Polymer excipients comprising n,n-diethylacrylamide (DEA) for biopharmaceutical formulations

Abstract

Provided in the present disclosure are polyacrylamide-based copolymer excipients that contain a water-soluble carrier monomer with an acrylamide reactive moiety and a functional dopant monomer comprising N,N-diethylacrylamide (DEA). The copolymers can reduce or prevent aggregation of biologic molecules and lipid-based vehicles in aqueous formulations at hydrophobic interfaces. Thus, the biologic molecules and lipidbased vehicles in the formulations containing the polyacrylamide-based copolymers can exhibit increased stability, such as increased thermal stability, as compared to the same formulations that do not contain the polyacrylamide-based copolymers. The polyacrylamide-based copolymers can be used with any biologic molecule or lipid-based vehicle that is susceptible to aggregation in an aqueous medium.

Description

POLYMER EXCIPIENTS COMPRISING N,N-DIETHYLACRYLAMIDE (DEA) FOR BIOPHARMACEUTICAL FORMULATIONS1. INTRODUCTION

[0001] Many biopharmaceuticals in aqueous based formulations are prone to irreversible aggregation when exposed to high temperatures and / or agitation and require careful storage and refrigerated transport (the cold chain) to retain activity over its shelf life. Maintaining the integrity of various biopharmaceuticals prone to aggregation presents a challenge to the pharmaceutical industry, healthcare providers, and people needing treatment with such biopharmaceuticals worldwide. While the mechanism of aggregation varies between various biopharmaceutical compounds, many contain hydrophobic patches or partially denature to reveal hydrophobic segments of the molecule that drives absorption onto interfaces (e.g., airwater, glass-water, or rubber-water interfaces). The high local concentrations of the molecules at these interfaces, coupled with interface-mediated partial unfolding, trigger initial nucleation of aggregation events that make way for further aggregation. This tendency to aggregate at interfaces increases with formulation concentrations, negatively impacting overall formulation stability.

[0002] Excipients are often overlooked as the “inactive” ingredients in pharmaceutical formulations. Yet, in many drug formulations excipients play an important role in drug viability improving solubility, absorption, and stability, of the active ingredient. An approach towards stabilizing biopharmaceuticals would use an excipient that could be easily and stably incorporated into highly concentrated commercial formulations without interacting with the therapeutic in the bulk, altering its pharmacokinetics, or increasing toxicity.

[0003] Accordingly, there is a need for improved biopharmaceutical formulations.2. SUMMARY

[0004] Provided in the present disclosure are polyacrylamide-based copolymer excipients that contain a water-soluble carrier monomer with an acrylamide reactive moiety and a functional dopant monomer comprising N,N-diethylacrylamide (DEA). The copolymers can reduce or prevent aggregation of biologic molecules and lipid-based vehicles in aqueous formulations at hydrophobic interfaces. Thus, the biologic molecules and lipid-based vehicles in the formulations containing the polyacrylamide-based copolymers can exhibit increased stability, such as increased thermal stability, as compared to the same formulations that donot contain the polyacrylamide-based copolymers. The polyacrylamide-based copolymers can be used with any biologic molecule or lipid-based vehicle that is susceptible to aggregation in an aqueous medium, including, but not limited to, proteins, such as antibodies and fragments thereof, cytokines, chemokines, hormones, vaccine antigens, cancer antigens, adjuvants, and combinations thereof.

[0005] The polyacrylamide-based copolymers can also be used with lipid-based vehicles that are susceptible to aggregation in an aqueous medium, including, but not limited to, liposomes, lipid nanoparticles, polymerosomes, and micelles, to prevent or reduce aggregation.

[0006] According to some embodiments, the polyacrylamide-based copolymer excipients provide stable formulation of a biologic compound. In some embodiments, these excipients are synthetic copolymers composed of a water-soluble carrier monomer, chosen to aid polymer solubility, and a functional dopant monomer comprising N,N-diethylacrylamide (DEA). The DEA monomer is hypothesized to promote polymer-interface interactions, reducing biologic molecule interactions at the interface, and thus improving biopharmaceutical formulation stability. In some embodiments, precision high-throughput synthesis using reverse additional fragmentation transfer (RAFT) polymerization is employed to generate a library of polyacrylamide-based copolymers including DEA. In the present disclosure, the polyacrylamide-based copolymers can provide a stable formulation of a biopharmaceutical formulation that exhibits pharmacokinetics that are significantly faster than a corresponding commercial biopharmaceutical formulation.

[0007] The herein described copolymer excipients can also be applied more broadly to improve the thermal stability of biopharmaceutical formulations, as simple "drop-in" excipients, without altering their bioactivity, pharmacokinetics or pharmacodynamics. For example, the copolymer excipients described herein can be used as a drop-in excipient in combination with other formulation approaches that are intended to alter or modulate the pharmacokinetics of the protein formulation.

[0008] Also provided in the present disclosure is a polyacrylamide-based copolymer comprising a water-soluble carrier monomer comprising an acrylamide reactive moiety; and a functional dopant monomer comprising N,N-diethylacrylamide (DEA); wherein the weight percent (wt%) of the water-soluble carrier monomer is from 70% to 98%; the weight percent(wt%) of the functional dopant monomer is from 2% to 30%; the average molecular weight (Mn) of the polyacrylamide-based copolymer is from 1,000 g / mol to 30,000 g / mol; and the degree of polymerization is from 10 to 250.

[0009] As disclosed herein, high throughput controlled radical polymerization techniques can be implemented to generate a library of polyacrylamide-based copolymer excipients including those comprising monomers of N,N-diethylacrylamide (DEA). Non-limiting examples of polyacrylamide-based copolymers as provided herein include a polyacrylamidebased copolymer comprising a water-soluble carrier monomer selected from N-(3- methoxypropyl)acrylamide (MP AM), 4-acryloylmorpholine (MORPH), N,N- dimethylacrylamide (DMA), N-hydroxyethyl acrylamide (HEAM), and acrylamide (AM); and a functional dopant monomer comprising DEA. In some embodiments, the functional dopant monomer comprises DEA, and further includes a functional dopant monomer selected from N-[tris(hydroxymethyl)-methyl]acrylamide (TRI), 2-acrylamido-2-methylpropane sulfonic acid (AMP), (3-acrylamidopropyl)trimethylammonium chloride (TMA), N- isopropylacrylamide (NIP), N-tert-butylacrylamide (TBA), and N-phenylacrylamide (PHE).

[0010] Provided in the present disclosure is a composition comprising from 0.005 wt% to 0.2 wt% of a polyacrylamide -based copolymer comprising from 70% to 95% by weight of a MORPH carrier monomer; and from 5% to 30% by weight of a DEA dopant monomer.

[0011] Also provided is a method for increasing stability of a formulation containing a biologic molecule, comprising adding from 0.005 wt% to 5 wt% of a polyacrylamide-based copolymer of the present disclosure to the formulation.

[0012] Also provided is a method for increasing stability of a protein formulation, comprising adding from 0.005 wt% to 5 wt% of a polyacrylamide-based copolymer of the present disclosure to the protein formulation.

[0013] Also provided is a method for increasing stability of a formulation containing a lipid- based vehicle, comprising adding about 0.005 wt% to about 5 wt% of a polyacrylamidebased copolymer of the present disclosure to the formulation.

[0014] Also provided is a method for reducing the rate of aggregation of a biologic molecule in an aqueous composition, comprising adding from 0.005 wt% to 5 wt% of a polyacrylamide-based copolymer of the present disclosure to the formulation.

[0015] Also provided is a method for reducing the rate of aggregation of a protein in an aqueous composition, comprising adding from 0.005 wt% to about 5 wt% of a polyacrylamide-based copolymer of the present disclosure to the protein formulation.

[0016] Also provided is a method for reducing the rate of aggregation of a lipid-based vehicle in an aqueous composition, comprising adding from 0.005 wt% to 5 wt% of a polyacrylamide-based copolymer of the present disclosure to the formulation.3. DETAILED DESCRIPTION

[0017] As summarized above, the present disclosure describes a library of copolymers comprising different water-soluble acrylamide monomers and functional dopant monomers comprising N,N-diethylacrylamide (DEA) in a variety of weight ratios, molecular weights, and degree of polymerization. The copolymers of the present disclosure can reduce or prevent aggregation of biologic molecules (e.g., protein and peptides) or lipid-based vehicles in aqueous formulations at hydrophobic interfaces, particularly molecules that are susceptible to aggregation in an aqueous medium. Proteins and other biologic molecules are often used in the treatment of a wide variety of diseases and disorders; however, maintaining the stability of such formulations and preventing aggregation of the molecules is a key challenge faced by the biopharmaceutical industry. Proteins, other biologic molecules, and lipid-based vehicles, including, but not limited to, liposomes, micelles, polymerosomes, and lipid nanoparticles, can aggregate due to a variety of factors, including thermal stress, chemical degradation, or exposure to surfaces and interfaces.

[0018] Non-covalent physical aggregation is mediated by forces like hydrophobic interaction, van der Waals interaction, hydrogen bonding, and electrostatic forces. Adsorption of such molecules to a variety of interfaces, particularly air-water interfaces, plays a key role in inducing aggregation. These aggregates could trigger immunogenic responses in the body and result in the production of anti-therapeutic antibodies.

[0019] The polyacrylamide-based copolymers of the present disclosure can reduce or prevent aggregation of biologic molecules and lipid-based vehicles in aqueous formulations, resulting in increased stability. The polyacrylamide-based copolymers can be used with any molecule that is susceptible to aggregation in an aqueous medium, including, but not limited to, proteins such as antibodies and fragments thereof, cytokines, chemokines, hormones, vaccine antigens, cancer antigens, adjuvants, and combinations thereof.

[0020] The polyacrylamide-based copolymers can also be used with lipid-based vehicles that are susceptible to aggregation in an aqueous medium, including, but not limited to, liposomes, lipid nanoparticles, polymerosomes, and micelles, to prevent or reduce aggregation.

[0021] The polyacrylamide-based copolymers of the present disclosure prevent aggregation of proteins, other biological molecules, and lipid-based vehicles such as liposomes, lipid nanoparticles, polymerosomes, and micelles, by providing an inert barrier at the hydrophobic interface of an aqueous formulation to prevent interaction between the molecules, such as protein-protein interactions. In some embodiments, the hydrophobic interface is an air-water interface. In some embodiments, the hydrophobic interface is an enclosure-water interface, including, but not limited to, a glass-water interface, a rubber-water interface, a plastic-water interface, or a metal-water interface. In some embodiments, the hydrophobic interface is an oil-water interface.

[0022] As described in the present disclosure, the subject copolymers can act as stabilizing agents for formulations containing biologic molecules. In some embodiments, the formulation is a protein formulation. The polyacrylamide-based copolymers can also act as stabilizing agents for formulations containing lipid-based vehicles that are susceptible to aggregation in an aqueous medium, including, but not limited to, liposomes, lipid nanoparticles, polymerosomes, and micelles. In some embodiments, the copolymers comprising a N,N-diethylacrylamide (DEA) copolymer were identified using a high- throughput screen of a large library of combinatorial acrylamide-based copolymer excipients. In some embodiments, these copolymers enhance the stability of the formulation without any modifying effects on the molecules in the formulation. For example, the copolymers can enhance protein formulation stability without any protein-modifying effects. In some embodiments, copolymers comprising a water-soluble "carrier" monomer and a functional "dopant" monomer act as stabilizing excipients to reduce interactions of the biologic molecule with an interface, such as the air- liquid interface. In some embodiments, the biologic molecule is a protein. In some embodiments, copolymers comprising a water-soluble "carrier" monomer and a functional "dopant" monomer act as stabilizing excipients to reduce interactions of a lipid-based vehicle with an interface, such as the air-liquid interface.

[0023] Thus, provided in the present disclosure is a method for reducing aggregation of a biologic molecule or lipid-based vehicle comprising a polyacrylamide-based copolymerexcipient as disclosed herein. In some embodiments, the biologic molecule is a protein. In some embodiments, the protein is selected from antibodies and fragments thereof, cytokines, chemokines, hormones, vaccine antigens, cancer antigens, adjuvants, and combinations thereof. In some embodiments, the biologic molecule is a nucleic acid. In some embodiments, the lipid-based vehicle is a liposome, micelle, polymerosome, or lipid nanoparticle. The polyacrylamide-based copolymer of the present disclosure comprises a water-soluble carrier monomer comprising an acrylamide reactive moiety and a functional dopant monomer comprising an acrylamide reactive moiety. In some embodiments, the copolymer comprises MP AM or MORPH carrier monomers with DEA dopant monomers.

[0024] Also provided are methods for increasing stability of a formulation containing a biologic molecule or a lipid-based vehicle. In some embodiments, methods for increasing thermal stability of a formulation containing a biologic molecule or a lipid-based vehicle are provided. In other embodiments, methods for reducing the rate of aggregation of a biologic molecule or a lipid-based vehicle in an aqueous composition are provided. The methods include adding the copolymer of the present disclosure to the formulation.3.1. Pharmaceutical Compositions

[0025] As summarized above, this disclosure provides a pharmaceutical composition comprising a polyacrylamide-based copolymer, containing a water-soluble carrier monomer and a functional dopant monomer comprising N,N-diethylacrylamide (DEA). In some embodiments, the polyacrylamide-based copolymer is amphiphilic.3.1.1. Polyacrylamide-based Copolymers

[0026] Provided in the present disclosure are polyacrylamide-based copolymers. In some embodiments, the polyacrylamide-based copolymers contain a water-soluble carrier monomer and a functional dopant monomer comprising N,N-diethylacrylamide (DEA). In some embodiments, the polyacrylamide- based copolymer is amphiphilic.

