Injectable polymeric biopharmaceutical formulations

Abstract

The present disclosure provides a solid composition comprising a plurality of particles, where the particles can include a biopharmaceutical agent and a polyacrylamide-based copolymer, and optionally a stabilizing agent. Further provided are injectable pharmaceutical compositions including the particles suspended in a liquid carrier. The inventors have demonstrated that particular polyacrylamide-based copolymers can be used as stabilizing excipients in particle formulations of biopharmaceutical agents, without interacting directly with the biopharmaceutical agent, or altering its pharmacokinetic properties. The pharmaceutical composition can be formulated for injection to a patient. Also provided is a syringe loaded with the injectable pharmaceutical composition, methods of administering via injection a therapeutically effective dose of a biopharmaceutical to a subject in need thereof.

Description

Attorney Docket No.38821-63329 (008WO) INJECTABLE POLYMERIC BIOPHARMACEUTICAL FORMULATIONS 1. BACKGROUND

[0001] Many biopharmaceuticals in aqueous based formulations are prone to irreversible aggregation, e.g., when exposed to high temperatures and / or agitation, and require formulation at low concentrations, careful storage, and refrigerated transport (the cold chain) to retain activity over their 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 can vary between biopharmaceutical agents, their tendency to aggregate at interfaces increases with formulation concentrations, negatively impacting overall formulation stability. Such inherent concentration and / or stability limitations of biopharmaceutical formulations often require that large-volume, low-concentration transfusions of biopharmaceutical therapies are delivered by injection, e.g., intravenously (IV). However, administration of such formulations places a burden on patients, often requiring lengthy transfusion procedures and access to clinical infrastructure, precluding large numbers of at-risk populations from effective treatments.

[0002] Many commercial excipients have been used in trying to overcome challenges associated with formulation of biopharmaceutical compounds. These systems can be limited by their critical micelle concentrations, possible toxicity through oxidative degradation, and undesirable interaction between the excipient and the cargo in the bulk.

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

[0004] The present disclosure provides a solid composition comprising a plurality of particles. The particles can include a biopharmaceutical agent, a polyacrylamide-based copolymer and one or more optional excipients including a stabilizing agent. The particles can have a particle size and size distribution that provides for a pharmaceutical composition having desirable injectability properties for delivery of the biopharmaceutical agent. The present disclosure further provides injectable pharmaceutical compositions including the particles suspended in a liquid carrier.Attorney Docket No.38821-63329 (008WO)

[0005] The particles of the composition can include a biopharmaceutical agent and a polyacrylamide-based copolymer. The inventors have demonstrated that particular polyacrylamide-based copolymers can be used as stabilizing excipients in particle formulations of biopharmaceutical agents, without interacting directly with the biopharmaceutical agent, or altering its pharmacokinetic properties. The results presented herein indicate that the polyacrylamide-based copolymers of this disclosure can be generally applied to confer a substantial stability benefit to high concentration particle-based compositions of biopharmaceutical agents (such as proteins or peptides) and modify injectability and depot formation properties of the resulting composition.

[0006] In some embodiments, the pharmaceutical composition is formulated for injection to a patient at a biopharmaceutical agent concentration that allows for administration of a therapeutically effective dose to be conducted in a low resource setting, in contrast, for example, to compositions which are administered via IV administration. In some embodiments, the pharmaceutical composition is formulated for administration via subcutaneous (SC) injection. In some embodiments, the pharmaceutical composition is formulated for administration via intramuscular (IM) injection. In some embodiments, the injectable pharmaceutical composition is storage stable.

[0007] In certain embodiments, the injectable composition is suitable for administration to the eye. In some embodiments, the mode of administration is intravitreal. In some embodiments, the mode of administration is suprachoroidal. The present disclosure provides injectable compositions capable of delivering an effective dose of the pharmaceutical agent in a volume suitable for delivery, e.g., into the vitreous. In certain embodiments, the injectable composition is formulated with a volume of 100 uL or less, such as 80 uL or less, 70 uL or less, 60 uL or less, or 50 uL or less).

