light scattering.

[0223] In some cases, the nanoaggregates may have a weight ratio of polymer to rapamycin in a range from about 2:1 to about 20:1.

[0224] In some cases, the nanoaggregates may have a weight ratio of polymer to rapamycin in a range from about 5:1 to about 8:1.

[0225] In some cases, the nanoaggregates may further comprise a targeting moiety, which includes an antibody, an antigen binding portion thereof, an antigen, a cell receptor, a cell receptor ligand, a ligand of a cellular protein, a ligand of a membrane protein, a small molecule ligand, a lectin ligand, or a combination thereof.

[0226] In some cases, the nanoaggregates may be free of human serum albumin, organic solvents, detergents, or oils. In some cases, the nanoaggregates may be free of human serum albumin, organic solvents, detergents, oils, or free acids. In some cases, the nanoaggregates may be free of human serum albumin. In some cases, the nanoaggregates may be free of organic solvents. In some cases, the nanoaggregates may be free of detergents. In some cases, the nanoaggregates may be free of oils. In some cases, the nanoaggregates may be free of free acids. In some cases, the nanoaggregates may be free of substances selected from human serum albumin, organic solvents, detergents, oils, free acids, and combinations thereof.

[0227] In some cases, the pharmaceutical composition may be free of human serum albumin, organic solvents, detergents, or oils. In some cases, the pharmaceutical composition may be free of human serum albumin, organic solvents, detergents, oils, or free acids. In some cases, the pharmaceutical composition may be free of human serum albumin. In some cases, the pharmaceutical composition may be free of organic solvents. In some cases, the pharmaceutical composition may be free of detergents. In some cases, the pharmaceutical composition may be free of oils. In some cases, the pharmaceutical composition may be free of free acids. In some cases, the pharmaceutical composition may be free of substances selected from human serum albumin, organic solvents, detergents, oils, free acids, and combinations thereof.

[0228] In some cases of the methods disclosed herein, 1% to 100% of the second end groups do not contain primary amines. In some cases, 1% to 100% of the second end groups contain hydroxyl groups. All percentages are based on the total number of second end groups.

[0229] In some cases, the pharmaceutical composition may have a pH in the range of about 3.0 to 6.9.

[0230] In some cases, suitable for use in the method, the bioactive agent may include at least a compound having formula (1) to formula (29) ( Figure 12A-12E ), a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

[0231] In some cases, the bioactive agent may comprise a compound having the formula

[0232] Formula (1)

[0233]

[0234] Formula (4)

[0235]

[0236] A pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

[0237] In some cases, the disease can be selected from one or more immune diseases, infectious diseases, cancers, and combinations thereof.

[0238] In some cases, immune disorders may include the aforementioned immunodeficiency disorders, overactive immune disorders, autoimmune diseases, and other diseases or conditions with an abnormal immune system.

[0239] In some cases, the method may further comprise the step of administering to the subject one or more subsequent bioactive agents selected from proteins, peptides, antibodies, fragments of antibodies, compounds, small molecule drugs, one or more chemotherapeutic drugs, vaccines, and combinations thereof. In some cases, the one or more subsequent bioactive agents may be selected from gemcitabine, taxanes, paclitaxel, docetaxel, cabazitaxel, larotaxel, milatataxel, ortataxel, tesetaxel, topoisomerase 1 (Top 1) inhibitors, camptothecin derivatives, irinotecan (CPT-11), SN-38, topotecan, topoisomerase 2 (Top2) inhibitors, doxorubicin, etoposide, ciprofloxacin, platinum-based anti-tumor drugs, 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 α2a, interferon α, granulocyte colony stimulating factor (G-CSF), Eubojin or filgrastim, T cell receptor (TCR), chimeric antigen receptor or chimeric antigen T cell receptor (CAR-T), vaccines and combinations thereof. Any bioactive agent disclosed herein may be suitable.

[0240] In some cases, one or more subsequent bioactive agents can each be administered to the subject before, simultaneously with, or after administration of the pharmaceutical composition. One or more subsequent bioactive agents can each be administered to the subject alone. In some cases, the subsequent bioactive agent can include 7-ethyl-10-hydroxycamptothecin (SN-38).

[0241] The pharmaceutical composition can 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) injection, subcutaneous (SC) injection, intramuscular (IM) injection, or intradermal (ID) injection may also be suitable.

[0242] In some cases, the pharmaceutical composition can be an adjuvant for a vaccine. In some cases, the pharmaceutical composition is a preventive vaccine, a therapeutic vaccine, or a combination thereof, wherein the pharmaceutical composition further comprises at least one immunizing agent for stimulating 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, coronavirus, dengue fever, diphtheria, Ebola, influenza, hepatitis, Hib disease, HIV / AIDS, HPV (human papillomavirus), Japanese encephalitis, measles, meningococcal disease, monkeypox, mumps, norovirus, pneumococcal disease, poliomyelitis, rabies, respiratory syncytial virus (RSV), rotavirus, rubella (German measles), herpes zoster, tetanus, pertussis, Zika and a combination thereof.

[0243] In some cases, the disease may be one or more cancers, including 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, cervical carcinoma, cholangiocarcinoma, colon cancer, epithelial cancer, esophageal cancer, esophageal carcinoma, gastric cancer, genitourinary cancer, glioblastoma, head and neck cancer, head and neck carcinoma, head and neck squamous cell carcinoma (HNSCC), hematopoietic cancer, testicular cancer, colorectal cancer, Hodgkin's lymphoma, Hodgkin's disease, hormone-refractory prostate cancer, kidney cancer. Cancer, colorectal cancer, liver cancer, lymphoma, melanoma, metastatic breast cancer, metastatic pancreatic cancer, mycosis fungoides, myeloid leukemia, nasopharyngeal cancer, nervous system cancer, neuroblastoma, non-small cell lung cancer (NSCLC), oral adenoid cystic carcinoma, ovarian cancer, pancreatic cancer, prostate cancer, prostatic cancer, lung cancer, renal cancer, sinonasal squamous cell carcinoma (SCC), skin cancer, small cell lung cancer (SCLC), head and neck squamous cell carcinoma (SCCHN), stage IIB-IV melanoma, T-cell lymphoma, triple negative breast cancer (TNBC), upper gastrointestinal adenocarcinoma, urothelial transitional cell carcinoma, or other cancers (including those cancers or neoplastic diseases to be diagnosed or identified). The disease can be any cancer disclosed above or below. In some cases, the cancer can be a solid tumor. In some cases, the cancer can be one or more blood cancers.

[0244] In some cases, the disease may be one or more cancers including ampullary cancer, adrenal cancer, breast cancer, ovarian cancer, lung cancer, NSCLC (non-small cell lung cancer), cholangiocellular carcinoma, small cell lung cancer, biliary tract cancer, bladder cancer, cervical cancer, soft tissue sarcoma, uterine sarcoma, colon cancer, gastric cancer, melanoma, nasopharyngeal carcinoma, neuroendocrine cancer, head and neck cancer, oral adenoid cystic carcinoma, pancreatic cancer, nasal sinonasal squamous cell carcinoma (SCC), thyroid cancer, one or more metastatic cancers arising therefrom, or a combination thereof.

[0245] In some cases, one or more cancers are selected from thyroid cancer, recurrent ER (+) high-grade ovarian cancer, ER (+) locally advanced or metastatic breast cancer, advanced neuroendocrine tumors, diffuse large B-cell lymphoma, advanced solid tumors, metastatic clear cell renal carcinoma, recurrent or refractory non-Hodgkin's lymphoma, chronic lymphocytic lymphoma, recurrent endometrial cancer, perivascular epithelial cell tumor (PEComa), advanced unresectable or metastatic malignant perivascular epithelial cell tumor, ovarian cancer, lung cancer, NSCLC (non-small cell lung cancer), small cell lung cancer, biliary tract cancer, bladder cancer, cervical cancer, soft tissue sarcoma, uterine sarcoma, colon cancer, gastric cancer, melanoma, head and neck cancer, pancreatic cancer, one or more metastatic cancers produced therefrom, and combinations thereof. In some cases, one or more cancers may be advanced unresectable or metastatic malignant perivascular epithelial cell tumor (PEComa).

[0246] As used herein, in one example, the subsequent bioactive agent can have a molecular weight ranging from about 10 to 1,000,000, in another example 100 to 500,000, in yet another example 100 to 200,000, in yet another example 500 to 200,000, in yet another example 1,000 to 200,000, in yet another example 5,000 to 200,000, in yet another example 10,000 to 200,000, in yet another example 15,000 to 200,000, in yet another example 20,000 to 200,000, in yet another example, and 25,000 to 200,000 in yet another example. In one example, the molecular weight of the bioactive agent may also have a molecular weight ranging from about 100 to 100,000, in yet another example 100 to 75,000, in yet another example 100 to 50,000, in yet another example 100 to 30,000, and in yet another example 100 to 25,000.

[0247] Subsequent bioactive agents may include drugs, proteins, recombinant proteins, antibodies, Fab antibody fragments, other antigen-binding antibody fragments, enzymes, viruses, viral fragments, and combinations thereof. Subsequent bioactive agents may be selected from peptides, monoclonal antibodies, fragments of monoclonal antibodies, polyclonal antibodies, fragments of polyclonal antibodies, synthetic antibodies, fragments of synthetic antibodies, or combinations thereof. Subsequent bioactive agents may include, for example, antibodies or antigen-binding portions thereof, such as alemtuzumab, bevacizumab, cetuximab, ibritumomab, rituximab, trastuzumab, gemtuzumab, antibodies against PD1 (e.g., Keytruda or pembrolizumab), and PD-1 antibodies. lizumab), 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), anti-TIM-3 (T cell immunoglobulin and mucin domain-3), anti-CD19, anti-CD20 (e.g., tositumomab); cytokines, such as interleukins, interferon α2a, interferon α, granulocyte colony stimulating factor (G-CSF), or eubojin (also known as filgrastim); T cell receptor (TCR); chimeric antigen receptor or chimeric antigen T cell receptor (CAR-T); STING protein; STING stimulator agonist; STING activator; STING inhibitor; STING antagonist; STING regulatory molecule; indoleamine 2,3-dioxygenase (IDO) inhibitor; indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor; peptide hormones, such as insulin, glucagon, glucagon-like peptide 1, erythropoietin (EPO), thyroid peroxidase (TPO), follicle stimulating hormone, etc.; ligands of cell surface receptors; lectins; nucleic acids, such as siRNA, ribozymes, antisense nucleic acids, naked nucleic acids, etc.; viruses; virus-like particles, etc. Examples may include ecallantide.