[0027] In some embodiments, the polyacrylamide-based copolymer comprises a non-ionic water-soluble acrylamide monomer and a functional dopant monomer that is N,N- diethylacrylamide (DEA). In some embodiments, the polyacrylamide- based copolymer further comprises a functional acrylamide dopant monomer selected from a hydrophobic functional acrylamide dopant monomer, an aromatic functional acrylamide dopant monomer,a hydrogen-bonding functional acrylamide dopant monomer, and an ionic functional acrylamide dopant monomer.

[0028] The polyacrylamide-based copolymers of the present disclosure contain a water-soluble carrier monomer. In some embodiments, the water-soluble carrier monomer is non-ionic. In some embodiments, the water-soluble carrier monomer is selected from N-(3- methoxypropyl)acrylamide (MP AM), 4-acryloylmorpholine (MORPH), N,N- dimethylacrylamide (DMA), N-hydroxyethyl acrylamide (HEAM), and acrylamide (AM), or combinations thereof. In some embodiments, the water-soluble carrier monomer is selected from MP AM and MORPH. In some embodiments, the water-soluble carrier monomer is N- (3-methoxypropyl)acrylamide (MP AM). In some embodiments, the water-soluble carrier monomer is 4-acryloylmorpholine (MORPH). In some embodiments, the water-soluble carrier monomer is N,N-dimethylacrylamide (DMA). In some embodiments, the water- soluble carrier monomer is N-hydroxyethylacrylamide (HEAM). In some embodiments, the water-soluble carrier monomer is acrylamide (AM). In some embodiments, the copolymer comprises a water-soluble carrier monomer selected from N-(3-methoxypropyl)acrylamide (MP AM) and 4-acryloylmorpholine (MORPH).

[0029] The polyacrylamide-based copolymers of the present disclosure also include a functional dopant monomer that comprises N,N-diethylacrylamide (DEA), e.g., consists essentially of or consists of DEA. In some embodiments, the polyacrylamide-based copolymer further comprises an additional hydrophobic functional acrylamide dopant monomer. In some embodiments, the hydrophobic functional acrylamide dopant monomer is N-isopropylacrylamide (NIP) or N-tert-butylacrylamide (TBA). In some embodiments, the hydrophobic functional acrylamide dopant monomer is N-isopropylacrylamide (NIP). In some embodiments, the hydrophobic functional acrylamide dopant monomer is N-tert- butylacrylamide (TBA). In some embodiments, the polyacrylamide-based copolymer further comprises an aromatic functional acrylamide dopant monomer. In some embodiments, the aromatic functional acrylamide dopant monomer is N-phenylacrylamide (PHE). In some embodiments, the polyacrylamide-based copolymer further comprises a hydrogen-bonding functional acrylamide dopant monomer. In some embodiments, the hydrogen-bonding functional acrylamide dopant monomer Is N-[tris(hydroxymethyl)- methyl] acrylamide (TRI). In some embodiments, the polyacrylamide-based copolymer further comprises an ionic functional acrylamide dopant monomer. In some embodiments, the ionic functionalacrylamide dopant monomer is 2-acrylamido-2-methylpropane sulfonic acid (AMP) or (3- acrylamidopropyl)trimethylammonium chloride (TMA). In some embodiments, the ionic functional acrylamide dopant monomer is 2-acrylamido-2- methylpropane sulfonic acid (AMP). In some embodiments, the ionic functional acrylamide dopant monomer is (3- acrylamidopropyl)trimethylammonium chloride (TMA).

[0030] In some embodiments, the polyacrylamide-based copolymer comprises a water- soluble carrier monomer selected from N-(3-methoxypropyl)acrylamide (MP AM), 4- acryloylmorpholine (MORPH), N,N-dimethylacrylamide (DMA), N-hydroxy ethylacrylamide (HEAM), and acrylamide (AM); and a functional dopant monomer that comprises N,N- diethylacrylamide (DEA).

[0031] In some embodiments, the water-soluble carrier monomer is N-(3- methoxypropyl)acrylamide (MP AM). In some embodiments, the water-soluble carrier monomer is N-(3-methoxypropyl)acrylamide (MP AM) and the functional dopant monomer is N,N-diethylacrylamide (DEA).

[0032] In some embodiments, the water-soluble carrier monomer is 4-acryloylmorpholine (MORPH). In some embodiments, the water-soluble carrier monomer is 4- acryloylmorpholine (MORPH) and the functional dopant monomer is N,N-diethylacrylamide (DEA).

[0033] In some embodiments, the water-soluble earner monomer is N,N- dimethylacrylamide (DMA). In some embodiments, the water-soluble carrier monomer is N,N- dimethylacrylamide (DMA) and the functional dopant monomer is N,N-diethylacrylamide (DEA).

[0034] In some embodiments, the water-soluble carrier monomer is N-hydroxy ethyl acrylamide (HEAM). In some embodiments, the water-soluble carrier monomer is N- hydroxyethyl acrylamide (HEAM) and the functional dopant monomer is N,N- diethylacrylamide (DEA).

[0035] In some embodiments, the water-soluble carrier monomer is acrylamide (AM). In some embodiments, the water-soluble carrier monomer is acrylamide (AM), and the functional dopant monomer is N,N-diethylacrylamide (DEA).

[0036] In some embodiments, the polyacrylamide-based copolymer comprises N-(3- methoxypropyl)acrylamide (MP AM) or 4-acryloylmorpholine (MORPH) as the water- soluble carrier monomer, and N,N-diethylacrylamide (DEA) as the functional dopant monomer.

[0037] In some embodiments, the polyacrylamide-based copolymer comprises N,N- dimethylacrylamide (DMA), N-hydroxyethyl acrylamide (HEAM), or acrylamide (AM) as the water-soluble carrier monomer, and the functional dopant monomer is N,N- diethylacrylamide (DEA).

[0038] In some embodiments, the amount of functional dopant monomer used in the copolymerization reaction is designed to maximize dopant loading while yielding functional copolymers with lower critical solution temperature (LCST) values above 37°C. In some embodiments, this results in copolymers that remain soluble at all relevant temperatures. In some embodiments, the polyacrylamide-based copolymer comprises about 2% to about 30% by weight of a functional dopant monomer, for example, about 5% to about 30%, about 10% to about 30%, about 15% to about 30%, about 20% to about 30%, about 25% to about 30%, about 2% to about 25%, about 5% to about 25%, about 10% to about 25%, about 15% to about 25%, about 20% to about 25%, about 2% to about 20%, about 5% to about 20%, about 10% to about 20%, about 15% to about 20%, about 2% to about 15%, about 5% to about 15%, about 10% to about 15%, about 2% to about 10%, about 5% to about 10%, or about 2% to about 5%, by weight of a functional dopant monomer. In some embodiments, the polyacrylamide-based copolymer comprises about 2%, about 5%, about 8%, about 10%, about 12%, about 15%, about 18%, about 20%, about 22%, about 25%, about 28%, or about 30% by weight of a functional dopant monomer. In some embodiments, the polyacrylamidebased copolymer comprises 2% to 30% by weight of a functional dopant monomer, for example, 5% to 30%, 10% to 30%, 15% to 30%, 20% to 30%, 25% to 30%, 2% to 25%, 5% to 25%, 10% to 25%, 15% to 25%, 20% to 25%, 2% to 20%, 5% to 20%, 10% to 20%, 15% to 20%, 2% to 15%, 5% to 15%, 10% to 15%, 2% to 10%, 5% to 10%, or 2% to 5%, by weight of a functional dopant monomer. In some embodiments, the polyacrylamide-based copolymer comprises 2%, 5%, 8%, 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, or 30% by weight of a functional dopant monomer. In some embodiments, the polyacrylamide-based copolymer comprises 2%, 5%, 8%, 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, or 30% by weight of N,N-diethylacrylamide (DEA).

[0039] In some embodiments, the polyacrylamide-based copolymer comprises about 70% to about 98% by weight of a water-soluble carrier monomer, for example, about 75% to about 98%, about 80% to about 98%, about 85% to about 98%, about 90% to about 98%, about 95% to about 98%, about 70% to about 95%, about 75% to about 95%, about 80% to about 95%, about 85% to about 95%, about 90% to about 95%, about 70% to about 90%, about 75% to about 90%, about 80% to about 90%, about 85% to about 90%, about 70% to about 85%, about 75% to about 85%, about 80% to about 85%, about 70% to about 80%, about 75% to about 80%, or about 70% to about 75%, by weight of a water-soluble carrier monomer. In some embodiments, the polyacrylamide-based copolymer comprises about 70%, about 72%, about 75%, about 78%, about 80%, about 82%, about 85%, about 88%, about 90%, about 92%, about 95%, or about 98% by weight of a water-soluble carrier monomer. In some embodiments, the polyacrylamide-based copolymer comprises 70% to 98% by weight of a water-soluble carrier monomer, for example, 75% to 98%, 80% to 98%, 85% to 98%, 90% to 98%, 95% to 98%, 70% to 95%, 75% to 95%, 80% to 95%, 85% to 95%, 90% to 95%, 70% to 90%, 75% to 90%, 80% to 90%, 85% to 90%, 70% to 85%, 75% to 85%, 80% to 85%, 70% to 80%, 75% to 80%, or 70% to 75%, by weight of a water-soluble carrier monomer. In some embodiments, the polyacrylamide-based copolymer comprises 70%, 72%, 75%, 78%, 80%, 82%, 85%, 88%, 90%, 92%, 95%, or 98% by weight of a water-soluble carrier monomer.

[0040] In some embodiments, the polyacrylamide-based copolymer comprises about 70% to about 98% by weight of a water-soluble carrier monomer and about 2% to about 30% by weight of a functional dopant monomer. For example, the polyacrylamide-based copolymer can contain about 70% to about 98%, about 70% to about 95%, about 70% to about 80%, about 80% to about 90%, about 90% to about 98%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 98% by weight of a water-soluble carrier monomer and about 2% to about 30%, about 5% to about 25%, about 5% to about 20%, about 2% to about 5%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, or about 25% to about 30%, about 2%, about 5%, about 8%, about 10%, about 12%, about 15%, about 18%, about 20%, about 22%, about 25%, about 28%, or about 30% by weight of a functional dopant monomer.

[0041] In some embodiments, the polyacrylamide-based copolymer comprises 70% to 98% by weight of a water-soluble carrier monomer and 2% to 30% by weight of a functionaldopant monomer. For example, the polyacrylamide-based copolymer can contain 70% to 98%, 70% to 95%, 70% to 80%, 80% to 90%, 90% to 98%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% by weight of a water-soluble carrier monomer and 2% to 30%, 5% to 25%, 5% to 20%, 2% to 5%, 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, or 25% to 30%, 2%, 5%, 8%, 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, or 30% by weight of a functional dopant monomer.

[0042] In some embodiments, the polyacrylamides-based copolymer comprises about 2% to about 30% by weight of the functional dopant monomer DEA. In some embodiments, the polyacrylamides-based copolymer comprises about 5% to about 30% by weight of the functional dopant monomer DEA. In some embodiments, the polyacrylamides-based copolymer comprises about 10% to about 28% by weight of the functional dopant monomer DEA. In some embodiments, the polyacrylamide-based copolymer comprises about 5% to about 26% by weight of the functional dopant monomer DEA. In some embodiments, the polyacrylamides-based copolymer comprises about 5% to about 10% by weight of the functional dopant monomer DEA. In some embodiments, the polyacrylamides-based copolymer comprises about 10% to about 15% by weight of the functional dopant monomer DEA. In some embodiments, the polyacrylamides-based copolymer comprises about 15% to about 20% by weight of the functional dopant monomer DEA. In some embodiments, the polyacrylamides-based copolymer comprises about 20% to about 26% by weight of the functional dopant monomer DEA.

[0043] In some embodiments, the polyacrylamides-based copolymer comprises 2% to 30% by weight of the functional dopant monomer DEA, such as 5% to 30%, 10% to 28%, 5% to 26%, 5% to 10%, 10% to 15%, 15% to 20%, or 20% to 26% by weight of the functional dopant monomer DEA.

[0044] In some embodiments, the polyacrylamides-based copolymer comprises MORPH as the water-soluble carrier monomer and about 2% to about 30% by weight of DEA as the functional dopant monomer. In some embodiments, the copolymer comprises MORPH and from about 5% to about 30% by weight of DEA. In some embodiments, the copolymer comprises MORPH and about 10% to about 28% by weight of DEA. In some embodiments, the copolymer comprises MORPH and about 5% to about 26% by weight of DEA. In some embodiments, the copolymer comprises MORPH and about 5% to about 10% by weight of DEA. In some embodiments, the copolymer comprises MORPH and about 10% to about 15%by weight of DEA. In some embodiments, the copolymer comprises MORPH and about 15% to about 20% by weight of DEA. In some embodiments, the copolymer comprises MORPH and about 20% to about 25% by weight of DEA. In some embodiments, the copolymer comprises MORPH and about 25% to about 30% by weight of DEA. In some embodiments, the copolymer comprises MORPH and about 20% to about 28% by weight of DEA. In some embodiments, the copolymer comprises MORPH and about 21% by weight of DEA. In some embodiments, the copolymer comprises MORPH and about 22% by weight of DEA. In some embodiments, the copolymer comprises MORPH and about 23% by weight of DEA. In some embodiments, the copolymer comprises MORPH and about 24% by weight of DEA. In some embodiments, the copolymer comprises MORPH and about 25% by weight of DEA.