[0008] According, in a first aspect, there is provided a solid composition comprising: a plurality of particles, the particles comprising: 70 wt% or more a biopharmaceutical agent; optionally, 5 wt% or less of a polyacrylamide-based copolymer; and optionally, 25 wt% or less of a stabilizing agent.Attorney Docket No.38821-63329 (008WO)

[0009] In some embodiments, there is provided a solid composition comprising a plurality of particles, the particles comprising a weight ratio of a biopharmaceutical agent to a polyacrylamide-based copolymer of 10:1 or greater.

[0010] In some embodiments, there is provided an injectable pharmaceutical composition comprising: a solid composition comprising: a plurality of particles, the particles comprising: 90 wt% or more a biopharmaceutical agent; and optionally 5 wt% or less of a polyacrylamide-based copolymer; and a liquid carrier in which the particles are suspended.

[0011] In some embodiments, there is provided an injectable pharmaceutical composition comprising: particles, the particles comprising: a biopharmaceutical agent; and a polyacrylamide-based copolymer; and a liquid carrier in which the particles are suspended, wherein: the injectable pharmaceutical composition comprises at least 500 mg / mL of the biopharmaceutical agent; and the liquid carrier is ethyl oleate.

[0012] In some embodiments, there is provided an injectable pharmaceutical composition comprising: particles, the particles comprising: a biopharmaceutical agent; and a polyacrylamide-based copolymer; and a liquid carrier in which the particles are suspended, wherein: the injectable pharmaceutical composition comprises at least 500 mg / mL of the biopharmaceutical agent; and the liquid carrier is triacetin, or a mixture comprising at least 50% v / v triacetin (e.g., at least 75% v / v, or at least 90% v / v) and dimethylacetamide (DMAC).Attorney Docket No.38821-63329 (008WO)

[0013] In some embodiments, there is provided an injectable pharmaceutical composition comprising: particles, the particles comprising: a biopharmaceutical agent; and a polyacrylamide-based copolymer; and a liquid carrier in which the particles are suspended, wherein: the injectable pharmaceutical composition comprises at least 500 mg / mL of the biopharmaceutical agent; and the liquid carrier is benzyl benzoate, or a mixture comprising at least 50% v / v benzyl benzoate (e.g., at least 75% v / v, or at least 90% v / v) and dimethylacetamide (DMAC).

[0014] In some embodiments, there is provided an injectable pharmaceutical composition comprising a plurality of particles and a liquid carrier in which the particles are suspended, wherein the particles comprise: 95 wt% (e.g., 96 wt%, 97 wt%, 98 wt%, or 99%) or more of a biopharmaceutical agent; and an optional polyacrylamide-based copolymer; and the composition comprises at least 500 mg / mL (e.g., at least 510 mg / mL, at least 520 mg / mL, at least 530 mg / mL, at least 540 mg / mL, at least 550 mg / mL, at least 560 mg / mL, at least 570 mg / mL, at least 580 mg / mL, at least 590 mg / mL, at least 600 mg / mL, at least 610 mg / mL, at least 620 mg / mL, at least 630 mg / mL, at least 640 mg / mL, or at least 650 mg / mL) of the biopharmaceutical agent.

[0015] In some embodiments, there is provided an injectable pharmaceutical composition comprising a plurality of particles and a liquid carrier in which the particles are suspended, wherein the particles comprise: 70 wt% (e.g., 75 wt%, 80 wt%, 85 wt%, or 90%) or more of a biopharmaceutical agent; an optional polyacrylamide-based copolymer; an optional stabilizing agent; and the composition comprises at least 500 mg / mL (e.g., at least 510 mg / mL, at least 520 mg / mL, at least 530 mg / mL, at least 540 mg / mL, at least 550 mg / mL, at least 560 mg / mL, atAttorney Docket No.38821-63329 (008WO) least 570 mg / mL, at least 580 mg / mL, at least 590 mg / mL, at least 600 mg / mL, at least 610 mg / mL, at least 620 mg / mL, at least 630 mg / mL, at least 640 mg / mL, or at least 650 mg / mL) of the biopharmaceutical agent.