[0248] In some cases, the method may include administering to a subject an effective dose of a pharmaceutical composition comprising a nanoaggregate containing a polymer and a bioactive agent; and administering to a subject one or more subsequent bioactive agents before, simultaneously with, or after administering the pharmaceutical composition. Any subsequent bioactive agent disclosed herein may be suitable. In some cases, the bioactive agent may be selected from alemtuzumab, bevacizumab, cetuximab, ibritumomab tiuxetan, rituximab, trastuzumab, gemtuzumab, anti-PD1 antibodies (e.g., keruida or pembrolizumab, opdivo or nivolumab, bavencia or avelumab, infivan or durvalumab, tezomib 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 against TIM-3 (T cell immunoglobulin and mucin domain-3), antibodies against CD19, antibodies against CD20 (e.g., tositumomab), one or more cytokines, interferon α2a, interferon α, granulocyte colony stimulating factor (G-CSF), Eubojin (also known as filgrastim), T cell receptor (TCR), chimeric antigen receptor or chimeric antigen T cell receptor (CAR-T), nucleic acids (e.g., siRNA, ribozymes, antisense nucleic acids, naked nucleic acids, etc.), viruses, virus-like particles, and combinations thereof. In some cases, the bioactive agent can be selected from alemtuzumab, bevacizumab, cetuximab, ibritumomab tiuxetan, rituximab, trastuzumab, gemtuzumab, Keytruda (pembrolizumab), Opdivo (nivolumab), Bavencia (avelumab), Imfinzi (durvalumab, tacentin or atezolizumab), anti-PD-L1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, anti-LAG3 antibodies, anti-TIM-3 antibodies, anti-CD19 antibodies, anti-CD20 antibodies, T cell receptors (TCR), chimeric antigen T cell receptors (CAR-T), and combinations thereof.

[0249] Subsequent bioactive agents may include vaccines. Vaccines may include antigens, toxins, modified or ineffective toxins, including natural or synthetic molecules that can cause an immune response in a biological system (e.g., in humans or animals). Vaccines may be connected to polymers by covalent bonds, non-covalent linkages, or combinations thereof. Commercially available vaccines and vaccines listed by the U.S. Centers for Disease Control and Prevention (CDC) may be suitable.

[0250] The subsequent bioactive agents described herein may include any chemical or small molecule drug, chemotherapeutic drug, inorganic-based drug, biological drug or macromolecular-based drug, modifications or derivatives thereof, and combinations thereof. NIH National Cancer Institute

[0251] (https: / / www.cancer.gov / about-cancer / treatment / drugs) or any future update listed chemotherapy drugs may be appropriate.

[0252] The subsequent biologically active composition can be administered by intravenous (IV), intramuscular (IM), subcutaneous (SC) or intradermal (ID) injection, orally, by inhalation, nasally, ocularly (e.g., using drops or ointments), transdermally (e.g., using patches), or a combination thereof. Combinations of any of the above routes of administration may also be suitable.

[0253] The nanoaggregates disclosed herein may be nanocomposites, i.e., nanoparticles of one or more materials or components (e.g., polymers alone, polymers and bioactive agents), wherein at least one dimension of the physical mixture is within the nanometer range as defined herein. In the present disclosure, such mixtures may contain different nanoscale phases or domains formed between bioactive agents and branched homopolymer molecules in a solid or liquid state. The nanocomposites may include a combination of a bulk matrix (e.g., a branched homopolymer and rapamycin) and a nanoscale phase, which may exhibit different properties due to differences in structure and chemical properties (e.g., domains formed by surface groups of rapamycin and branched polymers, and domains formed within branched polymers). Since the solubility of the domains / phases may be different, when the nanocomposites are dissolved in an aqueous solution, one phase may dissolve faster than another phase or other phases, resulting in the gradual disintegration of the composite nanoaggregates, causing the graded and controlled release of the composite components, and optionally, one or more components re-form into new forms, such as new nanoaggregates. The terms "nanocomplex," "nanoparticle," "nanoaggregate," "nanoaggregates," and "aggregate," "aggregates" are equivalent and are used interchangeably herein.

[0254] In one example, the size of the nanoaggregates described in the present disclosure before lyophilization is about 10 to about 500 nm in diameter, about 30 nm to about 300 nm in diameter in another example, 50 to 150 nm in yet another example, 50 to 120 nm in yet another example, 50 to 100 nm in yet another example, and 70 to 90 nm in a further example. Nanoaggregates can exhibit size-related properties that are significantly different from those observed in microparticles.

[0255] Applicants have found that when a polymer synthesized with a monomer to initiator molar ratio in the range of 50:1 to 80:1 (e.g., 60:1) is mixed with rapamycin at a polymer to rapamycin weight ratio of 5:1 to 7:1, the size of the formed nanoparticles before lyophilization is in the range of 50 to 150 nm, which allows the particles to easily pass through a 0.22 μm filter.

[0256] The nanoaggregates have a filtration rate through a 0.22 μm filter in the range of 50% to 100%. In some cases, polyoxazoline polymers having a specific range of monomer to initiator molar ratios may be suitable, such as polymers having a monomer to initiator molar ratio in the range of 50:1 to about 80:1, such as H-PEOXABP60, C 18 PEOXABP60、H / C 18 PEOXABP60, or a combination thereof.

[0257] As disclosed above and below, the nanoaggregates can be linked to targeting moieties or groups to form conjugates, such that the targeting moieties are incorporated with the desired nanocomposite particles. Figures 10A-10B ), the targeting moiety or group includes but is not limited to an antibody (or an antigen-binding portion thereof), an antigen, a cognate carbohydrate (e.g., sialic acid), a cell surface receptor ligand, a moiety that binds to a cell surface receptor (e.g., prostate-specific membrane antigen (PSMA)), a moiety that binds to a cell surface carbohydrate, an extracellular matrix ligand, a cytosolic receptor ligand, a growth factor, a cytokine, an incretin, a hormone, a lectin, a lectin target (e.g., galactose, a galactose derivative, N-acetylgalactosamine, mannose, a mannose derivative, etc.), a vitamin (e.g., folic acid, biotin, etc.), avidin, streptavidin, neutravidin, etc.

[0258] In some cases, the bioactive agent can be dissolved in methanol or ethanol in various amounts up to 40 mg / mL. The hydrocarbon (CH 3 (CH 2 )17 ) modified randomly branched PEOX60 (molar ratio of monomer to initiator = 60:1) (referred to herein as C 18 PEOXABP60) and dissolved in methanol or ethanol at different concentrations up to 100 mg / mL. The two solutions can then be mixed in various volumes so that the final homopolymer and bioactive agent weight ratio in the mixture is 2:1 to 20:1 to form nanoaggregates. The nanoaggregates can be rotary evaporated to dryness to form dry nanoaggregates. The dry nanoaggregates can then be redissolved or suspended in water or saline, followed by sterile filtration with a 0.22 μm filter and lyophilized for 20 to 72 hours, depending on the volume, to produce lyophilized nanoaggregates or dry powders.

[0259] In some cases, H / C 18 Polymer mixtures of PEOXABP60 may be suitable. Polymer mixture H / C 18 PEOXABP60 may include -OH, NH 2 , or a combination thereof.

[0260] In one example before freeze drying, the size of the nano-aggregate or nano-particle measured by light scattering may be about 50 to about 150nm, about 50 to about 100nm in one example, about 60 to about 100nm in another example, about 70 to about 100nm in another example, and about 70 to 95nm in another example. In some cases, the size of the nano-aggregate or nano-particle measured by light scattering before freeze drying may be about 50 to about 100nm. After freeze drying, the pharmaceutical composition may include nano-aggregates with a size of about 50 to about 150nm in diameter. The size can be measured by re-dissolving the dried nano-aggregates in saline, sodium bicarbonate solution, water, buffer, or a combination thereof. The size of the nano-aggregates can be measured by re-dissolving the dried nano-aggregates in a buffer (e.g., a combination of phosphate buffered saline (PBS) in one example, PBS and saline (sodium chloride) in another example, and a combination of saline and sodium bicarbonate in another example).

[0261] 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 pharmaceutically suitable carriers. Examples of routes of administration include parenteral administration, such as intravenous (IV), intradermal (ID), subcutaneous (SC), oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous administration can include one or more pharmaceutically suitable carriers, such as sterile diluents, such as water for injection, saline, oils, polyethylene glycols, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methyl parabens; 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. The pH can be adjusted with an acid or base, such as HCl or NaOH. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic as articles of manufacture. The pharmaceutical composition can be packaged in a container, pack or dispenser together with instructions for administration.

[0262] The pharmaceutical composition may be suitable for injection and may include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injections or dispersions. For intravenous administration, suitable carriers may include physiological saline, bacteriostatic water, Cremophor (BASF; Parsippany, NJ) or phosphate buffered saline (PBS). The composition is sterile and fluid to the extent that there is injectability. The composition must be stable under the conditions of manufacture and storage, and must be preserved to avoid the contaminating effects of microorganisms (such as bacteria and fungi). The pharmaceutical composition may contain one or more solvents or dispersion media, including, for example, water, ethanol, polyols (such as glycerol, propylene glycol, liquid PEG, polysorbate, etc.) and suitable mixtures thereof. Some pharmaceutically suitable carriers can be used to maintain the appropriate fluidity of the composition, such as by using a coating (such as lecithin), by maintaining the desired particle size in the case of a dispersion, using a thickener, and using a surfactant. Further pharmaceutically suitable carriers may include various antibacterial and antifungal agents (such as parabens, chlorobutanol, phenol, ascorbic acid, etc.) to prevent or inhibit the growth or action of microorganisms; and isotonic agents may be included in the composition as pharmaceutically suitable carriers, such as sugars, polyols (such as mannitol, sorbitol) or sodium chloride. Agents that delay absorption, such as aluminum monostearate or gelatin, can also be used as pharmaceutically suitable carriers.