[0045] In some embodiments, the polyacrylamides-based copolymer comprises MORPH as the water-soluble carrier monomer and 2% to 30% by weight of DEA as the functional dopant monomer, such as 5% to 30%, 10% to 28%, 5% to 26%, 5%> to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, or 20% to 28% by weight of DEA. In some embodiments, the copolymer comprises MORPH and 21% by weight of DEA, such as 22, 23%, 24%, or 25% by weight of DEA.

[0046] In some embodiments, the polyacrylamide-based copolymer comprises MP AM as the water-soluble carrier monomer and about 2% to about 16% by weight of DEA as the functional dopant monomer. In some embodiments, the polyacrylamide-based copolymer comprises MP AM as the water-soluble carrier monomer and about 5% to about 15% by weight of DEA as the functional dopant monomer. In some embodiments, the polyacrylamide-based copolymer comprises MPAM as the water-soluble carrier monomer and about 6% to about 10% by weight of DEA as the functional dopant monomer. In some embodiments, the polyacrylamide-based copolymer comprises MPAM as the water-soluble carrier monomer and about 7% by weight of DEA as the functional dopant monomer. In some embodiments, the polyacrylamide-based copolymer comprises MPAM as the water- soluble carrier monomer and about 8% by weight of DEA as the functional dopant monomer. In some embodiments, the polyacrylamide-based copolymer comprises MPAM as the water- soluble carrier monomer and about 9% by weight of DEA as the functional dopant monomer.

[0047] In some embodiments, the polyacrylamide-based copolymer comprises MPAM as the water-soluble carrier monomer and 2% to 16% by weight of DEA, such as 5% to 15%, or 6% to 10% by weight of DEA as the functional dopant monomer. In some embodiments, thepolyacrylamide-based copolymer comprises MPAM as the water-soluble carrier monomer and 7% by weight of DEA as the functional dopant monomer, such as 8%, or 9% by weight of DEA as the functional dopant monomer.

[0048] In some embodiments, the polyacrylamide-based copolymer further comprises NIP, TRI, AMP, TMA, TBA, or PHE as a functional dopant monomer. In some embodiments, NIP, AMP, TMA, TBA, or PHE functional dopant monomer is present at about 2% to about 16% by weight of the copolymer. In some embodiments, NIP, TRI, AMP, TMA, TBA, or PHE functional dopant monomer is present at about 5% to about 15% by weight of the copolymer. In some embodiments, NIP, TRI, AMP, TMA, TBA, or PHE functional dopant monomer is present at about 6% to about 14% by weight of the copolymer. In some embodiments, NIP, TRI, AMP, TMA, TBA, or PHE functional dopant monomer is present at about 12% to about 15% by weight of the copolymer. In some embodiments, NIP, TRI, AMP, TMA, TBA, or PHE functional dopant monomer is present at about 2% to about 5% by weight of the copolymer. In some embodiments, NIP, TRI, AMP, TMA, TBA, or PHE functional dopant monomer is present at about 5% to about 10% by weight of the copolymer.

[0049] In some embodiments, the polyacrylamide-based copolymer further comprises NIP, AMP, TMA, TBA, or PHE as a functional dopant monomer in an amount of 2% to 16%, such as 5% to 15%, 6% to 14%, or 12% to 15% by weight of the copolymer. In some embodiments, NIP, TRI, AMP, TMA, TBA, or PHE functional dopant monomer is present at 2% to 5% by weight of the copolymer. In some embodiments, NIP, TRI, AMP, TMA, TBA, or PHE functional dopant monomer is present at 5% to 10% by weight of the copolymer.

[0050] In some embodiments, the degree of polymerization (DP) of the polyacrylamide-based copolymer is about 10 to about 500, about 20 to about 200, about 50 to about 100, about 100 to about 200, about 200 to about 300, about 300 to about 400, or about 400 to about 500, or about 50, about 70, about 100, about 120, about 150, about 170, about 200, about 220, about 250, about 270, about 300, about 320, about 350, about 370, about 400, about 420, about 450, about 470, or about 500. In some embodiments, the DP of the copolymer is about 40. In some embodiments, the DP of the copolymer is about 50. In some embodiments, the DP of the copolymer is about 60. In some embodiments, the DP of the copolymer is about 70. In some embodiments, the DP of the copolymer is about 80. In some embodiments, the DP of the copolymer is about 90. In some embodiments, the DP of the copolymer is about 100.

[0051] In some embodiments, the degree of polymerization (DP) of the polyacrylamide-based copolymer is 10 to 500, 20 to 200, 50 to 100, 100 to 200, 200 to 300, 300 to 400, or 400 to 500, or 50, 70, 100, 120, 150, 170, 200, 220, 250, 270, 300, 320, 350, 370, 400, 420, 450, 470, or 500. In some embodiments, the DP of the copolymer is 40. In some embodiments, the DP of the copolymer is 50. In some embodiments, the DP of the copolymer is 60. In some embodiments, the DP of the copolymer is 70. In some embodiments, the DP of the copolymer is 80. In some embodiments, the DP of the copolymer is 90. In some embodiments, the DP of the copolymer is 100.

[0052] In some embodiments, the molecular weight of the polyacrylamide-based copolymer is about 1,000 g / mol to about 40,000 g / mol, such as about 1,000 g / mol to about 35,000 g / mol, about 1 ,000 g / mol to about 30,000 g / mol, about 1 ,000 g / mol to about 25,000 g / mol, about 1,000 g / mol to about 20,000 g / mol, about 1,000 g / mol to about 15,000 g / mol, about 1,000 g / mol to about 10,000 g / mol, about 1,000 g / mol to about 7,000 g / mol, about 1,000 g / mol to about 6,000 g / mol, about 1,000 g / mol to about 5,000 g / mol, about 1,000 g / mol to about 4,000 g / mol, about 1,000 g / mol to about 3,000 g / mol, about 3,000 g / mol to about 40,000 g / mol, about 3,000 g / mol to about 35,000 g / mol, about 3,000 g / mol to about 30,000 g / mol, about 3,000 g / mol to about 25,000 g / mol, about 3,000 g / mol to about 20,000 g / mol, about 3,000 g / mol to about 15,000 g / mol, about 3,000 g / mol to about 10,000 g / mol, about 3,000 g / mol to about 7,000 g / mol, about 3,000 g / mol to about 6,000 g / mol, about 3,000 g / mol to about 5,000 g / mol, about 3,000 g / mol to about 4,000 g / mol, about 4,000 g / mol to about 40,000 g / mol, about 4,000 g / mol to about 35,000 g / mol, about 4,000 g / mol to about 30,000 g / mol, about 4,000 g / mol to about 25,000 g / mol, about 4,000 g / mol to about 20,000 g / mol, about 4,000 g / mol to about 15,000 g / mol, about 4,000 g / mol to about 10,000 g / mol, about 4,000 g / mol to about 7,000 g / mol, about 4,000 g / mol to about 6,000 g / mol, about 4,000 g / mol to about 5,000 g / mol, about 5,000 g / mol to about 40,000 g / mol, about 5,000 g / mol to about 35,000 g / mol, about 5,000 g / mol to about 30,000 g / mol, about 5,000 g / mol to about 25,000 g / mol, about 5,000 g / mol to about 20,000 g / mol, about 5,000 g / mol to about 15,000 g / mol, about 5,000 g / mol to about 10,000 g / mol, about 5,000 g / mol to about 7,000 g / mol, about 5,000 g / mol to about 6,000 g / mol, about 6,000 g / mol to about 40,000 g / mol, about 6,000 g / mol to about 35,000 g / mol, about 6,000 g / mol to about 30,000 g / mol, about 6,000 g / mol to about 25,000 g / mol, about 6,000 g / mol to about 20,000 g / mol, about 6,000 g / mol to about 15,000 g / mol, about 6,000 g / mol to about 10,000 g / mol, about 6,000 g / mol to about 7,000 g / mol, about 7,000 g / mol to about 40,000 g / mol, about 7,000 g / mol to about 35,000g / mol, about 7000 g / mol to about 30,000 g / mol, about 7,000 g / mol to about 25,000 g / mol, about 7,000 g / mol to about 20,000 g / mol, about 7,000 g / mol to about 15,000 g / mol, about 7,000 g / mol to about 10,000 g / mol, about 10,000 g / mol to about 40,000 g / mol, about 10,000 g / mol to about 35,000 g / mol, about 10,000 g / mol to about 30,000 g / mol, about 10,000 g / mol to about 25,000 g / mol, about 10,000 g / mol to about 20,000 g / mol, about 10,000 g / mol to about 15,000 g / mol, about 15,000 g / mol to about 40,000 g / mol, about 15,000 g / mol to about 35,000 g / mol, about 15,000 g / mol to about 30,000 g / mol, about 15,000 g / mol to about 25,000 g / mol, about 15,000 g / mol to about 20,000 g / mol, about 20,000 g / mol to about 40,000 g / mol, about 20,000 g / mol to about 35,000 g / mol, about 20,000 g / mol to about 30,000 g / mol, about 20,000 g / mol to about 25,000 g / mol, about 25,000 g / mol to about 40,000 g / mol, about 25,000 g / mol to about 35,000 g / mol, about 25,000 g / mol to about 30,000 g / mol, about 30,000 g / mol to about 40,000 g / mol, about 30,000 g / mol to about 35,000 g / mol, or about 35,000 g / mol to about 40,000 g / mol. In some embodiments, the molecular weight of the copolymer is about 1,000 to about 30,000 g / mol. In some embodiments, the molecular weight of the copolymer is about 10,000 to about 20,000 g / mol. In some embodiments, the molecular weight of the copolymer is about 15,000 to about 20,000 g / mol. In some embodiments, the molecular weight of the copolymer is about 20,000 to about 25,000 g / mol. the molecular weight of the copolymer is about 25,000 to about 30,000 g / mol. In some embodiments, the molecular weight of the copolymer is about 30,000 to about 40,000 g / mol. In some embodiments, the molecular weight of the copolymer is about 2,000 to about 10,000 g / mol. In some embodiments, the molecular weight of the copolymer is about 3,000 to about 7,000 g / mol. In some embodiments, the molecular weight of the copolymer is about 4,000 to about 6,000 g / mol.

[0053] In some embodiments, the molecular weight of the polyacrylamide-based copolymer is 1,000 g / mol to 40,000 g / mol, such as 1,000 g / mol to 35,000 g / mol, 1,000 g / mol to 30,000 g / mol, 1,000 g / mol to 25,000 g / mol, 1,000 g / mol to 20,000 g / mol, 1,000 g / mol to 15,000 g / mol, 1,000 g / mol to 10,000 g / mol, 1,000 g / mol to 7,000 g / mol, 1,000 g / mol to 6,000 g / mol, 1,000 g / mol to 5,000 g / mol, 1,000 g / mol to 4,000 g / mol, 1,000 g / mol to 3,000 g / mol, 3,000 g / mol to 40,000 g / mol, 3,000 g / mol to 35,000 g / mol, 3,000 g / mol to 30,000 g / mol, 3,000 g / mol to 25,000 g / mol, 3,000 g / mol to 20,000 g / mol, 3,000 g / mol to 15,000 g / mol, 3,000 g / mol to 10,000 g / mol, 3,000 g / mol to 7,000 g / mol, 3,000 g / mol to 6,000 g / mol, 3,000 g / mol to 5,000 g / mol, 3,000 g / mol to 4,000 g / mol, 4,000 g / mol to 40,000 g / mol, 4,000 g / mol to 35,000 g / mol, 4,000 g / mol to 30,000 g / mol, 4,000 g / mol to 25,000 g / mol, 4,000 g / mol to20,000 g / mol, 4,000 g / mol to 15,000 g / mol, 4,000 g / mol to 10,000 g / mol, 4,000 g / mol to 7,000 g / mol, 4,000 g / mol to 6,000 g / mol, 4,000 g / mol to 5,000 g / mol, 5,000 g / mol to 40,000 g / mol, 5,000 g / mol to 35,000 g / mol, 5,000 g / mol to 30,000 g / mol, 5,000 g / mol to 25,000 g / mol, 5,000 g / mol to 20,000 g / mol, 5,000 g / mol to 15,000 g / mol, 5,000 g / mol to 10,000 g / mol, 5,000 g / mol to 7,000 g / mol, 5,000 g / mol to 6,000 g / mol, 6,000 g / mol to 40,000 g / mol, 6,000 g / mol to 35,000 g / mol, 6,000 g / mol to 30,000 g / mol, 6,000 g / mol to 25,000 g / mol, 6,000 g / mol to 20,000 g / mol, 6,000 g / mol to 15,000 g / mol, 6,000 g / mol to 10,000 g / mol, 6,000 g / mol to 7,000 g / mol, 7,000 g / mol to 40,000 g / mol, 7,000 g / mol to, 35,000 g / mol, 7000 g / mol to 30,000 g / mol, 7,000 g / mol to 25,000 g / mol, 7,000 g / mol to 20,000 g / mol, 7,000 g / mol to 15,000 g / mol, 7,000 g / mol to 10,000 g / mol, 10,000 g / mol to 40,000 g / mol, 10,000 g / mol to 35,000 g / mol, 10,000 g / mol to 30,000 g / mol, 10,000 g / mol to 25,000 g / mol, 10,000 g / mol to 20,000 g / mol, 10,000 g / mol to 15,000 g / mol, 15,000 g / mol to 40,000 g / mol, 15,000 g / mol to 35,000 g / mol, 15,000 g / mol to 30,000 g / mol, 15,000 g / mol to 25,000 g / mol, 15,000 g / mol to 20,000 g / mol, 20,000 g / mol to 40,000 g / mol, 20,000 g / mol to 35,000 g / mol, 20,000 g / mol to 30,000 g / mol, 20,000 g / mol to 25,000 g / mol, 25,000 g / mol to 40,000 g / mol, 25,000 g / mol to 35,000 g / mol, 25,000 g / mol to 30,000 g / mol, 30,000 g / mol to 40,000 g / mol, 30,000 g / mol to 35,000 g / mol, or 35,000 g / mol to 40,000 g / mol. In some embodiments, the molecular weight of the copolymer is 1,000 to 30,000 g / mol. In some embodiments, the molecular weight of the copolymer is 10,000 to 20,000 g / mol. In some embodiments, the molecular weight of the copolymer is 15,000 to 20,000 g / mol. In some embodiments, the molecular weight of the copolymer is 20,000 to 25,000 g / mol. the molecular weight of the copolymer is 25,000 to 30,000 g / mol. In some embodiments, the molecular weight of the copolymer is 30,000 to 40,000 g / mol. In some embodiments, the molecular weight of the copolymer is 2,000 to 10,000 g / mol. In some embodiments, the molecular weight of the copolymer is 3,000 to 7,000 g / mol. In some embodiments, the molecular weight of the copolymer is 4,000 to 6,000 g / mol.