[0016] In some embodiments, there is provided a storage stable solid composition comprising a plurality of particles, the particles comprising: a biopharmaceutical agent (e.g., as described herein); a polyacrylamide-based copolymer (e.g., as described herein); and a stabilizer (e.g., as described herein).

[0017] Also provided is a syringe loaded with the injectable pharmaceutical composition, methods of administering via injection a therapeutically effective dose of a biopharmaceutical to a subject in need thereof, and methods of preparing a subject injectable pharmaceutical composition.

[0018] In some embodiments, there is provided a method of preparing an injectable pharmaceutical composition, the method comprising: providing a mixture comprising: a biopharmaceutical agent; a polyacrylamide-based copolymer in aqueous solution; and an optional stabilizing agent, wherein the ratio of the polyacrylamide-based copolymer to the biopharmaceutical agent in the mixture is 5:95 or less (e.g., 4:96 or less, 3:97 or less, 2:98 or less, or 1:99 or less); spray drying the mixture to obtain particles comprising the biopharmaceutical agent and the polyacrylamide-based copolymer; contacting a liquid carrier with the particles to form a suspension of the particles in the liquid carrier. 3. BRIEF DESCRIPTION OF DRAWINGS

[0019] FIG. 1, panels a to c, illustrate characterization of MoNi. Panel a depicts two size- exclusion chromatography (SEC) traces of MoNi. Panel b shows a1H NMR spectrum of MoNi. Panel c depicts a differential scanning calorimetry (DSC) analysis of MoNi at aAttorney Docket No.38821-63329 (008WO) temperature ramp and cooling rate of 10 °C / min showing a glass transition temperature between 130 and 140 °C (top line 1 = cooling; lower line 2 = heating).

[0020] FIG. 2 is a schematic of the spray drying process and formulation of ultra-high- concentration (UHC) protein suspensions.

[0021] FIG. 3, panels a-c illustrate injection behavior of exemplary formulations. Panel a illustrates the injection through a 21G needle and depot forming behavior of formulation 4 (336 mg / mL BSA in sesame oil including 4-acryloylmorpholine77%-N- isopropylacrylamide23% MoNi and trehalose). Panel b illustrates the injection through a 21G needle and lack of depot forming behavior of formulation 3 (364 mg / mL BSA in sesame oil including trehalose, but no copolymer). Panel c illustrates the injection though a 26G needle and depot forming behavior of formulation 7 (400 mg / mL BSA in triacetin including the copolymer MoNi and trehalose).

[0022] FIG. 4, panels a-d illustrate angular frequency sweep and flow sweep of exemplary formulations. Panel a illustrates the angular frequency sweep for formulation 7 (400 mg / mL BSA in triacetin with MoNi). Panel b illustrates the flow sweep for formulation 7. Panel c illustrates the angular frequency sweep for formulation 6 (400 mg / mL BSA in triacetin without copolymer). Panel d illustrates the flow sweep for formulation 6.

[0023] FIG. 5, panels a-c illustrate rheological and stability characterization of ball milled BSA particles. Panel a illustrates angular frequency sweep of i) 400 mg / mL BSA particles resuspended in triacetin; and ii) 400 mg / mL BSA particles containing 5 wt% MoNi resuspended in triacetin. Panel a. iii) Comparative storage modulus of suspensions at 10 rad / sec. Panel b illustrates microscope images of BSA with 5 wt% MoNi particles formed by i) 15 minutes of ball milling; or ii) spray drying. Particles are resuspended in sesame oil for improved imaging. Panel d depicts a SEC trace of fresh BSA control, 15 minute ball milled BSA without MoNi, and 15 minute ball milled BSA with 5wt% MoNi. PBS with sodium azide is used as an eluent.