[0263] In further embodiments, the pharmaceutical composition may include one or more pharmaceutically suitable carriers that will protect the compound from being rapidly cleared from the subject's body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid may be used. Methods for preparing such formulations are apparent to those skilled in the art. Materials may also be commercially available from, for example, Alza Corporation and Nova Pharmaceuticals, Inc.

[0264] Sterile injectable solutions can be prepared in the following manner: the required amount of active compound is incorporated into an appropriate solvent containing one or a combination of ingredients listed above (as required), followed by filtration sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle comprising a basic dispersion medium and other ingredients required from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred preparation methods are vacuum drying and freeze drying, which produce a powder of the active ingredient plus any additional desired ingredients from a previously sterile filtered solution thereof.

[0265] Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of tablets, lozenges or capsules. Oral compositions can also be prepared using a fluid carrier to obtain a syrup or liquid preparation, or used as a mouthwash, wherein the compound in the fluid carrier is administered orally, swished and expectorated or swallowed.

[0266] Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, and the like may contain any of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as mint, methyl salicylate, or orange flavoring.

[0267] For administration by inhalation, the compounds are delivered in the form of, for example, an aerosol spray from a pressured container or dispenser that contains a suitable propellant (eg, a gas such as carbon dioxide); a nebulizer; or a spray.

[0268] Systemic administration can also be carried out by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants suitable for the barrier to be penetrated are 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, the active compound is formulated into an ointment, salves, gel or cream commonly known in the art. Another known penetrant is dimethyl sulfoxide.

[0269] The compounds may 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.

[0270] For ease of administration and uniformity of dosage, it is advantageous to formulate oral or parenteral compositions in dosage unit form. As used herein, dosage unit form refers to physically discrete units suitable as single doses for subjects to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic endpoint. The dosage, such as the preferred route of administration and amount, can be obtained by implementing methods known in the art based on empirical data obtained from preclinical and clinical studies. The dosage and delivery form may depend on and may be dependent on the characteristics of the bioactive agent, the characteristics of the polymer, the specific therapeutic effect to be achieved, the characteristics and conditions of the recipient, etc. For repeated administration over several days or longer, depending on the condition, treatment can be continued until the desired endpoint is reached.

[0271] In some cases, the present disclosure relates to nanoaggregates comprising a polymer and at least one water-insoluble or poorly water-soluble bioactive agent;

[0272] wherein the nanoaggregates are soluble in an aqueous solution to produce at least 1 mg / mL of the bioactive agent dissolved in the aqueous solution;

[0273] wherein the polymer is water-soluble;

[0274] Wherein the bioactive agent comprises a drug based on natural or synthetic small molecules, an inorganic-based drug, a biological drug, a drug based on natural or synthetic macromolecules, a derivative thereof, or a combination thereof; and

[0275] The polymers include:

[0276] 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 1% to 99% H and 1% to 99% hydrophobic moieties, wherein the hydrophobic moieties comprise saturated or unsaturated aliphatic hydrocarbons, aromatic hydrocarbons, or combinations thereof having 1 to about 22 carbons, and the second end group comprises a group modified with an amine, amide, imide, imide, carboxyl, hydroxyl, ester, ether, acetate, phosphate, ketone, aldehyde, sulfonate, or a combination thereof; or

[0277] a second polymer comprising one or more hydroxy dendrimers (HD), ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 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), (PPO-PEO), poly (γ-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 (vinylamine) (PEI), poly (N-vinyl pyrrolidone) (PVP), poly (L-leucine) (PLLeu), deoxycholic acid (DOCA), hydroxypropyl methylcellulose (HPMC), poly (hydroxybutyrate) (PHB), poly (ethylene oxide) (PEO), poly (γ-benzyl L-glutamate) (PBLG), phosphatidylserine (PS), poly (isohexyl cyanoacrylate) (PIHCA), poly (allylamine hydrochloride) (PAH), poly (γ-propargyl) (PP), or a combination thereof.

[0278] In some cases, about 1% to 100% of the second end groups may be free of primary amines. In some cases, 1% to 100% of the second end groups of the nanoaggregates disclosed herein may contain hydroxyl groups. All percentages are based on the total number of second end groups.

[0279] In some cases, the size of the nanoaggregates may be less than 150 nm before lyophilization. In some cases, the size of the nanoaggregates may be less than 120 nm before lyophilization. In some cases, the size of the nanoaggregates may be in the range of about 50 nm to about 120 nm before lyophilization.

[0280] In some cases, the poly(2-ethyloxazoline) can comprise a molar ratio of monomer to initiator in a range of 50:1 to 80:1.

[0281] In some cases, the nanoaggregates may have a weight ratio of polymer to bioactive agent in a range of about 2: 1 to about 200: 1. In some cases, the nanoaggregates may have a weight ratio of polymer to bioactive agent in a range of about 5: 1 to about 8:1.

[0282] In some cases, the nanoaggregate may further comprise a targeting moiety comprising an antibody, an antigen binding portion thereof, an antigen, a cell receptor, a ligand for a cell receptor, a ligand for a cell protein, a ligand for a membrane protein, a small molecule ligand, a lectin ligand, or a combination thereof.

[0283] 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.

[0284] 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 a drug based on natural or synthetic small molecules, an inorganic-based drug, a biopharmaceutical, a drug based on natural or synthetic macromolecules, a derivative thereof, or a combination thereof. In some cases, the biologically active agent may include a taxane, paclitaxel, docetaxel, cabazitaxel, larotaxel, milatataxel, ortataxel, tesetaxel, a topoisomerase 1 (Top 1) inhibitor, a camptothecin derivative, irinotecan (CPT-11), SN-38, topotecan, a topoisomerase 2 (Top 2) inhibitor, doxorubicin, etoposide, ciprofloxacin, an mTOR inhibitor, at least one STING polypeptide or a portion thereof, a nucleic acid encoding a STING polypeptide or a portion thereof, a STING inhibitor, a STING activator, a STING agonist, a STING antagonist, a STING modulatory molecule, an IDO inhibitor, an IDO1 inhibitor, or a combination thereof, wherein the mTOR inhibitor comprises everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, veltusertib, rufolimus, one or more dual PI3K-mTOR inhibitors, one or more ATP-competitive mTORC1 / 2 inhibitors, derivatives thereof, or a combination thereof.

[0285] In some cases, the biologically active agent can comprise 7-ethyl-10-hydroxycamptothecin (SN-38).

[0286] In some cases, suitable for use in the nanoaggregates disclosed herein, the bioactive agent may include at least a compound having formula (1) to formula (29) ( Figure 12A-12E ), a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

[0287] In some cases, the bioactive agent may comprise a compound having the formula

[0288] Formula (1):

[0289]

[0290] Formula (4)

[0291]

[0292] A pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

[0293] The present invention also relates to the use of nanoaggregates comprising a polymer and at least one water-insoluble or weakly water-soluble bioactive agent and optionally a pharmaceutically suitable carrier for the preparation of a medicament for treating a disease;

[0294] wherein the disease is selected from one or more immune diseases, infectious diseases, cancers, and combinations thereof;

[0295] wherein the nanoaggregates are soluble in an aqueous solution to produce at least 1 mg / mL of the bioactive agent dissolved in the aqueous solution;

[0296] wherein the polymer is water soluble; and

[0297] wherein the bioactive agent comprises a drug based on natural or synthetic small molecules, an inorganic-based drug, a biological drug, a drug based on natural or synthetic macromolecules, a derivative thereof, or a combination thereof;

[0298] The polymer includes:

[0299] 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 1% to 99% H and 1% to 99% hydrophobic moiety, wherein the hydrophobic moiety comprises a saturated or unsaturated aliphatic hydrocarbon, aromatic hydrocarbon, or a combination thereof having 1 to about 22 carbons, and the second end group comprises a group modified with an amine, amide, imide, imide, carboxyl, hydroxyl, ester, ether, acetate, phosphate, ketone, aldehyde, sulfonate, or a combination thereof; or

[0300] a second polymer comprising one or more hydroxy dendrimers (HD), ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 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), (PPO-PEO), poly(γ-L-glutamic acid) (PGA), poly(L-phenylalanine ethyl ester) (PAE), poly(L-lysine) (PLL), methyl PEG (mPEG), polyaspartic acid (PasP), poly(L-histidine) (PLH), poly(vinylamine) (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-glutamate) (PBLG), phosphatidylserine (PS), poly(isohexyl cyanoacrylate) (PIHCA), poly(allylamine hydrochloride) (PAH), poly(γ-propargyl) (PP); or

[0301] Its combination.

[0302] In some cases, the polymer can include a first polymer as disclosed herein.

[0303] In some cases, the polymer may be composed of a first polymer as disclosed herein. In some cases, the pharmaceutical composition may be free of a polymer selected from: one or more hydroxy dendrimers (HD), ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 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), (PPO-PEO), poly (γ-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 (vinylamine) (PEI), poly (N-vinyl pyrrolidone) (PVP), poly (L-leucine) (PLLeu), deoxycholic acid (DOCA), hydroxypropyl methylcellulose (HPMC), poly (hydroxybutyrate) (PHB), poly (ethylene oxide) (PEO), poly (γ-benzyl L-glutamate) (PBLG), phosphatidylserine (PS), poly (isohexyl cyanoacrylate) (PIHCA), poly (allylamine hydrochloride) (PAH), poly (γ-propargyl) (PP), and combinations thereof.

[0304] In some cases, about 1% to 100% of the second end groups may be free of primary amines. In some cases, 1% to 100% of the second end groups of the nanoaggregates disclosed herein may contain hydroxyl groups. All percentages are based on the total number of second end groups.