[0054] Also provided in the present disclosure is a polyacrylamide-based copolymer that contains a water-soluble carrier monomer comprising an acrylamide reactive moiety and a functional dopant monomer comprising DEA. In some embodiments, the polyacrylamidebased copolymer comprises about 70% to about 98% of a water-soluble carrier monomer with an acrylamide reactive moiety and about 2% to about 30% of DEA. In some embodiments, the number-averaged molecular weight (Mn) of the copolymer is about 1,000 g / mol to about 30,000 g / mol. In some embodiments, the degree of polymerization is about 10to about 250. In some embodiments, the polyacrylamide-based copolymer comprises 70% to 98% of a water-soluble carrier monomer with an acrylamide reactive moiety and 2% to 30% of DEA. In some embodiments, the number-averaged molecular weight (Mn) of the copolymer is 1,000 g / mol to 30,000 g / mol. In some embodiments, the degree of polymerization is 10 to 250. In some embodiments, the water-soluble carrier monomer is non-ionic. In some embodiments, the copolymer is amphiphilic.

[0055] In some embodiments, the polyacrylamide-based copolymer comprises about 70% to about 95% by weight of the water-soluble carrier monomer MORPH and about 5% to about 30% by weight of the functional dopant monomer DEA, wherein the number-averaged molecular weight (Mn) of the copolymer is about 1,000 g / mol to about 10,000 g / mol and the degree of polymerization is about 10 to about 100. In some embodiments, the polyacrylamide-based copolymer comprises about 74% to about 80% by weight of the water- soluble carrier monomer MORPH and about 20% to about 26% by weight of the functional dopant monomer DEA, wherein the number-averaged molecular weight (Mn) of the copolymer is about 1,000 g / mol to about 5,000 g / mol and the degree of polymerization is about 10 to about 50. In some embodiments, the polyacrylamide-based copolymer comprises about 77% by weight of the water-soluble carrier monomer MORPH and about 23% by weight of the functional dopant monomer DEA, wherein the number-averaged molecular weight (Mn) of the copolymer is about 3,200 g / mol and the degree of polymerization is about 26.

[0056] In some embodiments, the polyacrylamide-based copolymer comprises 70% to 95% by weight of the water-soluble carrier monomer MORPH and 5% to 30% by weight of the functional dopant monomer DEA, wherein the number-averaged molecular weight (Mn) of the copolymer is 1,000 g / mol to 10,000 g / mol and the degree of polymerization is 10 to 100. In some embodiments, the polyacrylamide-based copolymer comprises 74% to 80% by weight of the water-soluble carrier monomer MORPH and 20% to 26% by weight of the functional dopant monomer DEA, wherein the number- averaged molecular weight (Mn) of the copolymer is 1,000 g / mol to 5,000 g / mol and the degree of polymerization is 10 to 50. In some embodiments, the polyacrylamide-based copolymer comprises 77% by weight of the water-soluble carrier monomer MORPH and 23% by weight of the functional dopant monomer DEA, wherein the number- averaged molecular weight (Mn) of the copolymer is 3,200 g / mol and the degree of polymerization is 26.

[0057] In some embodiments, the composition includes about 0.001 wt% to about 1 wt% of the polyacrylamide-based copolymer, for example, about 0.001 wt% to about 0.5 wt%, about 0.001 wt% to about 0.1 wt%, about 0.001 wt% to about 0.05 wt%, about 0.001 wt% to about 0.03 wt%, about 0.005 wt% to about 1 wt%, about 0.005 wt% to about 0.5 wt%, about 0.005 wt% to about 0.1 wt%, about 0.005 wt% to about 0.05 wt%, about 0.005 wt% to about 0.03 wt%, about 0.01 wt% to about 1 wt%, about 0.01 wt% to about 0.5 wt%, about 0.01 wt% to about 0.1 wt%, about 0.01 wt% to about 0.05 wt%, or about 0.01 wt% to about 0.03 wt% of the polyacrylamide-based copolymer. In some embodiments, the composition includes about 0.01 wt% of the polyacrylamide-based copolymer.

[0058] In some embodiments, the composition includes 0.001 wt% to 1 wt% of the polyacrylamide-based copolymer, for example, 0.001 wt% to 0.5 wt%, 0.001 wt% to 0.1 wt%, 0.001 wt% to 0.05 wt%, 0.001 wt% to 0.03 wt%, 0.005 wt% to 1 wt%, 0.005 wt% to 0.5 wt%, 0.005 wt% to 0.1 wt%, 0.005 wt% to 0.05 wt%, 0.005 wt% to 0.03 wt%, 0.01 wt% to 1 wt%, 0.01 wt% to 0.5 wt%, 0.01 wt% to 0.1 wt%, 0.01 wt% to 0.05 wt%, or 0.01 wt% to 0.03 wt% of the polyacrylamide-based copolymer. In some embodiments, the composition includes 0.01 wt% of the polyacrylamide-based copolymer.3.1.2. Compositions containing a polyacrylamide-based copolymer

[0059] Also provided are compositions containing the polyacrylamide-based copolymers described in the present disclosure. In some embodiments, the composition comprises a polyacrylamide-based copolymer of the present disclosure and a pharmaceutically acceptable excipient.

[0060] In some embodiments, the composition includes a polyacrylamide-based copolymer of the present disclosure and a biologic molecule. In some embodiments, the biologic molecule is a protein. In some embodiments, the protein is a protein susceptible to aggregation in an aqueous medium. In some embodiments, the copolymer is uncharged, cationic, or anionic. In some embodiments, the copolymer is amphiphilic. In some embodiments, the carrier monomers are the water-soluble species and are responsible for both maintaining solubility and providing an inert barrier to prevent aggregation of the biological species, for example, to prevent protein-protein interactions. In some embodiments, the water-soluble carrier monomer is the predominant species within the polyacrylamide-based copolymer. In some embodiments, the functional dopant monomers (e.g., DEA) are copolymerized at lower weight percentages and are incorporated statisticallythroughout the resulting copolymer. In some embodiments, the dopants promote either polymer-interface interactions or polymer-protein interactions.

[0061] In some embodiments, the composition that contains a polyacrylamide-based copolymer of the present disclosure and a biologic molecule or lipid-based vehicle has a copolymer concentration of about 0.0001% to about 5% by weight of the composition, such as about 0.0001% to about 4%, about 0.0001% to about 3%, about 0.0001% to about 2%, about 0.0001% to about 1%, about 0.0001% to about 0.5%, about 0.0001% to about 0.4%, about 0.0001% to about 0.3%, about 0.0001% to about 0.2%, about 0.0001% to about 0.1%, about 0.0001% to about 0.05%, about 0.0001% to about 0.02%, about 0.0001% to about 0.01%, about 0.0001% to about 0.005%, about 0.005% to about 5%, about 0.005% to about 4%, about 0.005% to about 3%, about 0.005% to about 2%, about 0.005% to about 1 %, about 0.005% to about 0.5%, about 0.005% to about 0.4%, about 0.005% to about 0.3%, about 0.005%> to about 0.2%, about 0.005% to about 0.1%, about 0.005% to about 0.05%, about 0.005% to about 0.02%, about 0.005% to about 0.01%, about 0.01% to about 5%, about 0.01% to about 4%, about 0.01% to about 3%, about 0.01% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.4%, about 0.01% to about 0.3%, about 0.01% to about 0.2%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, about 0.01% to about 0.02%, about 0.02% to about 5%, about 0.02% to about 4%, about 0.02% to about 3%, about 0.02% to about 2%, about 0.02% to about 1%, about 0.02% to about 0.5%, about 0.02% to about 0.4%, about 0.02% to about 0.3%, about 0.02% to about 0.2%, about 0.02% to about 0.1%, about 0.02% to about 0.05%, about 0.05% to about 5%, about 0.05% to about 4%, about 0.05% to about 3%, about 0.05%’ to about 2%, about 0.05% to about 1%, about 0.05% to about 0.5%, about 0.05% to about 0.4%, about 0.05% to about 0.3%, about 0.05% to about 0.2%, about 0.05% to about 0.1%, about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.1% to about 0.5%, about 0.1% to about 0.4%, about 0.1% to about 0.3%, about 0.1% to about 0.2%, about 0.2% to about 5%, about 0.2% to about 4%, about 0.2% to about 3%, about 0.2% to about 2%, about 0.12% to about 1%, about 0.2% to about 0.5%, about 0.2% to about 0.4%, about 0.2% to about 0.3%, about 0.3% to about 5%, about 0.3% to about 4%, about 0.3% to about 3%, about 0.3% to about 2%, about 0.3% to about 1%, about 0.3% to about 0.5%, about 0.3% to about 0.4%, about 0.4% to about 5%, about 0.4% to about 4%, about 0.4% to about 3%, about 0.4% to about 2%, about 0.4% to about 1%, about 0.4% to about 0.5%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%,about 0.5% to about 2%, about 0.5% to about 1%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 3% to about 5%, about 3% to about 4%, or about 4% to about 5% by weight of the composition. In some embodiments, the copolymer concentration is about 0.0001% to about 5% by weight of the composition. In some embodiments, the copolymer concentration is about 0.001% to about 1% by weight, about 0.005% to about 0.5% by weight, about 0.005% to about 0.02% by weight, about 0.01% to about 0.2% by weight, about 0.1 % to about 0.4% by weight, or about 0.2% to about 0.3% by weight of the composition. In some embodiments, the copolymer concentration is about 0.005% by weight of the composition. In some embodiments, the copolymer concentration is about 0.01% by weight of the composition. In some embodiments, the copolymer concentration is about 0.05% by weight of the composition. In some embodiments, the copolymer concentration is about 0.1% by weight of the composition. In some embodiments, the copolymer concentration is about 1% by weight of the composition.

[0062] In some embodiments, the protein is selected from antibodies and fragments thereof, cytokines, chemokines, hormones, vaccine antigens, cancer antigens, adjuvants, and combinations thereof. In some embodiments, the composition exhibits reduced aggregation of the protein as compared to a composition of the same protein without the copolymer. In some embodiments, the composition exhibits reduced precipitation of the protein as compared to a composition of the same protein without the copolymer. In some embodiments, the composition comprises the protein in a concentration at least two times greater, at least three times greater, at least four times greater, or at least five times greater than the concentration of the same protein in the composition without the copolymer.

[0063] In some embodiments, the composition comprising a copolymer of the present disclosure and a biologic molecule further comprise one or more of a pharmaceutically acceptable carrier, an aqueous buffer, a tonicity modifier, and a preservative. As used herein, pharmaceutically acceptable carriers, tonicity modifiers, and preservatives are nontoxic to recipients at the dosages and concentrations employed. In some embodiments, the composition contains a buffer, such as phosphate, citrate, succinate, other organic acids, and histidine, where the term "buffer" refers to a mixture of a weak acid and its conjugate base, or vice versa, that is used to maintain the pH of a solution at a nearly constant value. In someembodiments, the buffer comprises one or more phosphate salts. In some embodiments, the buffer is sodium phosphate.

[0064] In some embodiments, the composition contains a tonicity modifier, such as sodium chloride, potassium chloride, mannitol, dextrose, glycerol, or magnesium chloride. In some embodiments, the tonicity modifier is sodium chloride (NaCl) or glycerol. In some embodiments, the tonicity modifier is glycerol.

[0065] In some embodiments, the composition contains one or more preservatives.

[0066] In some embodiments, the composition comprising the copolymers of the present disclosure is an aqueous composition. In some embodiments, the composition comprising the copolymers of the present disclosure comprises essentially water.

[0067] In some embodiments, the pH of the composition is about 4 to about 9, such as about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 9, about 7 to about 8, about 8 to about 9, or about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.4, about 8, about 8.5, or about 9. In some embodiments, the pH of the composition is about 4 to about 9. In some embodiments, the pH of the composition is about 6 to about 8. In some embodiments, the pH of the composition is about 7 to about 8. In some embodiments, the pH of the composition is about 7.4.