[0024] FIG. 6, panels a-d illustrate angular frequency sweep and flow sweep of exemplary formulations formed by spray drying. Panel a illustrates the angular frequency sweep for formulation 11 (460 mg / mL BSA in triacetin with MoNi copolymer). Panel b illustrates the flow sweep for formulation 11. Panel c illustrates the angular frequency sweep for formulation 10 (460 mg / mL BSA in triacetin without copolymer). Panel d illustrates the flowAttorney Docket No.38821-63329 (008WO) sweep for formulation 10. Adding MoNi copolymer results in a 4000x decrease in formulation stiffness.

[0025] FIG. 7, panels a-d illustrate rheological and stability characterization of spray dried particles. Panel a illustrates angular frequency sweep of i) 460 mg / mL BSA particles resuspended in triacetin; and ii) 460 mg / mL BSA particles containing 5 wt% MoNi resuspended in triacetin. Panel a. iii) Comparative storage modulus of suspensions at 10 rad / sec. Panel b depicts flow sweep of 460 mg / mL BSA particles resuspended in triacetin and 460 mg / mL BSA particles containing 5 wt% MoNi resuspended in triacetin. Panel c depicts a SEM ima mg / mL for particles formulated i) without and ii) with 5 wt% MoNi. Panel d depicts a SEC trace of fresh BSA control, spray dried BSA without MoNi, and spray dried BSA with 5wt% MoNi. PBS with sodium azide is used as an eluent.

[0026] FIG. 8, panels a-b illustrate the impact of trehalose and copolymer MoNi on BSA stability after lyophilization (panel a.) and milling (panel b.). Panel a demonstrates that trehalose and MoNi content during lyophilization show little impact on high molecular weight shoulder. Panel b further demonstrates that irrespective of trehalose content, MoNi reduces size of high molecular weight shoulder following 15 minutes of ball milling.

[0027] FIG. 9, panels a(i)-a(iii) and b show the results of assessment of exemplary particle compositions for protein stability using SEC. The BSA protein compositions were prepared via spray drying or ball milling. SEC allows for visualization of BSA monomer and dimer peak. Panel a(i): Full SEC traces of fresh, spray dried, and ball milled BSA. Panel a(ii): Dimer peak of fresh, spray dried, and ball milled BSA. Panel a(iii): High molecular weight peak of fresh, spray-dried particles (e.g., particles) with a 100:5 weight ratio of BSA, and ball milled BSA. Panel b: BSA monomer fraction after spray drying and ball milling. These results suggest that spray drying is a gentler process of forming particles than ball milling, but that MoNi is a useful protectant through the ball milling process.

[0028] FIG. 10, panels a-c and d(i)-d(ii) illustrate the assessment of injection force and flow rate of injection of exemplary compositions through different gauge needles. Panel a depicts a force sensor connected to a syringe pump was used to quantify the force of injection through standard gauge needles using a 1 mL syringe. Panel b depicts force of injection curves illustrate injection force needed to inject suspensions comprising 460 mg / mL BSA andAttorney Docket No.38821-63329 (008WO) 23 mg / mL MoNi through 27G ½ inch needles at varied flow rates. Panel c illustrates that force of injection is linear with flow rate and scales with needle gauge. Panel d(i) shows force of injection curves that illustrate the injection force needed to inject suspensions comprising 460 mg / mL BSA and 23 mg / mL MoNi suspensions through 27G ½ inch needles and 26G ½ inch needles at 1 mL / min. Panel d(ii) illustrates that injection force decreases with increased needle gauge. Injection force comparisons to BSA formulations not including MoNi are not included because formulations not including MoNi are not injectable through 26 or 27G needles.