[0305] In some cases, the polymer may include a second polymer comprising one or more hydroxy dendrimers (HD), ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 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), (PPO-PEO), poly (γ-L-glutamic acid) (PGA), poly (L-phenylalanine ethyl ester) (PAE), poly (L-lysine) (PLL), methyl PEG (mPEG), polyaspartic acid (PasP), poly (L-histidine) (PLH), polyvinylamine (PEI), poly (N-vinyl pyrrolidone) (PVP), poly (L-leucine) (PLLeu), deoxycholic acid (DOCA), hydroxypropyl methylcellulose (HPMC), poly (hydroxybutyrate) (PHB), poly (ethylene oxide) (PEO), poly (γ-benzyl L-glutamate) (PBLG), phosphatidylserine (PS), poly (isohexyl cyanoacrylate) (PIHCA), poly (allylamine hydrochloride) (PAH), poly (γ-propargyl) (PP), or a combination thereof.

[0306] In some cases, the polymer may include a first polymer and a second polymer including one or more subsequent polymers selected from one or more hydroxy dendrimers (HD), ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 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), (PPO-PEO), poly (γ-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 (vinylamine) (PEI), poly (N-vinyl pyrrolidone) (PVP), poly (L-leucine) (PLLeu), deoxycholic acid (DOCA), hydroxypropyl methylcellulose (HPMC), poly (hydroxybutyrate) (PHB), poly (ethylene oxide) (PEO), poly (γ-benzyl L-glutamate) (PBLG), phosphatidylserine (PS), poly (isohexyl cyanoacrylate) (PIHCA), poly (allylamine hydrochloride) (PAH), poly (γ-propargyl) (PP), and combinations thereof.

[0307] 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 a drug based on natural or synthetic small molecules, an inorganic-based drug, a biopharmaceutical, a drug based on natural or synthetic macromolecules, a derivative thereof, or a combination thereof. In some cases, the biologically active agent can include a taxane, paclitaxel, docetaxel, cabazitaxel, larotaxel, milatataxel, ortataxel, tesetaxel, a topoisomerase 1 (Top 1) inhibitor, a camptothecin derivative, irinotecan (CPT-11), SN-38, topotecan, a topoisomerase 2 (Top 2) inhibitor, doxorubicin, etoposide, ciprofloxacin, an mTOR inhibitor, at least one STING polypeptide or a portion thereof, a nucleic acid encoding the STING polypeptide or a portion thereof, a STING inhibitor, a STING activator, a STING agonist, a STING antagonist, a STING modulatory molecule, an IDO inhibitor, an IDO1 inhibitor, or a combination thereof, wherein the mTOR inhibitor includes everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, veltusertib, rufolimus, one or more dual PI3K-mTOR inhibitors, one or more ATP-competitive mTORC1 / 2 inhibitors, derivatives thereof, or a combination thereof. In some cases, the biologically active agent can comprise 7-ethyl-10-hydroxycamptothecin (SN-38).

[0308] The bioactive agent may include at least a compound of formula (1) to formula (29) ( Figure 12A-12E ), a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

[0309] In some cases, the bioactive agent may comprise a compound having the formula

[0310] Formula (1)

[0311]

[0312] Formula (4)

[0313]

[0314] A pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

[0315] In some cases, the disease may include one or more immune diseases, infectious diseases, cancers, and combinations thereof.

[0316] In some cases, the polymer may include a polyoxazoline (POX) comprising a linear portion, a branched portion, or a combination thereof, and wherein the polyoxazoline (POX) includes poly(2-oxazoline), poly(2-methyloxazoline), poly(2-ethyloxazoline), poly(2-propyloxazoline), poly(isopropyloxazoline), or a combination thereof.

[0317] Applicants unexpectedly discovered that when the polymer contains a certain amount of H-containing first end groups, improved nanoaggregate formation can be achieved. Applicants further discovered that when the polymer contains a certain amount of H-containing first end groups as disclosed herein, improved preparation methods can be achieved, such as shorter production cycle time, less mixing energy and other advantages.

[0318] The present disclosure will now be illustrated in the following non-limiting examples.

[0319] Example

[0320] The present invention is further defined in the following examples. It should be understood that these examples, although representing preferred embodiments of the present invention, are given by way of illustration only. From the above discussion and examples, those skilled in the art will be able to determine the essential characteristics of the present invention and to make various changes and modifications to the present invention to adapt it to various uses and conditions without departing from its spirit and scope.

[0321] Materials and measurements

[0322] polymer

[0323] As previously described in PCT Publication WO2014 / 123791 (incorporated herein by reference), an initiator (CH 3 (CH 2 ) 17 )-Br prepared hydrocarbon (CH 3 (CH 2 ) 17 ) modified randomly branched PEOX polymer (hereinafter referred to as "C 18 PEOXABP60”).

[0324] As described above, the initiator (CH 3 (CH 2 ) 5 )-Br Another hydrocarbon-modified randomly branched PEOX polymer with a monomer to initiator molar ratio of 60:1 was prepared.

[0325] As described above, the initiator (CH 3 (CH 2 ) 11)-Br Another hydrocarbon-modified randomly branched PEOX polymer with a monomer to initiator molar ratio of 60:1 was prepared.

[0326] Another hydrocarbon-modified randomly branched PEOX polymer having a monomer to initiator molar ratio = 60:1 was prepared as described above using the initiator methyl p-toluenesulfonate.

[0327] A hydrogen-modified randomly branched PEOX polymer (herein "H-PEOXABP60") having a monomer to initiator molar ratio = 60:1 was prepared as described above with p-toluenesulfonic acid as the initiator.

[0328] Another hydrogen-modified randomly branched PEOX polymer having a monomer to initiator molar ratio = 60:1 was prepared as described above using the initiator trifluoroacetic acid.

[0329] The hydrogen-modified randomly branched PEOX polymers having a monomer to initiator molar ratio of 60:1 are collectively referred to as "H-PEOXABP60".

[0330] Table 1 shows the results of the experiments with H(H-PEOXABP60) and C 18 Hydrocarbon (C 18 Some non-limiting examples of polymers with various first ends modified with PEOXABP60). H and C 18 The presence of hydrocarbon modified first end groups was measured by HPLC. 18 The molar ratio of hydrocarbons and the percentage of H.

[0331] Table 1. Examples of mixed polymers H-PEOXABP60 and C 18 H and C of PEOXABP60 18 The ratio of hydrocarbons and the percentage of H (molar ratio).

[0332]

[0333] Initiator molar ratio = 60:1 containing hydrocarbon (CH 3 (CH 2 ) 17 ) modified first terminal and H modified first terminal (hereinafter referred to as "H / C 18 PEOXABP60”) was used to generate nanoaggregates.

[0334] With H / C of about 0.3 18 Polymer H / C 18PEOXABP60 is terminated with a hydroxyl group as the second end group in water (referred to herein as "Polymer A1"). The pH value of the aqueous solution of the polymer is in the range of 3.0 to 6.9. If necessary, the aqueous solution of the polymer can be adjusted to have a pH value in the range of 5.6 to 7.5 or 3.0 to 10 using HCl or NaOH.

[0335] With H / C of 0.4 18 Polymer H / C 18 PEOXABP60 is terminated with a hydroxyl group as a second end group in water (referred to herein as "Polymer A2"). The aqueous solution of the polymer can be adjusted to have a pH value in the range of 3.0 to 6.9. The aqueous solution of another polymer can be adjusted with HCl or NaOH to have a pH value in the range of 7.0 to 10 or 5.6 to 7.5.

[0336] With H / C of about 0.7 18 Polymer H / C 18 PEOXABP60 is terminated with a hydroxyl group as a second end group in water (referred to herein as "Polymer A3"). The aqueous solution of the polymer has a pH value in the range of 3.0 to 6.9. If necessary, the aqueous solution of the polymer can be adjusted with HCl or NaOH to have a pH value in the range of 7.0 to 10 or 5.6 to 7.5.

[0337] All H / C 18 PEOXABP60 polymer can be called H / C 18 PEOXABP60-OH.

[0338] With H / C of about 0.7 18 Polymer H / C 18 PEOXABP60 is end-capped with EDA (the molar ratio of the polyoxazoline reactive chain end to EDA is about 1:10), producing a polymer having a second end group comprising a group modified with a primary amine (referred to herein as "Polymer B1"). The aqueous solution of the polymer has a pH value in the range of 7.0 to 10. HCl or NaOH can be used to adjust the aqueous solution of another polymer to have a pH value in the range of 8.9 to 9.7. The aqueous solution of another polymer can be adjusted to have a pH value in the range of 3.0 to 6.9.

[0339] With H / C of about 0.4 18 Polymer H / C 18PEOXABP60 is end-capped with EDA (the molar ratio of polyoxazoline reactive chain ends to EDA is about 1:10), resulting in a polymer having a second end group comprising a group modified with a primary amine (referred to herein as "Polymer B2"). An aqueous solution of the polymer may be adjusted to have a pH in the range of 7.0 to 10. An aqueous solution of another polymer may be adjusted to have a pH in the range of 3.0 to 10 or 5.6 to 7.5 using HCl or NaOH.

[0340] With H / C of about 0.3 18 Polymer H / C 18 PEOXABP60 was end-capped with EDA (the molar ratio of polyoxazoline reactive chain ends to EDA was about 1:10), resulting in a polymer having a second end group comprising a group modified with a primary amine (referred to herein as "Polymer B3"). An aqueous solution of the polymer may be adjusted to have a pH in the range of 7.0 to 10. An aqueous solution of another polymer may be adjusted to have a pH in the range of 3.0 to 10 or 5.6 to 7.5 using HCl or NaOH.

[0341] All with -NH 2 The H / C 18 PEOXABP60 polymer can be called H / C 18 PEOXABP60-NH 2 .

[0342] Nanoparticle measurements

[0343] The sizes of various polymers, polymer-only nanoaggregates, and drug-induced polymer-drug nanoaggregates were measured by dynamic light scattering (DLS) using a Malvern Zetasizer Nano ZS Zen 3600 particle size analyzer (Malvern Panalytical Inc., Westborough, MA01581, USA).