[0068] Also provided are compositions containing the polyacrylamide-based copolymers of the present disclosure and a lipid-based vehicle. In some embodiments, the lipid-based vehicle is selected from liposomes, polymerosomes, micelles, and lipid nanoparticles.

[0069] In some embodiments, the copolymers of the present disclosure are used as formulation additives in formulations comprising one or more biologic molecules (e.g., as described herein).3.1.3. Properties of the copolymer compositions

[0070] The polyacrylamide-based copolymers of the present disclosure have unique properties and, when used in an aqueous formulation with a biologic molecule, can impart beneficial properties to the formulation.

[0071] In some embodiments, the copolymers described in the present disclosure reduce or prevent aggregation of a biologic molecule or lipid-based vehicle, such as when formulated in an aqueous formulation containing a biologic molecule or lipid-based vehicle. In some embodiments, the biologic molecule is a protein. Thus, in some embodiments, the copolymers described in the present disclosure reduce or prevent protein aggregation, such as when formulated in an aqueous formulation containing the protein.

[0072] The copolymers can be used with any protein that is susceptible to aggregation in an aqueous medium. Non-limiting examples include antibodies and fragments thereof, cytokines, chemokines, hormones, vaccine antigens, cancer antigens, adjuvants, and combinations thereof. In some embodiments, the polyacrylamide-based copolymers reduce or prevent aggregation of a protein susceptible to aggregation in an aqueous medium.

[0073] The copolymers of the present disclosure can also increase the stability of a formulation. According to embodiments of the disclosure, the copolymers described herein can be added to improve the stability of a formulation containing, for example, a biologic molecule or a lipid-based vehicle, for example, peptides, proteins, and conjugates thereof, nucleic acids and oligonucleotides, liposomes, polymerosomes, micelles, and lipid nanoparticles. In some embodiments, addition of a copolymer of the present disclosure increases the stability of a protein formulation. In some embodiments, addition of a copolymer of the present disclosure increases the stability of a liposome formulation. In some embodiments, addition of a copolymer of the present disclosure increases the stability of a micelle formulation. In some embodiments, addition of a copolymer of the present disclosure increases the stability of a lipid nanoparticle formulation. In some embodiments, the addition of a copolymer of the present disclosure increases the stability of a formulation comprising one or more nucleic acids. In some embodiments, the addition of a copolymer of the present disclosure increases the stability of a formulation comprising one or more messenger RNA (mRNA). In some embodiments, the addition of a copolymer of the present disclosure increases the stability of a formulation comprising one or more small interfering RNA (siRNA). In some embodiments, the addition of a copolymer of the present disclosure increases the stability of a formulation comprising one or more deoxyribose nucleic acids (DNA).

[0074] In some embodiments, the copolymers of the present disclosure increase the thermal stability of a formulation containing a biologic molecule, which, in some embodiments, is aprotein. Protein formulations typically require costly refrigerated transport and storage to prevent loss of protein integrity. Maintaining protein integrity is a challenge for the pharmaceutical industry, health care providers, and patients worldwide, particularly in the developing and low-income regions where cold chain required for maintaining protein potency and efficacy is imperfect, overburdened or nonexistent. This results in large amounts of therapeutic protein formulations being wasted and potentially endangering the lives of patients. Thus, interruptions in the cold chain can be costly. The copolymers of the present disclosure can imbue long-term stability and / or cold chain resilience to protein formulations. For example, while commercial protein formulations have good shelf lives when stored properly (i.e., refrigerated), interruptions in the cold chain can decrease protein bioactivity and formulation integrity.

[0075] Protein formulations containing the copolymers of the present disclosure are, in some embodiments, stable for extended periods of time at temperatures higher than what is typically required for cold chain storage. For example, protein formulations containing the copolymers of the present disclosure can be stored at room temperature (between about 20 °C to about 22 °C) or at elevated temperatures, such as about 25 °C, about 30 °C, about 35 °C, about 40 °C, about 45 °C, or higher while maintaining protein integrity. In some embodiments, protein formulations containing the copolymers of the present disclosure can be stored at a higher temperature than typically required, such as at about -20 °C, or about 0 °C, or about 2 °C, or about 4 °C, or about 8 °C, or about 20 °C, instead of at a lower temperature, such as at about -80 °C, or about -60 °C, or about -40 °C. In some embodiments, the copolymers provide for protein formulations to be stored at room temperature or higher temperatures rather than requiring cold chain storage. In some embodiments, cold chain storage is not required to maintain protein integrity.

[0076] In some embodiments, use of the copolymers of the present disclosure in protein formulations maintains formulation integrity, bioactivity, pharmacokinetics, and pharmacodynamics over a longer period of time when exposed to conditions such as elevated temperatures and agitation as compared to the same formulation without the copolymer. In some embodiments, the formulations maintain protein integrity for about 1 day, about 1 week, about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, about 24 months, or longer at higher temperatures as compared to the same formulation that does not contain the copolymer of the present disclosure.

[0077] In some embodiments, the copolymers of the present disclosure reduce the rate of aggregation of a biologic molecule in an aqueous formulation. In some embodiments, the copolymers of the present disclosure reduce the rate of aggregation of a protein in an aqueous protein formulation. In some embodiments, the protein is a protein that tends to aggregate in an aqueous medium. In some embodiments, the protein is an antibody, or fragments thereof, a cytokine, a chemokine, a hormone, a vaccine antigen, a cancer antigen, an adjuvant, and combinations thereof. In some embodiments, this allows for formulation of more concentrated protein solutions, thus reducing the volume of the protein solution that needs to be administered, for example, to a patient. In some embodiments, the composition comprises the protein in a concentration at least two times greater, at least three times greater, at least four times greater, or at least five times greater than the concentration of the same protein in the composition without the copolymer.

[0078] Thus, use of the copolymers of the present disclosure can imbue long-term stability and / or cold chain resilience to protein formulations. In some embodiments, a protein in a composition that comprises a copolymer of the present disclosure exhibits increased stability when stored at room temperature as compared to a protein composition that does not contain the copolymer. In some embodiments, the increased stability is at least 10-fold, at least 15- fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45 -fold, at least 50-fold, or greater as compared to a protein composition that does not contain the copolymer.

[0079] In some embodiments, the copolymers of the present disclosure preserve protein activity through 6 months of stressed aging without modifying one or more of formulation pharmacokinetics, protein secondary structure, formulation clarity, and in vivo bioactivity. In some embodiments, the copolymer reduces protein aggregation in the formulation when stored at ambient temperature (about 23 °C to about 27 °C) as compared to a protein formulation that does not contain the copolymer. In some embodiments, the copolymer reduces protein aggregation in the formulation when stored at 37 °C as compared to a protein formulation that does not contain the copolymer. In some embodiments, the copolymer reduces protein aggregation in the formulation when stored at 50 °C as compared to a protein formulation that does not contain the copolymer.

[0080] In some embodiments, the copolymer increases the time to aggregation of a protein formulation by at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, or at least 50-fold when stored at 37 °C as compared to a protein formulation that does not contain the copolymer. Time to aggregation can be assessed by any known method, including, for example, by a transmittance assay. In some embodiments, the copolymer increases the time to aggregation of a protein formulation by at least 10-fold when stored at 37 °C as compared to a protein formulation that does not contain the copolymer. In some embodiments, the copolymer increases the time to aggregation of a protein formulation by at least 20-fold when stored at 37 °C as compared to a protein formulation that does not contain the copolymer. In some embodiments, the copolymer increases the time to aggregation of a protein formulation by at least 30-fold when stored at 37 °C as compared to a protein formulation that does not contain the copolymer. In some embodiments, the copolymer increases the time to aggregation of a protein formulation by at least 40-fold when stored at 37 °C as compared to a protein formulation that does not contain the copolymer. In some embodiments, the copolymer increases the time to aggregation of a protein formulation by at least 50-fold when stored at 37 °C as compared to a protein formulation that does not contain the copolymer. In some embodiments, the copolymer increases the time to aggregation of a protein formulation by at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35- fold, at least 40-fold, at least 45-fold, or at least 50-fold when stored at 50 °C as compared to a protein formulation that does not contain the copolymer. In some embodiments, the copolymer increases the time to aggregation of a protein formulation by at least 10-fold when stored at 50 °C as compared to a protein formulation that does not contain the copolymer. In some embodiments, the copolymer increases the time to aggregation of a protein formulation by at least 20-fold when stored at 50 °C as compared to a protein formulation that does not contain the copolymer. In some embodiments, the copolymer increases the time to aggregation of a protein formulation by at least 30-fold when stored at 50 °C as compared to a protein formulation that does not contain the copolymer. In some embodiments, the copolymer increases the time to aggregation of a protein formulation by at least 40-fold when stored at 50 °C as compared to a protein formulation that does not contain the copolymer. In some embodiments, the copolymer increases the time to aggregation of a protein formulation by at least 50-fold when stored at 50 °C as compared to a protein formulation that does not contain the copolymer.

[0081] In addition to refrigerated transport, the early stages of the cold chain, maintaining proper transport and storage conditions during local distribution and once in patients' handspresents a challenge in many parts of the world. As described herein, the addition of the polyacrylamide-based copolymers can preserve protein formulation integrity during even severe cold chain interruptions. In some embodiments, this provides a reduction in cold chain requirements for protein transportation and storage that are difficult to maintain in underresourced environments. As disclosed herein, the polyacrylamide-based copolymers as formulation additives can improve cold chain resilience, thereby expanding global access to critical drugs and vaccines. In some embodiments, addition of the copolymer maintains the in vitro bioactivity of a protein formulation for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months. In some embodiments, addition of the copolymer maintains the in vitro bioactivity of a protein formulation for at least 1 month. In some embodiments, addition of the copolymer maintains the in vitro bioactivity of a protein formulation for at least 2 months. In some embodiments, addition of the copolymer maintains the in vitro bioactivity of a protein formulation for at least 3 months.

[0082] In some embodiments, the copolymer present in a formulation with a protein does not alter the pharmacokinetic (PK) or pharmacodynamic (PD) properties of the active ingredients within the formulation.3.2. Methods of use

[0083] As summarized above, provided in the present disclosure are methods of using the compositions and co-formulations described in the present disclosure that contain a polyacrylamide-based copolymer containing a water-soluble carrier monomer and a functional dopant monomer (e.g., DEA).

[0084] Provided is a method for increasing stability of a formulation containing a biologic molecule or lipid-based vehicle. According to embodiments of the disclosure, the copolymers described herein can be added to improve the stability of formulations comprising peptides, proteins, and conjugates thereof, nucleic acids and oligonucleotides, liposomes, polymerosomes, micelles, and lipid nanoparticles. In some embodiments, provided is a method for increasing stability of a protein formulation. In some embodiments, provided is a method of increasing thermal stability of a formulation containing a biologic molecule or lipid-based vehicle. In some embodiments, provided is a method for increasing thermal stability of a protein formulation. Also provided is a method of reducing the rate of aggregation of a biologic molecule or lipid-based vehicle in an aqueous formulation. In some embodiments, the molecule is a molecule that tends to aggregate in an aqueous medium. Insome embodiments, the protein is an antibody, or fragments thereof, a cytokine, a chemokine, a hormone, a vaccine antigen, a cancer antigen, an adjuvant, and combinations thereof.