[0029] FIG. 11, panels a-c illustrate injection force studies of exemplary compositions through different gauge needles and after vertical storage. Panel a(i) further illustrates that force of injection is linear with flow rate, and ii) scales with needle gauge. Panel b shows a picture of syringe used for vertical storage of exemplary composition for up to 120 hours. Panel c depicts the injection force of a 460 mg / mL BSA with 5% MoNi in triacetin composition at day 0 and day 35 using a 26 G ½ inch needle and a flow rate of 1 mL / min.

[0030] FIG. 12, panels a-b shows the results of stressed aging test (30 minutes at 60oC) on exemplary BSA formulations. Panel a depicts SEC traces of BSA formulations following stressed aging. Panel b illustrates the corresponding BSA monomer fraction after stressed aging conditions. BSA in solution in PBS at 20 mg / mL saw significant aggregation. BSA suspensions in triacetin saw minimal aggregation. BSA suspension in triacetin containing 5 wt% MoNi in the particles of the suspension had no high molecular weight peaks beyond the dimer peak at 31 minutes indicating good stability. BSA in triacetin without MoNi in the particles shows a small high molecular weight peak at 16 minutes, but relatively good stability.

[0031] FIG. 13, panels a(i)-a(iii) show the assessment of storage stability of exemplary composition (460 mg / mL BSA formulations in triacetin with and without 5 wt% MoNi in the particles of the suspension) stored for 48 hours at 4C, 25C, and 37C. Panel a(i) depicts full SEC traces of formulations after 48 hours. Panel a(ii) depicts the dimer peak of all formulations after 48 hours. Panel a(iii) depicts a high molecular weight peak of all formulations after 48 hours. Generally, all formulations show good stability after 48 hours with the majority of light scattering signal coming from the monomer peak. Samples containing MoNi in the particles on average show smaller dimer and high molecular weight peaks than samples without MoNi suggesting improved storage stability.Attorney Docket No.38821-63329 (008WO)

[0032] FIG. 14, panels a(i)-a(iii) show the assessment of storage stability of exemplary composition (460 mg / mL BSA formulations in triacetin with and without 5 wt% MoNi in the particles of the suspension) stored for 120 hours at 4oC, 25oC, and 37oC. Panel a(i) depicts full SEC traces of exemplary formulations after 120 hours. Panel a(ii) shows dimer peak of all formulations after 120 hours. Panel a(iii) shows a high molecular weight peak of all formulations after 120 hours. BSA formulations containing MoNi in the particles stored for 120 hours in a syringe showed no particle settling. Generally, all formulations show good stability after 120 hours with the majority of light scattering signal coming from the monomer peak. Samples containing MoNi in the particles on average show smaller high molecular weight peaks than samples without MoNi suggesting improved storage stability.

[0033] FIG. 15 shows the results of a centrifuge study to evaluate suspension stability in the following media from left to right: triacetin alone; triacetin with 20% benzyl benzoate; triacetin with 20% benzyl alcohol; and triacetin with 20% safflower oil.

[0034] FIG. 16 illustrates viscometer measurements for various liquid carriers. This graph illustrates how the viscosity of a higher viscosity non-solvent (propylene glycol (PG) or triacetin (T)) can be reduced by adding a lower viscosity additive, such as benzyl alcohol (BA).

[0035] FIG. 17, panels a-d show that injection force measurements (1 mL / min through a 26G, ½ inch needle) show a significant reduction in injection force when DMAc is used in combination with triacetin as a non-solvent. Panel a shows the plateau injection force for triacetin suspensions (100%) vs. suspensions in various blends of triacetin: DMAc and triacetin: DMAc : BA. Panel b shows the injection force of triacetin suspensions vs DMAc content. Panel c shows the injection force of triacetin suspensions (100%) vs suspensions in various blends of triacetin : DMAc and triacetin : DMAc : BA over time. Panel d shows that the addition of polymer MoNi affects the consistency of BSA powder dispersed in DMAc. The left image of panel d illustrates a formulation having 450 mg / mL BSA DMAc including MoNi. The right image of panel d illustrates a formulation having 450 mg / mL BSA in DMAc without the addition of MoNi.