[0344] Example 1-2

[0345] With H / C 18 PEOXABP60-A (Polymer A1) polymer:rapamycin nanoparticles

[0346] H / C 18 PEOXABP60-A (polymer A1) (750 mg) and rapamycin (150 mg) were dissolved in 5 mL of methanol for about 20 minutes. The methanol was then removed using a rotary evaporator to produce dry nanoaggregates. The dried nanoaggregate powder was re-dissolved in water to produce an aqueous solution of nanoaggregates containing 3.5 mg / mL or 5 mg / mL rapamycin (weight ratio of polymer: rapamycin = 5:1). Examples of light scattering (LS) measurement data are shown in Fig.11AThe size of the nanoaggregates ranges from 100 to about 106 nm.

[0347] H / C 18 PEOXABP60-A (polymer A1) (750 mg) and rapamycin (100 mg) were dissolved in 5 mL of methanol and treated as described above to produce aqueous nanoaggregate solutions containing 3.5 mg / mL or 5 mg / mL rapamycin (weight ratio of polymer: rapamycin = 7.5:1). Examples of LS measurement data are shown in Fig. 11B The size of the nanoaggregates ranges from 100 to about 102 nm.

[0348] The aqueous solution of nanoaggregates was passed through a 0.8 μm filter and then a 0.22 μm filter. The filtrate (i.e., sterilized nanoaggregates) was aliquoted and lyophilized for more than 24 hours depending on the amount of lyophilized nanoaggregates used to produce the lyophilized nanoaggregates. The vials were stoppered and the ready-to-use white powder was stored at room temperature.

[0349] Example 3

[0350] With H / C 18 PEOXABP60-NH 2 (Polymer B1) Polymer:Rapamycin Nanoparticles

[0351] H / C 18 PEOXABP60-NH 2 (Polymer B1) (750 mg) and rapamycin (150 mg) were dissolved in 5 mL of methanol and treated as described above to produce an aqueous solution of nanoaggregates containing 5 mg / mL rapamycin (weight ratio of polymer:rapamycin = 5:1). Examples of LS measurement data are shown in Fig. 11C The size of the nanoaggregates in the finished product (ie after freeze-drying) ranged from 91 to about 112 nm.

[0352] The aqueous solution of nanoaggregates was passed through a 0.8 μm filter and then a 0.22 μm filter. The filtrate (i.e., sterilized nanoaggregates) was aliquoted and lyophilized for more than 24 hours depending on the amount of nanoaggregates used to produce lyophilized nanoaggregates. The vials were stoppered and the ready-to-use white powder was stored at room temperature.

[0353] Example 4

[0354] Rapamycin stability assay

[0355] The stability of the nanoaggregates prepared in Examples 1-3 was measured by measuring the degradation products and impurities of rapamycin by HPLC at room temperature and over a period of 0-147 hours.

[0356] The nanoaggregates prepared in Examples 1-3 have good stability over the measured time period.

[0357] Example 5

[0358] With H / C 18 PEOXABP60-A (polymer A1) polymer: nanoparticles of formula (1)

[0359] The above prepared H / C 18 The polymer A1 (100 mg) was mixed with the compound of formula (1) (2 mg) in 1 mL of water and treated as 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.

[0360] Example 6

[0361] With H / C 18 PEOXABP60-A (polymer A3) polymer: nanoparticles of formula (1)

[0362] The above prepared H / C 18 The polymer A3 (500 mg) was mixed with the compound of formula (1) (10 mg) in 5 mL of water and treated as 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.

[0363] Example 7

[0364] With H / C 18 PEOXABP60-NH 2 (Polymer B3) Nanoparticles with a polymer:paclitaxel ratio of 3:1 to 10:1 grain

[0365] As a routine procedure, paclitaxel was dissolved in methanol to a concentration of up to 40 mg / mL. Polymer B3 was dissolved in methanol alone to a concentration of up to 100 mg / mL. The two solutions were then mixed by volume to result in a final polymer to paclitaxel weight ratio of 3:1 to 10:1 in the mixture. The mixture was then lyophilized.

[0366] The size of the aggregates measured by light scattering was approximately 70 to 90 nm in diameter before lyophilization and 120-140 nm after lyophilization.

[0367] Alternatively, paclitaxel and polymer B3 can be dissolved in a common solvent (e.g., acetone, methanol, or ethanol) and then added dropwise to water while stirring or sonicating, followed by sterile filtration with a 0.22 μm filter. The finished product can then be produced by lyophilization, and the size of the aggregates measured by light scattering.

[0368] Branched polymers (e.g., C 4 , C 6 , C 12 or C 22 Hydrocarbon modified randomly branched PEOX, PEI and PPI polymers, C 4 , C 6 , C 12 , C18 and C 22 Hydrocarbon-modified PAMAM, PEI and PPI dendrimers and dendrimer grafts, and C 4 , C 6 , C 12 , C 18 and C 22 Other taxane-induced aggregates or nanoparticles of branched PLL / polymers (such as hydrocarbon-modified PLL).

[0369] Example 8

[0370] With H / C 18 PEOXABP60-NH 2 (Polymer B3) Nanoparticles with a polymer:paclitaxel ratio of 7:1

[0371] H / C 18 PEOXABP60-NH 2 (Polymer B3) (700mg) was dissolved in 9.33mL methanol to obtain a solution of 75mg / mL. A 15mg / mL paclitaxel solution was also prepared by dissolving 100mg paclitaxel in 6.67mL methanol. The two solutions were mixed for 20 minutes to obtain a solution containing 6.25mg paclitaxel and 43.75mg polymer per mL, providing a solution with a polymer:drug ratio of 7:1. The mixture was placed on a rotary evaporator, and methanol was removed to dryness. The resulting solid was redissolved in 33.3mL water (while stirring) to a final concentration of paclitaxel of 3mg / mL. The solution was passed through a 0.8μm filter and then a 0.22μm filter. The lyophilized filtrate. The vial was plugged and stored at room temperature as a ready-to-use white powder.

[0372] Examples 9-11

[0373] With H / C 18 PEOXABP60-A (polymer A2) polymer: (SN-38 / irinotecan) nanoparticles

[0374] At 50°C and with stirring, 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) for about 20 minutes. The organic solvent was then removed using a rotary evaporator to produce dry nanoaggregates. The dried nanoaggregate powder was re-dissolved in 5% glucose to produce an aqueous solution of nanoaggregates containing 2 mg / mL of total API (polymer: (SN-38 / irinotecan) weight ratio = 4: 1, SN-38 / irinotecan molar ratio = 2.5 / 1). An example of LS measurement data is shown in Fig.14A (Formulation 1). The size of the nanoaggregates was about 110 nm.

[0375] At 50°C and with stirring, H / C 18PEOXABP60-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) for about 20 minutes. The organic solvent was then removed using a rotary evaporator to produce dry nanoaggregates. The dried nanoaggregate powder was re-dissolved in 5% glucose to produce an aqueous solution of nanoaggregates containing 2 mg / mL total API (weight ratio of polymer: (SN-38 / irinotecan) = 2.6: 1, molar ratio of SN-38 / irinotecan = 1.5 / 1). Examples of LS measurement data are shown in Fig. 14B (Formulation 2). The size of the nanoaggregates was about 110 nm.

[0376] At 50°C and with stirring, 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) for about 20 minutes. The organic solvent was then removed using a rotary evaporator to produce dry nanoaggregates. The dried nanoaggregate powder was re-dissolved in 5% glucose to produce an aqueous solution of nanoaggregates containing 2 mg / mL total API (weight ratio of polymer: (SN-38 / irinotecan) = 4: 1, molar ratio of SN-38 / irinotecan = 5 / 1). Examples of LS measurement data are shown in Fig. 14C (Formulation 3). The size of the nanoaggregates was about 120 nm.

[0377] At 50°C, H / C 18 PEOXABP60-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) for about 30 minutes. The organic solvent was then removed using a rotary evaporator to produce dry nanoaggregates. The dried nanoaggregate powder was re-dissolved in 5% glucose to produce an aqueous solution of nanoaggregates containing 2 mg / mL total API (weight ratio of polymer: (SN-38 / irinotecan) = 1.75: 1, molar ratio of SN-38 / irinotecan = 1 / 1). Examples of LS measurement data are shown in Fig.14D (Formulation 4). The size of the nanoaggregates was about 94 nm.

[0378] With H / C 18 PEOXABP60-B (polymer B1) polymer: (SN-38 / irinotecan) nanoparticles

[0379] At 50°C and with stirring, H / C 18PEOXABP60-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) for about 30 minutes. The organic solvent was then removed using a rotary evaporator to produce dry nanoaggregates. The dried nanoaggregate powder was re-dissolved in 5% glucose to produce an aqueous solution of nanoaggregates containing 2 mg / mL total API (weight ratio of polymer: (SN-38 / irinotecan) = 1.75: 1, molar ratio of SN-38 / irinotecan = 2.5 / 1). Examples of LS measurement data are shown in Fig.14E (Formulation 3). The size of the nanoaggregates was about 108 nm.

[0380] The aqueous solution of nanoaggregates was passed through a 0.8 μm filter and then a 0.2 μm filter. The filtrate (i.e., sterilized nanoaggregates) was aliquoted and lyophilized for 24-100 hours depending on the amount of nanoaggregates used to prepare lyophilization. The vials were stoppered and the ready-to-use white powder was stored at room temperature.

[0381] Example 12

[0382] Maximum tolerated dose (MTD) studies in mice

[0383] Severe combined immunodeficient (SCID) mice were injected with various amounts of irinotecan / CPT-11 and nano-SN-38 produced in Examples 10-12 until the MTD was reached.

[0384] Example 13

[0385] Cell-based cytotoxicity assays

[0386] SN-38 was tested for cytotoxicity against HCT-116 cell lines using a standard in vitro cytotoxicity assay. Cell viability was evaluated using the Promega Cell Titer 96 Aqueous One kit. Overall, Nano-formulated SN-38 was approximately 250-fold more cytotoxic than irinotecan, exhibiting a half-maximal effective concentration (EC) of approximately 0.13 μM for HCT-116 cells. 50 ), while irinotecan has an EC of about 32.6 μM 50 ( Fig.15 ). Nano-SN-38 was tested on cells: produced in the above example and polymer:SN-38=4:1; SN-38 / irinotecan mixture: a physical mixture of SN-38 and irinotecan in a molar ratio of 4:1 dissolved in DMSO; SN-38 control: SN-38 dissolved in DMSO (dimethyl sulfoxide); and irinotecan control: irinotecan dissolved in water. Representative measurement data are shown in Fig.15 and Table 2.