[0085] In some embodiments, the methods include adding about 0.001 wt% to about 5 wt% of the polyacrylamide-based copolymer of the present disclosure to the formulation containing a biologic molecule or lipid-based vehicle, such as adding about 0.001 wt% to about 4 wt%, about 0.001 wt% to about 3 wt%, about 0.001 wt% to about 2 wt%, about 0.001 wt% to about 1 wt%, about 0.001 wt% to about 0.5 wt%, about 0.001 wt% to about 0.4 wt%, about 0.001 wt% to about 0.3 wt%, about 0.001 wt% to about 0.2 wt%, about 0.001 wt% to about 0.1 wt%, about 0.001 wt% to about 0.05 wt%, about 0.001 wt% to about 0.02 wt%, about 0.001 wt% to about 0.01 wt%, about 0.001 wt% to about 0.005 wt%, about 0.005 wt% to about 5 wt%, about 0.005 wt% to about 4 wt%, about 0.005 wt% to about 3 wt%, about 0.005 wt% to about 2 wt%, about 0.005 wt% to about 1 wt%, about 0.005 wt% to about 0.5 wt%, about 0.005 wt% to about 0.4 wt%, about 0.005 wt% to about 0.3 wt%, about 0.005 wt% to about 0.2 wt%, about 0.005 wt% to about 0.1 wt%, about 0.005 wt% to about 0.05 wt%, about 0.005 wt% to about 0.02 wt%, about 0.005 wt% to about 0.01 wt%, about 0.01 wt% to about 5 wt%, about 0.01 wt% to about 4 wt%, about 0.01 wt% to about 3 wt%, about 0.01 wt% to about 2 wt%, about 0.01 wt% to about 1 wt%, about 0.01 wt% to about 0.5 wt%, about 0.01 wt% to about 0.4 wt%, about 0.01 wt% to about 0.3 wt%, about 0.01 wt% to about 0.2 wt%, about 0.01 wt% to about 0.1 wt%, about 0.01 wt% to about 0.05 wt%, about 0.01 wt% to about 0.02 wt%, about 0.02 wt% to about 5 wt%, about 0.02 wt% to about 4 wt%, about 0.02 wt% to about 3 wt%, about 0.02 wt% to about 2 wt%, about 0.02 wt% to about 1 wt%, about 0.02 wt% to about 0.5 wt%, about 0.02 wt% to about 0.4 wt%, about 0.02 wt% to about 0.3 wt%, about 0.02 wt% to about 0.2 wt%, about 0.02 wt% to about 0.1 wt%, about 0.02 wt% to about 0.05 wt%, about 0.05 wt% to about 5 wt%, about 0.05 wt% to about 4 wt%, about 0.05 wt% to about 3 wt%, about 0.05 wt% to about 2 wt%, about 0.05 wt% to about 1 wt%, about 0.05 wt% to about 0.5 wt%, about 0.05 wt% to about 0.4 wt%, about 0.05 wt% to about 0.3 wt%, about 0.05 wt% to about 0.2 wt%, about 0.05 wt% to about 0.1 wt%, about 0.1 wt% to about 5 wt%, about 0.1 wt% to about 4 wt%, about 0.1 wt% to about 3 wt%, about 0.1 wt% to about 2 wt%, about 0.1 wt% to about 1 wt%, about 0.1 wt% to about 0.5 wt%, about 0.1 wt% to about 0.4 wt%, about 0.1 wt% to about 0.3 wt%, about 0.1 wt% to about 0.2 wt%, about 0.2 wt% to about 5 wt%, about 0.2 wt% to about 4 wt%, about 0.2 wt% to about 3 wt%, about 0.2 wt% to about 2 wt%, about 0.2 wt% to about 1 wt%, about 0.2 wt% to about 0.5 wt%, about 0.2 wt% to about 0.4 wt%, about 0.2 wt% to about 0.3 wt%,about 0.3 wt% to about 5 wt%, about 0.3 wt% to about 4 wt%, about 0.3 wt% to about 3 wt%, about 0.3 wt% to about 2 wt%, about 0.3 wt% to about 1 wt%, about 0.3 wt% to about 0.5 wt%, about 0.3 wt% to about 0.4 wt%, about 0.4 wt% to about 5 wt%, about 0.4 wt% to about 4 wt%, about 0.4 wt% to about 3 wt%, about 0.4 wt% to about 2 wt%, about 0.4 wt% to about 1 wt%, about 0.4 wt% to about 0.5 wt%, about 0.5 wt% to about 5 wt%, about 0.5 wt% to about 4 wt%, about 0.5 wt% to about 3 wt%, about 0.5 wt% to about 2 wt%, about 0.5 wt% to about 1 wt%, about 1 wt% to about 5 wt%, about 1 wt% to about 4 wt%, about 1 wt% to about 3 wt%, about 1 wt% to about 2 wt%, about 2 wt% to about 5 wt%, about 2 wt% to about 4 wt%, about 2 wt% to about 3 wt%, about 3 wt% to about 5 wt%, about 3 wt% to about 4 wt%, about 4 wt% to about 5 wt%, or about 0.005 wt%, about 0.01 wt%, or about 0.1 wt% of the polyacrylamide-based copolymer of the present disclosure to the formulation. In some embodiments, the method includes adding about 0.0005 wt% to about 5 wt% of the polyacrylamide-based copolymer of the present disclosure to the formulation. In some embodiments, the method includes adding about 0.001 wt% to about 1 wt% of the polyacrylamide-based copolymer of the present disclosure to the formulation. In some embodiments, the formulation comprises a biologic molecule. In some embodiments, the formulation comprises a protein. In some embodiments, the formulation comprises a lipid- based vehicle. In some embodiments, the lipid-based vehicle comprises a liposome, lipid nanoparticle, polymerosome, or micelle.3.2.1. Other uses of the polyacrylamide-based copolymers

[0086] The polyacrylamide-based copolymers of the present disclosure can be used in any composition or formulation where a surfactant is used. For example, the copolymers of the present disclosure can be used in applications including, but not limited to, cosmetic products, hair products, lotions, food products, nutritional products, pigments, and ink. In some embodiments, copolymers are used to improve food texture or improve mouthfeel. In some embodiments, the copolymers are used in biopharmaceutical compositions for animal or veterinary use. In some embodiments, the presence of the copolymer improves the stability of the formulation.3.3. Definitions

[0087] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present application; othersuitable methods and materials known in the art are also used in some aspects of this disclosure. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entireties. In case of conflict, the present specification, including definitions, will control. When trade names are used herein, the trade name includes the product formulation, the generic drug, and the active pharmaceutical ingredient(s) of the trade name product, unless otherwise indicated by context.

[0088] The terms “subject” and “patient” are used interchangeably. A subject can be a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, goats, rabbits, rats, mice, etc.) or a primate (e.g., monkey, ape, and human), for example a human. In certain embodiments, the subject is a mammal, e.g., a human, diagnosed with a disease or disorder provided herein. In another embodiment, the subject is a mammal, e.g., a human, at risk of developing a disease or disorder provided herein. In a specific embodiment, the subject is human.

[0089] The terms “therapies” and “therapy” are used in their broadest sense understood in the clinical arts.

[0090] In this disclosure, the terms “a,” “an,” and “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” has the same meaning as “A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed in this disclosure, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section.

[0091] Values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (for example, 1%, 2%, 3%, and 4%) and the sub-ranges (for example, 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.

[0092] The term “about” as used in the present disclosure can allow for a degree of variability in a value or range that is within 5% of a stated value or of a stated limit of a range.

[0093] In the methods described in the present disclosure, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0094] The term “polymer” refers to a substance or material consisting of repeating monomer subunits.

[0095] An “acrylamide monomer,” as used herein, refers to a monomer species that possesses an acrylamide functional group. The term “acrylamide monomer” includes not only monomeric acrylamide, but derivatives of monomeric acrylamide. Examples of acrylamide monomers include, but are not limited to, acrylamide (AM), N-(3-methoxypropyl)acrylamide (MP AM), 4-acryloylmorpholine (MORPH), N,N-dimethylacrylamide (DMA), N- hydroxyethyl acrylamide (HEAM), N-[tris(hydroxymethyl)-methyl]acrylamide (TRI), 2- acrylamido-2-methylpropane sulfonic acid (AMP), (3-acrylamidopropyl)trimethylammonium chloride (TMA), N-isopropylacrylamide (NIP), N,N-diethylacrylamide (DEA), N-tert- butylacrylamide (TBA), and N-phenylacrylamide (PHE).

[0096] The term “polyacrylamide-based copolymer” refers to polymers that are formed from the polymerization of two or more monomer species, in which at least one of the monomer species possesses an acrylamide functional group (acrylamide monomer) and the monomers are structurally different. In some embodiments, the polyacrylamide-based copolymer is formed from the polymerization of two structurally different acrylamide monomers (two structurally different monomers that each possess an acrylamide functional group). The resulting copolymer can be an alternating copolymer wherein the monomer species areconnected in an alternating fashion; a random copolymer, wherein the monomer species are connected to each other within a polymer chain without a defined pattern; a block copolymer, wherein polymeric blocks of one monomer species are connected to polymeric blocks made up of another monomer species; and graft copolymer, wherein the main polymer chain consists of one monomer species, and polymeric blocks of another monomer species are connected to the main polymer chain as side branches. In some embodiments, the polyacrylamide-based copolymers of the present disclosure are formed from the polymerization of a water-soluble carrier monomer and a functional dopant monomer. In some embodiments, the polyacrylamide-based copolymers of the present disclosure are random copolymers.

[0097] As defined herein, the term “water-soluble carrier monomer” refers to an acrylamide monomer species that is the water-soluble species within the polyacrylamide-based copolymer. In some embodiments, the water-soluble carrier monomer is the predominant species within the polyacrylamide-based copolymer. In some embodiments, the water-soluble carrier monomer imparts aqueous solubility to the copolymer. In some embodiments, the water-soluble carrier monomer within the polyacrylamide-based copolymer provides an inert barrier at the interface of an aqueous formulation to prevent protein-protein interactions. In some embodiments, the interface is an air-water interface. In some embodiments, the interface is an enclosure-water interface, including, but not limited to, a glass- water interface, a rubber-water interface, a plastic-water interface, or a metal-water interface. In some embodiments, the interface is an oil-water interface. In some embodiments, the interface is an interface between a liquid and tubing. In some embodiments, the interface is an interface between a liquid and a catheter. In some embodiments, the enclosure-water interface is in a pump system. In some embodiments, the enclosure-water interface is in a closed-loop system. In some embodiments, the water-soluble carrier monomer is nonionic. Examples of water- soluble carrier monomers include, but are not limited to, acrylamide (AM), N-(3- methoxypropyl)acrylamide (MP AM), 4-acryloylmorpholine (MORPH), N,N- dimethylacrylamide (DMA), and N -hydroxy ethyl acrylamide (HEAM).

[0098] The term “functional dopant monomer,” as used herein, refers to an acrylamide monomer species that has physicochemical properties (e.g., hydrophobicity, charge) different from those of the water-soluble carrier monomer. In some embodiments, the functional dopant monomer within the polyacrylamide -based copolymer promotes association of thepolymers to an interface; such interfaces can include, but are not limited to, polymer-air- water interface interactions, polymer-protein interactions, polymer-peptide interactions, polymer-micelle interactions, polymer-liposome interactions, and polymer-lipid nanoparticle interactions. The functional dopant monomer can act as a stabilizing moiety to facilitate interactions with biomolecules, for example, proteins, peptides, antibodies, antibody-drug conjugates, nucleic acids, lipid particles, and combinations thereof (e.g., to prevent aggregation of the biomolecules). The functional dopant monomers can be further classified into hydrogen-bonding, ionic, hydrophobic, and aromatic monomers based on their chemical composition. Typically, the functional dopant monomers are copolymerized at a lower weight percentage as compared to the water-soluble carrier monomers.

[0099] The term “polymerization” refers to the process in which monomer molecules undergo a chemical reaction to form polymeric chains or three-dimensional networks. Different types of polymerization reactions are known in the art, for example, addition (chain-reaction) polymerization, condensation polymerization, ring-opening polymerization, free radical polymerization, controlled radical polymerization, atom transfer radical polymerization (ATRP), single-electron transfer living radical polymerization (SET-LRP), reversible addition-fragmentation chain transfer (RAFT) polymerization, nitroxide-mediated polymerization (NMP), and emulsion polymerization. In some embodiments, the copolymers of the present disclosure are prepared using RAFT polymerization.

[0100] The term “degree of polymerization” (DP) refers to the number of monomer units in a polymer. It is calculated by dividing the average molecular weight of a polymer sample by the molecular weight of the monomers. As defined herein, the average molecular weight of a polymer can be represented by the number-averaged molecular weight (Mn), the weightaverage molecular weight (Mw), the Z-average molecular weight (Mz) or the molecular weight at the peak maxima of the molecular weight distribution curve (Mp). The average molecular weight of a polymer can be determined by a variety of analytical characterization techniques known to those skilled in the art, for example, gel permeation chromatography (GPC), static light scattering (SLS) analysis, multi-angle laser light scattering (MALLS) analysis, nuclear magnetic resonance spectroscopy (NMR), intrinsic viscometry (IV), melt flow index (MFI), and matrix-assisted laser desorption / ionization mass spectrometry (MALDI-MS), and combinations thereof. Degree of polymerization can also be determined experimentally using suitable analytical methods known in the art, such as nuclear magneticspectroscopy (NMR), Fourier Transform infrared spectroscopy (FT-IR) and Raman spectroscopy.

[0101] The term "amphiphilic" refers to chemical substances that possess both hydrophilic (water-loving, polar) and lipophilic (fat-loving, nonpolar) properties. Examples of common amphiphilic compounds include detergents, soaps, surfactants, lipoproteins, and phospholipids. In some embodiments, the amphiphilic substance is a charged species. In some embodiments, the amphiphilic substance is a neutral species.

[0102] A "lipid-based vehicle," as used herein, refers to structures having a protective outer layer of lipids that can be used as drug delivery vehicles. For example, a lipid-based vehicle can be used to encapsulate and transport cargo (e.g., a therapeutic agent) to a biologic target. Examples of lipid-based vehicles include, but are not limited to, liposomes, micelles, polymerosomes, and lipid nanoparticles.

[0103] "Biologic molecule," as used herein, refers to molecules such as proteins, nucleic acids, polysaccharides, and lipids.

[0104] The term "protein" is defined as a class of large molecules comprising one or more long chains of amino acids. A wide variety of proteins may be considered as belonging to a family of proteins based on having similar structural features, having particular biological functions, and / or being related to specific microorganisms, particularly disease-causing microorganisms. Such proteins include, for example, antibodies (immunoglobulins), cytokines, chemokines, enzymes, hormones, vaccine antigens, cancer antigens, adjuvants, nutritional markers, and tissue specific antigens.

[0105] The term "nucleic acid," as used herein, includes deoxyribonucleic acid (DNA), ribonucleic acid (RNA), messenger RNA (mRNA), small-interfering RNA (siRNA), short hairpin RNA (shRNA), and microRNA (miRNA).