[0036] FIG. 18, panels a-c show the results of in-vivo administration to mice of 4 mg BSA by either 200 injections of 20 mg / mL BSA in PBS (bolus injection), or 9 μL injections of 450 mg / mL BSA in triacetin (high concentration paste / triacetin paste) (N 3 per group). Panel aAttorney Docket No.38821-63329 (008WO) depicts the fluorescent signal following in-vivo administration of 4 mg BSA by either 200 injections of 20 mg / mL BSA in PBS (bolus injection), or 9 μL injections of 450 mg / mL BSA in triacetin (high concentration paste / triacetin paste). Panel b shows comparative administration volume of high concentration paste and 20 mg / mL bolus injection. Panel c shows comparative half-life of BSA subcutaneous absorption from high concentration paste and bolus administration.

[0037] FIG. 19, panels a-b show the results of in vivo administration of 9 uL of 450 mg / mL BSA in a 70:30 triacetin: DMAc suspension. Panel a is a fluorescence decay curve associated with the in-vivo administration of 4 mg of BSA by 9 uL injections of 450 mg / mL BSA in 70:30 triacetin : DMAc. Panel b shows the half-life of subcutaneous absorption of a paste in 100% triacetin; a bolus injection (20 mg / mL BSA in PBS); and a suspension in 70:30 triacetin : DMAc (N 3 per group).

[0038] FIG. 20, panels a-b illustrate the products obtained after spray drying formulations containing polysorbate 80 and Pluronic L-61. Panel a shows images of falcon tubes containing comparative products recovered from spray drying equal mass of BSA with polysorbate 80 (left tube) and Pluronic L-61 (right tube). Panel b shows the spray dryer glass component after spray drying Pluronic L-61. As evident in the image, spray drying Pluronic L-61 results in a tacky powder that sticks to the spray dryer glass components, thus resulting in a poor yield of the spray dried product (see panel a, right tube, showing little recovered product).

[0039] FIG. 21, panels a-c illustrate SEC traces for fresh BSA and BSA (Fresh BSA Standard) spray dried with MoNi (BSA_MoNi), polysorbate 80 (BSA_Tw80), and no additive (BSA_NoMoNi). Panel a shows for all spray dried samples, the monomer and dimer peaks appear similar. Panel b shows differences between the spray dried samples for the high molecular weight aggregate peaks. Panel c shows the Area fraction of the high molecular weight peak is smallest for fresh BSA standard, followed by BSA spray dried in MoNi, BSA spray dried with polysorbate 80, and finally BSA spray dried without an additive.

[0040] FIG. 22, panels a-c illustrate SEC analysis of high molecular weight aggregates in aged protein pastes made with BSA, BSA with MoNi, and BSA with polysorbate 80. BSA aged at 20 mg / mL in PBS was used as a control. All samples were aged at 60 °C for 60 minutes. Panel a shows the full SEC traces, and panel b shows differences between theAttorney Docket No.38821-63329 (008WO) samples for the high molecular weight aggregate peaks. Panel c shows the Area percentage of the high molecular weight peaks for each sample.

[0041] FIG. 23, panels a-c show injection force experiments (1 mL / min through a 26G ½ inch needle) with 450 mg / mL BSA suspensions in triacetin. The BSA has been spray dried with either polysorbate 80 (Tween 80) or MoNi at equal molar amounts (7.14 μmol per gram of BSA). Panel a shows the injection force (N) over time (seconds). Panel b shows the plateau injection force for the formulation including MoNi vs polysorbate 80 (Tween 80). Panel c depicts SEM of particle morphology for i) BSA MoNi and ii) BSA polysorbate 80 (Tween 80) particles (scale bars are 10

[0042] FIG. 24, panels a-b: Panel a depicts comparative protein concentration as predicted from density measurements and measured via nanodrop from a known slurry volume. Panel b illustrates injection force as a function of concentration for BSA particles (with mol% matched MoNi or Tween 80) in 70 Triacetin: 30 DMAc. Injection force as a function of particle concentration is fit to a particle jamming model.