[0387] Table 2. Cytotoxicity data

[0388] preparation Cell lines <![CDATA[EC 50 (μM)]]> Nano SN-38(4:1) HCT-116 0.13 SN-38 / irinotecan mixture HCT-116 0.11 Irinotecan control HCT-116 32.6 SN-38 control HCT-116 0.10

[0389] Embodiment 14

[0390] With H / C 18 PEOXABP60-A (polymer A1) polymer: nanoparticles of formula (1)

[0391] The prepared above-mentioned 18 The polymer A1 (200 mg) of formula (1) was dissolved in water to produce a 100 mg / g solution. The compound of formula (1) (8 mg) was added to the polymer solution and the mixture was processed as described above to produce an aqueous solution of nanoaggregates of formula (1) containing 2 mg / mL with a weight ratio of polymer: formula (1) = 25:1. The solution was filtered with a 0.8 μm filter and then a 0.22 μm filter, and then lyophilized for 20-100 h to produce a lyophilized dry powder. The vial was stoppered and the ready-to-use white powder was stored at room temperature.

[0392] The prepared above-mentioned 18 The polymer A1 (400 mg) of formula (1) was dissolved in water to produce a 100 mg / g solution. The compound of formula (1) (8 mg) was added to the polymer solution and the mixture was processed as described above to produce an aqueous solution of nanoaggregates of formula (1) containing 2 mg / mL with a weight ratio of polymer: formula (1) = 50:1. The solution was filtered with a 0.8 μm filter and then a 0.22 μm filter, and then lyophilized for 20-100 h to produce a lyophilized dry powder. The vial was stoppered and the ready-to-use white powder was stored at room temperature.

[0393] With H / C 18 PEOXABP60-A (polymer A2) polymer: nanoparticles of formula (1)

[0394] The prepared above-mentioned 18 The polymer A2 (400 mg) of formula (1) was dissolved in water to produce a 100 mg / g solution. The compound of formula (1) (8 mg) was added to the polymer solution and the mixture was processed as described above to produce an aqueous solution of nanoaggregates of formula (1) containing 2 mg / mL with a weight ratio of polymer: formula (1) = 50:1. The solution was filtered with a 0.8 μm filter and then a 0.22 μm filter, and then lyophilized for 20-100 h to produce a lyophilized dry powder. The vial was stoppered and the ready-to-use white powder was stored at room temperature.

[0395] The prepared above-mentioned 18The polymer A3 (400 mg) of the present invention is dissolved in water to produce a 100 mg / g solution. The compound of formula (1) (8 mg) is added to the polymer solution and the mixture is processed as described above to produce an aqueous solution of nanoaggregates of formula (1) containing 2 mg / mL with a weight ratio of polymer: formula (1) = 50:1. The solution is filtered with a 0.8 μm filter and then a 0.22 μm filter, and then freeze-dried for 20-100 h to produce a freeze-dried dry powder. The vial is stoppered and the ready-to-use white powder is stored at room temperature.

[0396] Embodiment 15

[0397] Adjuvant formulation 5: The above-prepared 18 The polymer B3 (400 mg) of the present invention is dissolved in water to produce a 100 mg / g solution. The compound of formula (1) (8 mg) is added to the polymer solution and the mixture is processed as 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 is filtered with a 0.8 μm filter and then a 0.22 μm filter, and then freeze-dried for 20-100 h to produce a freeze-dried dry powder. The vial is stoppered and the ready-to-use white powder is stored at room temperature.

[0398] The prepared above-mentioned 18 The polymer B3 (200 mg) of formula (1) was dissolved in water to produce a 100 mg / g solution. The compound of formula (1) (8 mg) was added to the polymer solution and the mixture was processed as 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 with a 0.8 μm filter and then a 0.22 μm filter, and then freeze-dried for 20-100 h to produce a freeze-dried dry powder. The vial was stoppered and the ready-to-use white powder was stored at room temperature.

Claims

1. A pharmaceutical composition comprising: A nanoaggregate comprising a polymer and at least one water-insoluble or poorly water-soluble bioactive agent; and Optionally, a pharmaceutically suitable carrier; wherein the pharmaceutical composition is soluble in an aqueous solution to produce at least 1 mg / mL of the at least one biologically active agent dissolved in the aqueous solution; wherein the polymer is water soluble; and 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 1% to 99% H and 1% to 99% of the hydrophobic moiety, the hydrophobic moiety comprises a saturated or unsaturated aliphatic hydrocarbon, an aromatic hydrocarbon, or a combination thereof having 1 to about 22 carbons, and the second end group comprises a group modified with an amine, an amide, an imine, an imide, a carboxyl group, a hydroxyl group, an ester, an ether, an acetate, a phosphate, a ketone, an aldehyde, a sulfonate, or a combination thereof; or A second polymer comprising one or more hydroxy dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 generation dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); polycaprolactone (PCL); (PPO-PEO); poly(γ-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(vinylamine) (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-glutamate) (PBLG); phosphatidylserine (PS); poly(isohexyl cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); or Its combination.

2. The pharmaceutical composition of claim 1, wherein the polymer comprises the first polymer.

3. The pharmaceutical composition of claim 1, wherein the polymer comprises the second polymer, the second polymer comprising the one or more hydroxy dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 generation dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); polycaprolactone (PCL); (PPO-PEO); poly (γ-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 (vinylamine) (PEI); poly (N-vinyl pyrrolidone) (PVP); poly (L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly (hydroxybutyrate) (PHB); poly (ethylene oxide) (PEO); poly (L-glutamic acid-γ-benzyl ester) (PBLG); phosphatidylserine (PS); poly (isohexyl cyanoacrylate) (PIHCA); poly (allylamine hydrochloride) (PAH); poly (γ-propargyl) (PP); or a combination thereof.

4. according to the pharmaceutical composition described in any one in claim 1 to 3, wherein said polymer comprises poly-oxazoline (POX), and said poly-oxazoline comprises linear part, branched part or its combination, and wherein said poly-oxazoline (POX) comprises poly-(2-methyloxazoline), poly-(2-ethyloxazoline), poly-(2-propyloxazoline) and poly-(isopropyloxazoline), or its combination.

5. The pharmaceutical composition of claim 4, wherein the polyoxazoline is poly(2-ethyloxazoline).

6. according to the pharmaceutical composition described in any one in claim 4 to 5, wherein said polyoxazoline is included in the mol ratio of monomer and initiator in the scope of 50:1 to 80:

1.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein 1% to 100% of the second end groups do not contain primary amines.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein 1% to 100% of the second terminal groups comprise hydroxyl groups.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the size of the nanoaggregates before lyophilization is less than 120 nm.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the nanoaggregates have a weight ratio of the polymer to the bioactive agent in the range of about 2:1 to about 200:

1.

11. according to the pharmaceutical composition described in any one in claim 1 to 10, wherein said nano aggregate further comprises a targeting moiety, and said targeting moiety comprises an antibody, an antigen binding portion thereof, an antigen, a cell receptor, a cell receptor ligand, a ligand of a cell protein, a ligand of a membrane protein, a small molecule ligand, a lectin ligand or a combination thereof.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the nanoaggregates do not contain human serum albumin, organic solvents, detergents or oils.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the pharmaceutical composition does not contain human serum albumin, organic solvents, detergents or oils.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the bioactive agent comprises a drug based on natural or synthetic small molecules, an inorganic-based drug, a biological drug, a drug based on natural or synthetic macromolecules, a derivative thereof, or a combination thereof.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the bioactive agent comprises a taxane, paclitaxel, docetaxel, cabazitaxel, larotaxel, milatataxel, ortataxel, tesetaxel, a topoisomerase 1 (Top1) inhibitor, a camptothecin derivative, irinotecan (CPT-11), SN-38, topotecan, topoisomerase 2 (Top 2) inhibitors, doxorubicin, etoposide, ciprofloxacin, mTOR inhibitors, at least one STING polypeptide or a portion thereof, a nucleic acid encoding the STING polypeptide or a portion thereof, a STING inhibitor, a STING activator, a STING agonist, a STING antagonist, a STING regulatory molecule, an IDO inhibitor, an IDO1 inhibitor, or a combination thereof, wherein the mTOR inhibitor comprises everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, veltusertib, rifolimus, one or more dual PI3K-mTOR inhibitors, one or more ATP-competitive mTORC1 / 2 inhibitors, derivatives thereof, or a combination thereof.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the pharmaceutical composition is a medicament for treating or preventing a disease selected from one or more immune diseases, infectious diseases, cancers, and combinations thereof.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the bioactive agent comprises at least one compound having Formula (1) to Formula (29), a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

18. A pharmaceutical composition according to any one of claims 1 to 17, wherein the bioactive agent comprises a compound having the formula Formula (1) Formula (4) A pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

19. The pharmaceutical composition according to claim 18, wherein the pharmaceutical composition is an adjuvant for a vaccine.

20. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition is a prophylactic vaccine, a therapeutic vaccine, or a combination thereof, wherein the pharmaceutical composition further comprises at least one immunizing agent for stimulating an immune response in a subject in need thereof.

21. The pharmaceutical composition of claim 20, wherein the immunizing agent comprises an inactive microorganism selected from bacteria, viruses, fungi, protozoa, worms, parasites, prions, parts thereof, or combinations thereof; toxins; nucleic acids encoding the toxins; proteins; nucleic acids encoding the proteins; oligonucleic acids; DNA; RNA; mRNA; siRNA; sgRNA; fragments thereof; or combinations thereof.

22. The pharmaceutical composition according to any one of claims 18 to 21, wherein the pharmaceutical composition is formulated for the treatment or prevention of at least one infectious disease.