[0106] The term "antibody" refers to large, Y-shaped proteins produced by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The term "antibody" includes monoclonal antibodies (for example, full length or intact monoclonal antibodies), polyclonal antibodies, multivalent antibodies, multispecific antibodies (e.g., bispecific or trispecific antibodies, so long as they exhibit the desired biological activity) and can also include certain antibody fragments. An antibody can behuman, humanized and / or affinity matured. "Antibody fragments" comprise only a portion of an intact antibody, where in certain embodiments, the portion retains at least one, and typically most or all, of the functions normally associated with that portion when present in an intact antibody. In one embodiment, an antibody fragment comprises an antigen binding site of the intact antibody and thus retains the ability to bind antigen. In another embodiment, an antibody fragment, for example one that comprises the Fe region, retains at least one of the biological functions normally associated with the Fe region when present in an intact antibody, such as FcRn binding, antibody half-life modulation, ADCC function and complement binding. In one embodiment, an antibody fragment is a monovalent antibody that has an in vivo half-life substantially similar to an intact antibody. For example, such an antibody fragment may comprise an antigen binding arm linked to an Fe sequence capable of conferring in vivo stability to the fragment.

[0107] The term "aggregation" refers to the formation of higher molecular weight, amorphous species due to non-covalent adherence ("clumping") of smaller species. The aggregation process can be irreversible or reversible. Many biological and synthetic molecules can undergo aggregation, including proteins, peptides, lipid particles, nucleic acids, inorganic nanoparticles and organic nanoparticles (e.g., micelles, lipid nanoparticles, liposomes, polymerosomes) that may further comprise an encapsulated species.

[0108] In the case of protein aggregation, formation of protein aggregates can be due to the protein's intrinsic disordered nature, or misfolding of protein molecules, which results in the exposure of hydrophobic residues and surfaces that are normally buried within the interior of the protein three-dimensional structure. Due to the hydrophobic effect, the exposed hydrophobic portions of a misfolded protein have the tendency to interact with other misfolded protein molecules to shield the exposed hydrophobic surfaces, which can lead to protein aggregation.

[0109] Some biologic molecules are more "susceptible to aggregation" than others. For example, the amino-acid sequence and overall three-dimensional structure of a protein is relevant to its susceptibility to aggregation. For example, transmembrane proteins are more prone (or susceptible) to aggregation than non-membrane proteins, particularly when expressed recombinantly without the use of a stabilizing agent. Proteins that are subject to conditions beyond the physiological conditions (37 °C, - neutral pH, isotonic) may also be more susceptible to aggregation than when in their native environment. Stress conditionssuch as temperature fluctuations, light, mechanical perturbation (e.g., shaking), surfaces, ultrasonic vibration, pH changes, and changes in ionic strength can affect protein stability and induce aggregation. Protein aggregation can lead to the formation of sub-visible or visible particles (i.e., precipitation). The extent of sub- visible protein aggregation can be measured by a variety of analytical methods known in the art, for example, size-exclusion chromatography (SEC), gel electrophoresis, asymmetric field- flow fractionation (AF4), analytical ultracentrifugation (AUC), mass spectrometry (MS), optical microscopy, fluorescence microscopy, dynamic light scattering (DLS), multi-angle laser light scattering (MALLS), flow imaging, turbidity / nephelometry, and transmittance measurement.

[0110] As used herein, the term "reduced aggregation" of a biologic molecule or lipid-based vehicle includes all forms of reducing aggregation. The degree or amount of aggregation observed (e.g., in the composition) can be reduced as compared to a composition of the same biologic molecule or lipid-based vehicle in the absence of the polyacrylamide-based copolymer of the present disclosure. Thus, "reduced aggregation" includes no observable aggregation or reduced amounts of aggregation (e.g., reduced levels of aggregated protein). Thus, the amount of aggregates present in the composition can be reduced by at least about 10 mol%, about 20 mol%, about 30 mol%, about 40 mol%, about 50 mol%, about 60 mol%, about 70 mol%, about 80 mol%, about 90 mol%, or about 100 mol% as compared to the amount of aggregates of the same biologic molecule or lipid- based vehicle in the absence of the polyacrylamide-based copolymer. Aggregation can be measured by any method known in the art, including, but not limited to, size-exclusion chromatography (SEC), gel electrophoresis, asymmetric field-flow fractionation (AF4), analytical ultracentrifugation (AUC), mass spectrometry (MS), optical microscopy, fluorescence microscopy, dynamic light scattering (DLS), multi-angle laser light scattering (MALLS), flow imaging, turbidity / nephelometry, and transmittance measurement.

[0111] As used herein, the term "increased stability," when referring to a formulation containing a biologic molecule or lipid-based vehicle, refers to a measurable decrease in the amount of aggregation over a fixed period of time under testing or fixed storage conditions as compared to the amount of aggregates of the same biologic molecule or lipid- based vehicle in the absence of the polyacrylamide-based copolymer.

[0112] The terms "aggregated protein" or "protein aggregates" as used herein refer to a collection of proteins that are disordered or misfolded and grouped together. The aggregatescan be soluble or insoluble. Protein aggregates include, but are not limited to, inclusion bodies, soluble and insoluble precipitates, soluble non-native oligomers, gels, fibrils, films, filaments, protofibrils, amyloid deposits, amyloid fibrils, plaques, and dispersed non-native intracellular oligomers. In some embodiments, the proteins in a protein aggregate are, prior to their aggregation, soluble precursors. Protein aggregation can be prevented in compositions containing the polyacrylamide-based copolymer of the present disclosure. Protein aggregation can also be reduced in a composition containing the polyacrylamide-based copolymer of the present disclosure as compared to a composition containing the same protein that does not contain the polyacrylamide-based copolymer of the present disclosure. Thus, the polyacrylamide-based copolymer can reduce or prevent the aggregation of a protein.4. ADDITIONAL EMBODIMENTS

[0113] The disclosure is further described by the following non- limiting clauses:Clause 1. A polyacrylamide-based copolymer comprising: a water-soluble carrier monomer selected from N-(3-methoxypropyl)acrylamide (MP AM), 4-acryloylmorpholine (MORPH), N,N-dimethylacrylamide (DMA), N- hydroxyethyl acrylamide (HEAM), and acrylamide (AM), and combinations thereof; and a functional dopant monomer comprising N,N-diethylacrylamide (DEA).Clause 2. The copolymer of clause 1, wherein: the water-soluble carrier monomer is selected from N-(3-methoxypropyl)acrylamide (MP AM) and 4-acryloylmorpholine (MORPH).Clause 3. The copolymer of clause 1 or 2, wherein the weight percent (wt%) of the water-soluble carrier monomer is from 70% to 98%.Clause 4. The copolymer of any one of clauses 1-3, wherein the weight percent (wt%) of the N,N-diethylacrylamide (DEA) is from 2% to 30%.Clause 5. The copolymer of clause 4, wherein the weight percent (wt%) of the N,N- diethylacrylamide (DEA) is from 2% to 16%.Clause 6. The copolymer of any one of clauses 2-5, wherein the water-soluble carrier monomer is MORPH.Clause 7. The copolymer of any one of clauses 2-5, wherein the water-soluble carrier monomer is MP AM.Clause 8. The copolymer of any one of clauses 1-7 wherein the copolymer further comprises a functional dopant monomer selected from N-[tris(hydroxymethyl)- methyl] acrylamide (TRI), 2-acrylamido-2-methylpropane sulfonic acid (AMP), (3- acrylamidopropyl)trimethylammonium chloride (TMA), N-isopropylacrylamide (NIP), N- tert-butylacrylamide (TBA), and N-phenylacrylamide (PHE), and combinations thereof.Clause 9. The copolymer of any one of clauses 1-8, wherein the degree of polymerization is from 10 to 500.Clause 10. The copolymer of clause 9, wherein the degree of polymerization is from 20 to 200.Clause 11. The copolymer of clause 10, wherein the degree of polymerization is 50.Clause 12. The copolymer of any one of clauses 1-11, wherein the molecular weight of the copolymer is from 1,000 to 40,000 g / mol.Clause 13. The copolymer of clause 12, wherein the molecular weight of the copolymer is from 2,000 to 10,000 g / mol.Clause 14. The copolymer of clause 13, wherein the molecular weight of the copolymer is from 4,000 to 6,000 g / mol.Clause 15. The copolymer of any one of clauses 1-14, wherein the copolymer is amphiphilic.Clause 16. A polyacrylamide-based copolymer comprising: a water-soluble carrier monomer comprising an acrylamide reactive moiety; and a functional dopant monomer comprising N,N-diethylacrylamide (DEA); wherein: the weight percent (wt%) of the water-soluble carrier monomer is from 70% to 98%; the weight percent (wt%) of the functional dopant monomer is from 2% to 30%; the average molecular weight (Mn) of the polyacrylamide-based copolymer is about 1,000 g / mol to about 30,000 g / mol; andthe degree of polymerization is about 10 to about 250.Clause 17. The copolymer of clause 16, wherein the water-soluble carrier monomer is selected from N-(3-methoxypropyl)acrylamide (MP AM), 4- acryloylmorpholine (MORPH),N,N-dimethylacrylamide (DMA), N-hydroxy ethyl acrylamide (HEAM), and acrylamide (AM).Clause 18. The copolymer of clause 17, wherein the water-soluble carrier monomer is selected from N-(3-methoxypropyl)acrylamide (MP AM) and 4-acryloylmorpholine (MORPH).Clause 19. The copolymer of any one of clauses 16-18, wherein the functional dopant monomer further comprises a monomer selected from N-[ tri s( hydroxymethyl )methy 1 |acrylamide (TRI), 2-acrylamido-2-methylpropane sulfonic acid (AMP), (3-acrylamidopropyl)trimethylammonium chloride (TMA), N-isopropylacrylamide (NIP), N-tert-butylacrylamide (TBA), and N-phenylacrylamide (PHE), and combinations thereof.Clause 20. A composition comprising the copolymer of any one of clauses 1-19 and a pharmaceutically acceptable excipient.Clause 21. A composition comprising the copolymer of any one of clauses 1-19, wherein the composition is a cosmetic product, a hair product, a lotion, a food product, a veterinary product, or a nutritional product.Clause 22. A composition comprising the copolymer of any one of clauses 1-19 and a protein.Clause 23. The composition of clause 22, wherein the protein is a protein susceptible to aggregation in an aqueous medium.Clause 24. The composition of any one of clauses 20-23, wherein the copolymer concentration is from 0.1% to about 10% by weight of the composition.Clause 25. The composition of clause 24, wherein the copolymer concentration is fromO.5% by weight, or about 5% by weight of the composition.Clause 26. The composition of clause 25, wherein the copolymer concentration is 1% by weight of the composition.Clause 27. The composition of any one of clauses 20-26, wherein the composition comprises one or more of an aqueous buffer, a tonicity modifier, and a preservative.Clause 28. The composition of any one of clauses 20-27, wherein the composition is an aqueous composition.Clause 29. The composition of clause 28, wherein the pH of the composition is from 4 to 9.Clause 30. The composition of clause 28, wherein the pH of the composition is about 6 to about 8.Clause 31. A method for increasing thermal stability of a protein formulation, comprising adding from 0.0005 wt% to 5 wt% of the copolymer of any one of clauses 1-19 to the protein formulation.Clause 32. A method for increasing stability of a protein formulation, comprising adding about 0.005 wt% to about 5 wt% of the copolymer of any one of clauses 1-19 to the protein formulation.Clause 33. A method for reducing the rate of aggregation of a protein in an aqueous composition, comprising adding from 0.005 wt% to 5 wt% of the copolymer of any one of clauses 1-19 to the protein formulation.Clause 34. The method of any one of clauses 31-33, wherein the protein is a protein that aggregates in an aqueous medium.5. EXAMPLES

[0114] The Examples in this section are offered by way of illustration, and not by way of limitation. The examples can represent only some embodiments, and it should be understood that the following examples are illustrative and not limiting. All substituents, unless otherwise specified, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. The specific synthetic steps for each of the routesdescribed may be combined in different ways, or in conjunction with steps from different schemes, to prepare the compounds described herein.5.1. Example 1 - Synthesis of polyacrylamide-based copolymers

[0115] Synthesis of first copolymer library via automated parallel synthesis: Copolymerizations of carriers and dopants are carried out using RAFT polymerization ([Total Monomer] / [CTA] = 50, [CTA] / [AIBN] = 0.2). MPAM, MORPH, and DMA carrier monomers copolymerized with DEA dopant monomer are polymerized in DMF using 2- CPDT or BM1433 as the CTA and AIBN as the initiator. Total vinyl monomer molarity is held at 2.72M (MPAM copolymerizations), 2.86M (MORPH copolymerizations), and 3.84M (DMA copolymerizations) such that the homopolymerization of the carrier monomer in DMF would be carried at a constant 40 wt.%. HEAM carrier monomer copolymerized with DEA dopant monomer is polymerized in DMF / EtOH mixture using 2-CPDT or BM1433 as the CTA and AIBN as the initiator. Total vinyl monomer molarity is held at 2.58M (HEAM copolymerizations) such that the homopolymerization of HEAM in DMF would be carried at a constant 30 wt.%. AM carrier monomer copolymerized with DEA dopant monomer is polymerized in DMF / water mixture using BM1433 as the CTA and ACVA as the initiator. Total vinyl monomer molarity is held at 4.05M (AM copolymerizations) such that the homopolymerization of AM in DMF would be carried at a constant 30 wt.%.

[0116] Reaction mixtures were prepared by combining stock solutions: (i) carriers, (ii) dopant, and (hi) CTA and initiator.