23. The pharmaceutical composition of claim 22, wherein the pharmaceutical composition is formulated for the treatment or prevention of at least one infectious disease selected from the group consisting of varicella, coronavirus, dengue fever, diphtheria, Ebola, influenza, hepatitis, Hib disease, HIV / AIDS, HPV (human papillomavirus), Japanese encephalitis, measles, meningococcal disease, monkeypox, mumps, norovirus, pneumococcal disease, poliomyelitis, rabies, respiratory syncytial virus (RSV), rotavirus, rubella (German measles), herpes zoster, tetanus, pertussis, Zika, and combinations thereof.

24. The pharmaceutical composition of any one of claims 1 to 23, wherein the bioactive agent comprises a topoisomerase 1 (Top 1) inhibitor, a camptothecin derivative, irinotecan (CPT-11), SN-38, topotecan, a topoisomerase 2 (Top 2) inhibitor, doxorubicin, etoposide, ciprofloxacin, or a combination thereof.

25. The pharmaceutical composition according to any one of claims 1 to 24, wherein the pharmaceutical composition further comprises one or more subsequent bioactive agents selected from the group consisting of proteins, peptides, antibodies, antibody fragments, compounds, small molecule drugs, one or more chemotherapeutic drugs, and combinations thereof. The pharmaceutical composition further comprises one or more subsequent bioactive agents selected from the group consisting of proteins, peptides, antibodies, antibody fragments, compounds, small molecule drugs, one or more chemotherapeutic drugs, and combinations thereof.

26. A method for treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject an effective dose of a pharmaceutical composition, the pharmaceutical composition include: A nanoaggregate comprising a polymer and at least one water-insoluble or poorly water-soluble bioactive agent; and Optionally, a pharmaceutically suitable carrier; wherein the pharmaceutical composition is soluble in an aqueous solution to produce at least 1 mg / mL of the bioactive agent dissolved in the aqueous solution; wherein the polymer is water soluble; and 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 1% to 99% H and 1% to 99% of the hydrophobic moiety, the hydrophobic moiety comprises a saturated or unsaturated aliphatic hydrocarbon, an aromatic hydrocarbon, or a combination thereof having 1 to about 22 carbons, and the second end group comprises a group modified with an amine, an amide, an imine, an imide, a carboxyl group, a hydroxyl group, an ester, an ether, an acetate, a phosphate, a ketone, an aldehyde, a sulfonate, or a combination thereof; or A second polymer comprising one or more hydroxy dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 generation dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); polycaprolactone (PCL); (PPO-PEO); poly(γ-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(vinylamine) (PEI); poly(N-vinylpyrrolidone) (PVP); poly(L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly(hydroxybutyrate) (PHB); polyethylene oxide (PEO); poly(γ-benzyl L-glutamate) (PBLG); phosphatidylserine (PS); poly(isohexyl cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); or Its combination.

27. The method of claim 26, wherein the polymer comprises the first polymer.

28. The method of claim 26, wherein the polymer comprises the second polymer, the second polymer comprising the one or more hydroxy dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 generation dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); polycaprolactone (PCL); (PPO-PEO); poly (γ-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 (vinylamine) (PEI); poly (N-vinyl pyrrolidone) (PVP); poly (L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly (hydroxybutyrate) (PHB); poly (ethylene oxide) (PEO); poly (L-glutamic acid-γ-benzyl ester) (PBLG); phosphatidylserine (PS); poly (isohexyl cyanoacrylate) (PIHCA); poly (allylamine hydrochloride) (PAH); poly (γ-propargyl) (PP); or a combination thereof.

29. according to the method described in any one in claim 26 to 28, wherein said polymkeric substance comprises poly-oxazoline (POX), and said poly-oxazoline comprises linear moiety, branched moiety or its combination, and wherein said poly-oxazoline (POX) comprises poly-(2-methyloxazoline), poly-(2-ethyloxazoline), poly-(2-propyloxazoline) and poly-(isopropyloxazoline), or its combination.

30. The method of claim 29, wherein the polyoxazoline is poly(2-ethyloxazoline).

31. according to the method described in any one in claim 29 to 30, wherein said poly-oxazoline is included in the mol ratio of the monomer in the scope of 50:1 to 80:1 and initiator.

32. The method of any one of claims 26 to 31, wherein the size of the nanoaggregates prior to lyophilization is less than 120 nm.

33. The method of any one of claims 26 to 32, wherein the nanoaggregates have a weight ratio of the polymer to the bioactive agent in the range of about 2:1 to about 200:

1.

34. according to the method described in any one in claim 26 to 33, wherein said nano-aggregate further comprises a targeting moiety, and said targeting moiety comprises an antibody, an antigen binding portion thereof, an antigen, a cell receptor, a cell receptor ligand, a ligand of a cellular protein, a ligand of a membrane protein, a small molecule ligand, a lectin ligand or a combination thereof.

35. The method of any one of claims 26 to 34, wherein the nanoaggregates are free of human serum albumin, organic solvents, detergents or oils.

36. The method of any one of claims 26 to 35, wherein the pharmaceutical composition does not contain human serum albumin, organic solvents, detergents or oils.

37. The method of any one of claims 26 to 36, wherein the bioactive agent comprises a drug based on natural or synthetic small molecules, an inorganic-based drug, a biological drug, a drug based on natural or synthetic macromolecules, a derivative thereof, or a combination thereof.

38. The method according to any one of claims 26 to 37, wherein the bioactive agent comprises a taxane, paclitaxel, docetaxel, cabazitaxel, larotaxel, milatataxel, ortataxel, tesetaxel, a topoisomerase 1 (Top 1) inhibitor, a camptothecin derivative, irinotecan (CPT-11), SN-38, topotecan, topoisomerase 2 (Top 2) inhibitors, doxorubicin, etoposide, ciprofloxacin, mTOR inhibitors, at least one STING polypeptide or a portion thereof, a nucleic acid encoding the STING polypeptide or a portion thereof, a STING inhibitor, a STING activator, a STING agonist, a STING antagonist, a STING regulatory molecule, an IDO inhibitor, an IDO1 inhibitor, or a combination thereof, wherein the mTOR inhibitor comprises everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, veltusertib, rifolimus, one or more dual PI3K-mTOR inhibitors, one or more ATP-competitive mTORC1 / 2 inhibitors, derivatives thereof, or a combination thereof.

39. The method according to any one of claims 26 to 38, wherein the pharmaceutical composition is a medicament for treating or preventing a disease selected from one or more immune diseases, infectious diseases, cancers, and combinations thereof.

40. The method according to any one of claims 26 to 39, wherein the bioactive agent comprises at least one compound having Formula (1) to Formula (29), a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

41. The method of any one of claims 26 to 40, wherein the bioactive agent comprises a compound having the formula Formula (1) Formula (4) A pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

42. The method of any one of claims 26 to 41, wherein the pharmaceutical composition is administered to the subject by intravenous (IV) injection, subcutaneous (SC) injection, intramuscular (IM) injection, intradermal (ID) injection, or a combination thereof.

43. The method of any one of claims 26 to 42, wherein the pharmaceutical composition is an adjuvant for a vaccine.

44. The method of any one of claims 26 to 42, wherein the pharmaceutical composition is a prophylactic vaccine, a therapeutic vaccine, or a combination thereof, wherein the pharmaceutical composition further comprises at least one immunizing agent for stimulating an immune response in a subject in need thereof.

45. The method of any one of claims 43 to 44, wherein the pharmaceutical composition is selected for the treatment or prevention of at least one infectious disease selected from the group consisting of varicella, coronavirus, dengue fever, diphtheria, Ebola, influenza, hepatitis, Hib disease, HIV / AIDS, HPV (human papillomavirus), Japanese encephalitis, measles, meningococcal disease, monkeypox, mumps, norovirus, pneumococcal disease, poliomyelitis, rabies, respiratory syncytial virus (RSV), rotavirus, rubella (German measles), herpes zoster, tetanus, pertussis, Zika, and combinations thereof.

46. ​​The method of any one of claims 26 to 45, wherein from 1% to 100% of the second end groups are free of primary amines.

47. The method of any one of claims 26 to 46, wherein from 1% to 100% of the second end groups comprise hydroxyl groups.

48. The method of any one of claims 26 to 47, wherein the bioactive agent comprises a topoisomerase 1 (Top 1) inhibitor, a camptothecin derivative, irinotecan (CPT-11), SN-38, topotecan, a topoisomerase 2 (Top 2) inhibitor, doxorubicin, etoposide, ciprofloxacin, or a combination thereof.

49. The method of any one of claims 26 to 48, further comprising the step of administering to the subject one or more subsequent bioactive agents selected from the group consisting of proteins, peptides, antibodies, antibody fragments, compounds, small molecule drugs, one or more chemotherapeutic drugs, vaccines, and combinations thereof, wherein each of the one or more subsequent bioactive agents is administered to the subject before, simultaneously with, or after administration of the pharmaceutical composition.

50. The method of claim 49, wherein the one or more subsequent bioactive agents are selected from gemcitabine, a taxane, paclitaxel, docetaxel, cabazitaxel, larotaxel, milatataxel, ortataxel, tesetaxel, topoisomerase 1 (TOPI) 1) inhibitors, camptothecin derivatives, irinotecan (CPT-11), SN-38, topotecan, topoisomerase 2 (Top2) inhibitors, doxorubicin, etoposide, ciprofloxacin, platinum-based anti-tumor agents, 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 α2a, interferon α, granulocyte colony stimulating factor (G-CSF), Eubojin or filgrastim, T cell receptor (TCR), chimeric antigen receptor or chimeric antigen T cell receptor (CAR-T), vaccines and combinations thereof.

51. A nanoaggregate comprising a polymer and at least one water-insoluble or poorly water-soluble bioactive agent; wherein the nanoaggregates are soluble in an aqueous solution to produce at least 1 mg / mL of the bioactive agent dissolved in the aqueous solution; wherein the polymer is water soluble; wherein the bioactive agent comprises a drug based on natural or synthetic small molecules, an inorganic-based drug, a biological drug, a drug based on natural or synthetic macromolecules, a derivative thereof, or a combination thereof; and 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 1% to 99% H and 1% to 99% of the hydrophobic moiety, the hydrophobic moiety comprises a saturated or unsaturated aliphatic hydrocarbon, an aromatic hydrocarbon, or a combination thereof having 1 to about 22 carbons, and the second end group comprises a group modified with an amine, an amide, an imine, an imide, a carboxyl group, a hydroxyl group, an ester, an ether, an acetate, a phosphate, a ketone, an aldehyde, a sulfonate, or a combination thereof; or A second polymer comprising one or more hydroxy dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 generation dendrimers or combinations thereof; poly(ethylene glycol) (PEG); poly(lactic acid) (PLA); poly(lactic-co-glycolic acid) (PLGA); poly(propylene oxide) (PPO); polycaprolactone (PCL); (PPO-PEO); poly(γ-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(vinylamine) (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-glutamate) (PBLG); phosphatidylserine (PS); poly(isohexyl cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); or Its combination.

52. according to the nano-aggregate described in claim 51, wherein said polymer comprises poly-oxazoline (POX), and said poly-oxazoline comprises linear part, branched part or its combination, and wherein said poly-oxazoline (POX) comprises poly-(2-methyloxazoline), poly-(2-ethyloxazoline), poly-(2-propyloxazoline) and poly-(isopropyloxazoline), or its combination.

53. The nanoaggregate of claim 52, wherein the polyoxazoline is poly(2-ethyloxazoline).

54. according to each nano-aggregate of claim 52 to 53, wherein said polyoxazoline comprises the mol ratio of monomer and initiator in the scope of 50:1 to 80:

1.

55. The nanoaggregate according to any one of claims 51 to 54, wherein 1% to 100% of the second end groups are free of primary amines.

56. The nanoaggregate according to any one of claims 51 to 55, wherein 1% to 100% of the second end groups comprise hydroxyl groups.

57. The nanoaggregate according to any one of claims 51 to 56, wherein the size of the nanoaggregate before lyophilization is less than 120 nm.

58. The nanoaggregate of any one of claims 51 to 57, wherein the nanoaggregate has a weight ratio of the polymer to the bioactive agent in the range of about 2:1 to about 200:

1.

59. The nanoaggregate of any one of claims 51 to 58, wherein the nanoaggregate has a weight ratio of the polymer to the bioactive agent in the range of about 5:1 to about 8:

1.

60. A nanoaggregate according to any one of claims 51 to 59, wherein the nanoaggregate further comprises a targeting moiety comprising an antibody, an antigen binding portion thereof, an antigen, a cell receptor, a cell receptor ligand, a ligand of a cellular protein, a ligand of a membrane protein, a small molecule ligand, a lectin ligand, or a combination thereof.

61. The nanoaggregate according to any one of claims 51 to 60, wherein the nanoaggregate does not contain human serum albumin, organic solvents, detergents or oils.

62. The nanoaggregate of any one of claims 51 to 61, wherein the bioactive agent comprises a taxane, paclitaxel, docetaxel, cabazitaxel, larotaxel, milatataxel, ortataxel, tesetaxel, a topoisomerase 1 (Top1) inhibitor, a camptothecin derivative, irinotecan (CPT-11), SN-38, topotecan, topoisomerase 2 (Top 2) inhibitors, doxorubicin, etoposide, ciprofloxacin, mTOR inhibitors, at least one STING polypeptide or a portion thereof, a nucleic acid encoding the STING polypeptide or a portion thereof, a STING inhibitor, a STING activator, a STING agonist, a STING antagonist, a STING regulatory molecule, an IDO inhibitor, an IDO1 inhibitor, or a combination thereof, wherein the mTOR inhibitor comprises everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, veltusertib, rifolimus, one or more dual PI3K-mTOR inhibitors, one or more ATP-competitive mTORC1 / 2 inhibitors, derivatives thereof, or a combination thereof.

63. The nanoaggregate according to any one of claims 51 to 62, wherein the pharmaceutical composition is a medicament for treating or preventing a disease selected from one or more immune diseases, infectious diseases, cancers, and combinations thereof.

64. The nanoaggregate according to any one of claims 51 to 63, wherein the bioactive agent comprises at least one compound of Formula (1) to Formula (29), a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

65. The nanoaggregate of claim 64, wherein the bioactive agent comprises a compound having the formula Formula (1) Formula (4) A pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

66. Use of nanoaggregates for preparing a drug for treating a disease, the nanoaggregates comprising a polymer and at least one water-insoluble or weakly water-soluble bioactive agent, and optionally a pharmaceutically suitable carrier; wherein the disease is selected from one or more immune diseases, infectious diseases, cancers, and combinations thereof; wherein the nanoaggregates are soluble in an aqueous solution to produce at least 1 mg / mL of the bioactive agent dissolved in the aqueous solution; wherein the polymer is water soluble; and wherein the bioactive agent comprises a drug based on natural or synthetic small molecules, an inorganic-based drug, a biological drug, a drug based on natural or synthetic macromolecules, a derivative thereof, or a combination thereof; and 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 1% to 99% H and 1% to 99% of the hydrophobic moiety, the hydrophobic moiety comprises a saturated or unsaturated aliphatic hydrocarbon, an aromatic hydrocarbon, or a combination thereof having 1 to about 22 carbons, and the second end group comprises a group modified with an amine, an amide, an imine, an imide, a carboxyl group, a hydroxyl group, an ester, an ether, an acetate, a phosphate, a ketone, an aldehyde, a sulfonate, or a combination thereof; or A second polymer comprising one or more hydroxy dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 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); (PPO-PEO); poly(γ-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(vinylamine) (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-glutamate) (PBLG); phosphatidylserine (PS); poly(isohexyl cyanoacrylate) (PIHCA); poly(allylamine hydrochloride) (PAH); poly(γ-propargyl) (PP); or Its combination.

67. The use of claim 66, wherein the polymer comprises the first polymer.

68. according to the purposes described in any one in claim 66 to 67, wherein said polymer comprises poly-oxazoline (POX), described poly-oxazoline comprises linear portion, branched portion or its combination, and wherein said poly-oxazoline (POX) comprises poly-(2-methyloxazoline), poly-(2-ethyloxazoline), poly-(2-propyloxazoline) and poly-(isopropyloxazoline), or its combination.

69. The use of claim 66, wherein the polymer comprises the second polymer, the second polymer comprising the one or more hydroxy dendrimers (HD); ethylenediamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated-4, 5, 6, 7, 8, 9, 10 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); (PPO-PEO); poly (γ-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 (vinylamine) (PEI); poly (N-vinyl pyrrolidone) (PVP); poly (L-leucine) (PLLeu); deoxycholic acid (DOCA); hydroxypropyl methylcellulose (HPMC); poly (hydroxybutyrate) (PHB); poly (ethylene oxide) (PEO); poly (L-glutamic acid-γ-benzyl ester) (PBLG); phosphatidylserine (PS); poly (isohexyl cyanoacrylate) (PIHCA); poly (allylamine hydrochloride) (PAH); poly (γ-propargyl) (PP); or a combination thereof.

70. The use according to claims 66 to 69, wherein the bioactive agent comprises a taxane, paclitaxel, docetaxel, cabazitaxel, larotaxel, milatataxel, ortataxel, tesetaxel, a topoisomerase 1 (Top 1) inhibitor, a camptothecin derivative, irinotecan (CPT-11), SN-38, topotecan, topoisomerase 2 (Top 2) inhibitors, doxorubicin, etoposide, ciprofloxacin, mTOR inhibitors, at least one STING polypeptide or a portion thereof, a nucleic acid encoding the STING polypeptide or a portion thereof, a STING inhibitor, a STING activator, a STING agonist, a STING antagonist, a STING regulatory molecule, an IDO inhibitor, an IDO1 inhibitor, or a combination thereof, wherein the mTOR inhibitor comprises everolimus, rapamycin, temsirolimus, zotarolimus, torin-1, torin-2, veltusertib, rifolimus, one or more dual PI3K-mTOR inhibitors, one or more ATP-competitive mTORC1 / 2 inhibitors, derivatives thereof, or a combination thereof.

71. The use according to any one of claims 66 to 70, wherein the pharmaceutical composition is a medicament for treating or preventing a disease selected from one or more immune diseases, infectious diseases, cancers, and combinations thereof.

72. The use according to any one of claims 66 to 71, wherein the bioactive agent comprises at least one compound of Formula (1) to Formula (29), a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

73. The use according to claim 72, wherein the bioactive agent comprises a compound having the formula Formula (1) Formula (4) A pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a combination thereof.

74. The use according to any one of claims 66 to 73, wherein the medicament is an adjuvant for a vaccine.

75. The use according to any one of claims 66 to 73, wherein the medicament is a prophylactic vaccine, a therapeutic vaccine, or a combination thereof, wherein the pharmaceutical composition further comprises at least one immunizing agent for stimulating an immune response in a subject in need thereof.

76. The use of any one of claims 66 to 75, wherein the medicament is formulated for the treatment or prevention of at least one infectious disease selected from the group consisting of varicella, coronavirus, dengue fever, diphtheria, Ebola, influenza, hepatitis, Hib disease, HIV / AIDS, HPV (human papillomavirus), Japanese encephalitis, measles, meningococcal disease, monkeypox, mumps, norovirus, pneumococcal disease, poliomyelitis, rabies, respiratory syncytial virus (RSV), rotavirus, rubella (German measles), herpes zoster, tetanus, pertussis, Zika, and combinations thereof.

77. The use according to any one of claims 66 to 76, wherein from 1% to 100% of the second end groups are free of primary amines.

78. The use according to any one of claims 66 to 77, wherein 1% to 100% of the second end groups comprise hydroxyl groups.

79. The use according to any one of claims 66 to 78, wherein the bioactive agent comprises a topoisomerase 1 (Top 1) inhibitor, a camptothecin derivative, irinotecan (CPT-11), SN-38, topotecan, a topoisomerase 2 (Top 2) inhibitor, doxorubicin, etoposide, ciprofloxacin, or a combination thereof.

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