[0117] Parallel syntheses of polyacrylamide-based copolymer excipients (also referred to as AC / DC excipients) are conducted on a Chemspeed Swing XL automated synthesizer robot equipped with a 4-Needle Head tool and an iSynth reactor. The Reactions are performed in 8 mL disposable iSynth reactor vials. All aspirations and dispensing reagent solutions are performed using a the 4-Needle Head tool equipped with a 2 x 10 mL and 2 x 1 mL syringes fitted with septa piercing needles, with both the 1 mL and 10 mL syringes. All solvent lines are primed with 60 mL (6 strokes of syringe volume) of degassed DMF. Typical aspiration and dispense rates of the reagents are 10 mL / min for both the 1 mL syringes. An airgap of 50 pL and an extra volume of 50 pL are used for the 1 mL syringes, and an airgap of 50 pL and an extra volume of 100 pL is used for the 10 mL syringes during aspirations using the 4- Needle Head tool. The needles and lines are rinsed after each reagent dispense task with 3 mL inside and outside volume of the priming solvent for the 1 mL syringes and with 20 mLinside and outside volume of the priming solvent for the 10 mL syringes. The DMF reservoir is degassed by continuous nitrogen sparging. All stock solutions are prepared in septa capped reagent vials and degassed by sparging with argon for 15 minutes before transfer into the Chemspeed. The atmosphere within the Chemspeed is reduced to <1 % oxygen by purging with nitrogen while exhaust ports are closed. Reactor vials are exposed to nitrogen flow until the start of the reaction. The calculated aliquots of stock solutions and solvent are transferred to the reactors via the automated liquid handling system. Upon dispensing, reactor vials are manually sealed in the inert atmosphere, removed from the Chemspeed, manually shaken to combine reagents, and heated to 65 °C in an oven for 24 hours, after which, reaction vials are cooled to room temperature and exposed to air.

[0118] A procedure to remove the CTA Z groups from the AC / DC excipients containing MORPH, DMA, HEAM, and MP AM copolymers is adapted from the literature. The reaction vial is diluted to 6 mL with DMF. LPO (2 eq.) and AIBN (20 eq.) are added to the reaction mixture, which is sealed with a cap utilizing a PTFE seal. The reaction mixture is sparged with nitrogen gas for 10 minutes while heating at 90 °C and subsequently heated for 12 hours at 90 °C. A procedure to remove the CTA Z groups from the AC / DC excipients containing AM copolymers is adapted from the literature. The reaction vial is diluted to 5 mL with miliQ water. H2O2 (20 eq.) is added to the reaction vial, which is sealed and heated to 60 °C for 12 hours. The resulting copolymers are isolated by precipitation as outlined below.

[0119] AC / DC excipients synthesized with AM and HEAM carriers are precipitated twice from acetone. AC / DC excipients synthesized with DMA and MORPH are precipitated twice from diethyl ether. AC / DC excipients synthesized with MP AM are precipitated twice from diethyl ether and hexane (3:1 ratio) mixtures. The number (Mn) and weight (Mw) average molecular weights and dispersity for the AC / DC excipients containing MORPH, MP AM, DMA, and HEAM are determined using SEC in DMF with poly(ethyleneglycol) standards. Mn, Mw, and dispersity for the AC / DC excipients containing AM are determined using aqueous SEC-MALLS.

[0120] Synthesis of second polymeric library: A typical procedure to synthesize a MORPH- DEA AC / DC excipient is as follows and is nearly identical for all other carrier / dopant combinations, where only the carrier / dopant selection and concentration are changed. MORPH (41.5 eq.), DEA (8.5 eq.), 2CPDT (1 eq.) and AIBN (0.2 eq.) are combined and diluted with DMF to a total volume of 2.25 mL (33.3 w / v vinyl monomer concentration) inan 8 mL scintillation vial equipped with a PTFE septa. The reaction mixture is sparged with nitrogen gas for 10 minutes and then heated for 12 hours at 65°C. To remove the Z-terminus of the resulting polymer, AIBN (20 eq.) and LPO (2 eq.) are added to the reaction mixture, which is then sparged with nitrogen gas for 10 minutes and heated for 12 hours at 90 °C. Z- group removal is confirmed by the ratio of the refractive index to UV 0- = 310 nm) intensity in SEC analysis. Resulting polymers are precipitated three times from ether, and dried under vacuum overnight. Resulting composition and molecular weights are determined via1HNMR spectroscopy and SEC with poly(ethyleneglycol) standards.

[0121] Copolymer molecular weight characterization: Mn, Mw, and dispersity for copolymers with HEAM, DMA, MP AM, and MORPH carrier monomers are determined via SEC implementing poly(ethyleneglycol) standards (American Polymer Standards Corporation) after passing through two size exclusion chromatography columns.

[0122] Mn, Mw, and dispersity for copolymers with AM are determined via SEC-MALLS after passing through a size exclusion chromatography column in a mobile phase of phosphate-buffered saline containing 300 ppm sodium azide. Detection is carried out with a Optilab T-rEX (Wyatt Technology Corporation) refractive index detector operating at 658 nm and a TREOS II light scattering detector (Wyatt Technology Corporation) operating at 659 nm. The dn / dc value for AM copolymers are assumed to be 0.185 in this media.

[0123] Method for Determining Experimental VM wt.% Values: The handling of viscous monomers (HEAM, MP AM, MORPH) by the Chemspeed can result in monomer loadings that differ from the target monomer loadings for select copolymerizations during the initial AC / DC copolymer library synthesis. Experimental weight percentages are approximated from the peak molecular weights (Mp) of the SEC traces. Because only viscous monomers are affected, changes to Mp arise from inadequate addition of carrier monomer (aside from small changes in pervaded volume in the differing weight percentages of the dopant monomer compared to the carrier). Thus, to calculate the experimental weight percentages, Mp, max is determined for a given carrier / dopant pair.

[0124] High-throughput synthesis of polyacrylamide library: A library of AC / DC excipients are synthesized combinatorially through statistical copolymerizations of water-soluble carrier monomers and functional dopant DEA monomer. The carrier monomers are the predominant species and responsible for both maintaining solubility and providing an inert barrier toprevent protein-protein interactions. The functional dopants can copolymerize at lower weight percentages and are incorporated statistically throughout the resulting copolymer. The dopant DEA is selected by design to promote either polymer-interface interactions or polymer-protein interactions. The library targets a degree of polymerization (DP) of 50 for the copolymers. The experimental degree of polymerization (DP) of the carrier monomer is approximated using equation (SI).

[0125] This value is used to approximate the experimental weight percentages (wt%). The experimental weight percentage values of the carrier monomer and the functional dopant monomer for each copolymer are determined usingNMR and SEC .

[0126] The library is generated through parallel synthesis with a Chemspeed Swing XL Auto Synthesizer, a liquid handling robot in an inert environment. RAFT polymerization is implemented because it affords precise copolymerization stoichiometry, low dispersity, and controlled molecular weights for a wide scope of monomers. Polyacrylamide derivatives are used for both the carrier and dopant monomers due to the scope and availability of commercially available water-soluble monomers (carriers) and functional monomers (dopants) and polymeric stability. While monomeric acrylamide derivatives often exhibit acute toxicides, polyacrylamide derivatives, when properly purified from their monomeric precursors, demonstrate a high degree of biocompatibility. Moreover, the reactivity ratios between the various acrylamide monomers are close to 1 , yielding copolymers with little to no dopant gradient composition. Carrier monomers include acrylamide (AM), hydroxy ethylacrylamide (HEAM), dimethylacrylamide (DMA), acryloylmorpholine (MORPH), and methoxypropylacrylamide (MP AM) as they are nonionic and water soluble (ordered in increasing hydrophobicity). Dopant monomer is N,N-diethylacrylamide (DEA), which could be further classified as a hydrophobic monomer based on its chemical composition.6. EQUIVALENTS AND INCORPORATION BY REFERENCE

[0127] While the various embodiments of the present disclosure have been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changesin form and details can be made herein without departing from the spirit and scope of the disclosure.

[0128] All publications, patents, patent applications, and other documents cited in this application, including U.S. Provisional Appl. No. 63 / 344,991 and published international application no. WO 2021 / 211976, are hereby incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent, patent application, or other document were individually indicated to be incorporated by reference for all purposes.

Claims

WHAT IS CLAIMED IS:

1. A polyacrylamide-based copolymer comprising: a water-soluble carrier monomer selected from N-(3-methoxypropyl)acrylamide (MP AM), 4-acryloylmorpholine (MORPH), N,N-dimethylacrylamide (DMA), N- hydroxyethyl acrylamide (HEAM), and acrylamide (AM), and combinations thereof; and a functional dopant monomer comprising N,N-diethylacrylamide (DEA).

2. The copolymer of claim 1, wherein: the water-soluble carrier monomer is selected from N-(3-methoxypropyl)acrylamide (MP AM) and 4-acryloylmorpholine (MORPH).

3. The copolymer of claim 1 or 2, wherein the weight percent (wt%) of the water-soluble carrier monomer is from 70% to 98%.

4. The copolymer of any one of claims 1-3, wherein the weight percent (wt%) of the N,N-diethylacrylamide (DEA) is from 2% to 30%.

5. The copolymer of claim 4, wherein the weight percent (wt%) of the N,N- diethylacrylamide (DEA) is from 2% to 16%.

6. The copolymer of any one of claims 2-5, wherein the water-soluble carrier monomer is MORPH.

7. The copolymer of any one of claims 2-5, wherein the water-soluble carrier monomer is MP AM.

8. The copolymer of any one of claims 1-7 wherein the copolymer further comprises a functional dopant monomer selected from N-|tris(hydroxymethyl)-methyl|acrylamide (TRI), 2-acrylamido-2-methylpropane sulfonic acid (AMP), (3- acrylamidopropyl)trimethylammonium chloride (TMA), N-isopropylacrylamide (NIP), N- tert-butylacrylamide (TBA), and N-phenylacrylamide (PHE), and combinations thereof.

9. The copolymer of any one of claims 1-8, wherein the degree of polymerization is from 10 to 500.

10. The copolymer of claim 9, wherein the degree of polymerization is from 20 to 200.

11. The copolymer of claim 10, wherein the degree of polymerization is 50.

12. The copolymer of any one of claims 1-11, wherein the molecular weight of the copolymer is from 1,000 to 40,000 g / mol.

13. The copolymer of claim 12, wherein the molecular weight of the copolymer is from 2,000 to 10,000 g / mol.

14. The copolymer of claim 13, wherein the molecular weight of the copolymer is from 4,000 to 6,000 g / mol.

15. The copolymer of any one of claims 1-14, wherein the copolymer is amphiphilic.

16. A polyacrylamide-based copolymer comprising: a water-soluble carrier monomer comprising an acrylamide reactive moiety; and a functional dopant monomer comprising N,N-diethylacrylamide (DEA); wherein: the weight percent (wt%) of the water-soluble carrier monomer is from 70% to 98%; the weight percent (wt%) of the functional dopant monomer is from 2% to 30%; the average molecular weight (Mn) of the polyacrylamide-based copolymer is about 1,000 g / mol to about 30,000 g / mol; and the degree of polymerization is about 10 to about 250.

17. The copolymer of claim 16, wherein the water-soluble carrier monomer is selected from N-(3-methoxypropyl)acrylamide (MP AM), 4-acryloylmorpholine (MORPH), N,N- dimethylacrylamide (DMA), N -hydroxy ethyl acrylamide (HEAM), and acrylamide (AM).

18. The copolymer of claim 17, wherein the water-soluble carrier monomer is selected from N-(3-methoxypropyl)acrylamide (MP AM) and 4-acryloylmorpholine (MORPH).

19. The copolymer of any one of claims 16-18, wherein the functional dopant monomer further comprises a monomer selected from N-[tris(hydroxymethyl)methyl]acrylamide (TRI), 2-acrylamido-2-methylpropane sulfonic acid (AMP), (3-acrylamidopropyl)trimethylammonium chloride (TMA), N-isopropylacrylamide (NIP), N- tert-butylacrylamide (TBA), and N-phenylacrylamide (PHE), and combinations thereof.

20. A composition comprising the copolymer of any one of claims 1-19 and a pharmaceutically acceptable excipient.

21. A composition comprising the copolymer of any one of claims 1-19, wherein the composition is a cosmetic product, a hair product, a lotion, a food product, a veterinary product, or a nutritional product.

22. A composition comprising the copolymer of any one of claims 1-19 and a protein.

23. The composition of claim 22, wherein the protein is a protein susceptible to aggregation in an aqueous medium.

24. The composition of any one of claims 20-23, wherein the copolymer concentration is from O.f % to about 10% by weight of the composition.

25. The composition of claim 24, wherein the copolymer concentration is from 0.5% by weight, or about 5% by weight of the composition.

26. The composition of claim 25, wherein the copolymer concentration is 1% by weight of the composition.

27. The composition of any one of claims 20-26, wherein the composition comprises one or more of an aqueous buffer, a tonicity modifier, and a preservative.

28. The composition of any one of claims 20-27, wherein the composition is an aqueous composition.

29. The composition of claim 28, wherein the pH of the composition is from 4 to 9.

30. The composition of claim 28, wherein the pH of the composition is about 6 to about 8.

31. A method for increasing thermal stability of a protein formulation, comprising adding from 0.0005 wt% to 5 wt% of the copolymer of any one of claims 1-19 to the protein formulation.

32. A method for increasing stability of a protein formulation, comprising adding about 0.005 wt% to about 5 wt% of the copolymer of any one of claims 1-19 to the protein formulation.

33. A method for reducing the rate of aggregation of a protein in an aqueous composition, comprising adding from 0.005 wt% to 5 wt% of the copolymer of any one of claims 1-19 to the protein formulation.

34. The method of any one of claims 31-33, wherein the protein is a protein that aggregates in an aqueous medium.

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