[0043] FIG. 25, panels a-b show the SEM images of the BSA microparticle formulations.

[0044] FIG. 26, panels a-b show photographic images of the BSA microparticle formulations suspended in triacetin and loaded in 1 mL Schott syringes. Panel a shows a photographic image of the syringe loaded with 004A (480 mg / mL) formulation suspended in triacetin. Panel b shows a photographic image of the syringe loaded with 004B (458 mg / mL) formulation suspended in triacetin.

[0045] FIG. 27, panels a-b are graphs of the injection force (N) of the BSA microparticle suspensions over 5 seconds at various flow rates. Panel a shows injection force (N) over 5 seconds for BSA microparticle suspension 004A (480 mg / mL BSA) in triacetin injected at 2mL / min, 4 mL / min and 6 mL / min from a 1 mL Schott syringe (27G thin-walled needle and V9519 coated plunger). Panel b shows injection force (N) over 5 seconds for BSA microparticle suspension 004B (458 mg / mL BSA) in triacetin injected at 2mL / min, 4 mL / min and 6 mL / min from a 1 mL Schott syringe (27G thin-walled needle and V9519 coated plunger).Attorney Docket No.38821-63329 (008WO)

[0046] FIG 28 illustrates the injection force measurements of 004A (480 mg / mL BSA) and 004B (458 mg / mL) microparticle suspensions in triacetin injected at different flow rates from 1 mL Schott syringes (27G thin-walled needle and V9519 coated plunger). This graph shows that injection force (N) for suspensions of 004A and 004B in triacetin is linear with flow rate.

[0047] FIG. 29, panels a-g illustrate that high concentration suspension technology can be effectively used to deliver hIgG. Panel a depicts SEM images of spray dried IgG with MoNi b depicts SEC trace of fresh hIgG control, spray dried hIgG without MoNi, spray dried hIgG with 5 wt% MoNi, spray dried hIgG with 25 wt% trehalose and 5 wt% MoNi. PBS with sodium azide is used as an eluent. Panel c shows graph of injection force as a function of concentration for hIgG microparticles with MoNi in triacetin. Injection force as a function of particle concentration is fit to a particle jamming model. Panel d depicts injection force for 350 mg / mL hIgG, 5 wt% MoNi suspensions at 1mL / min through 26G ½ inch needles with DMAc, benzyl alcohol (BA) and benzyl benzoate (BB) non-solvent additives. Panel e(i) shows representative IVIS images of mice demonstrating subcutaneous absorption of fluorescently-tagged hIgG administered via a PBS bolus injection or a high concentration protein suspension. Panel e(ii) depicts a graph of fluorescent signal in the subcutaneous space is fit to a single phase exponential decay mode to identify half-life of subcutaneous absorption. Panel f depicts a graph of comparative half- life of subcutaneous absorption for hIgG administered via PBS bolus injection or UHC protein suspensions formulated with triacetin. Panel g depicts a graph of comparative volume of administration for bolus injection and high concentration protein suspension.

[0048] FIG. 30, panels a-b. Panel a, i) shows full SEC traces of fresh hIgG control, spray dried hIgG with no additives, spray dried hIgG with 1X MoNi (5 wt%), spray dried hIgG with 2X MoNi (10 wt%), spray dried hIgG with 25 wt% trehalose and 5 wt% MoNi, and spray dried IgG with 30 wt% Trehalose. Panel a, ii) shows SEC trace of only high molecular weight aggregate. PBS with sodium azide is used as an eluent. Panel b shows a graph of percent change in hIgG aggregates due to spray drying, as a percent of total protein content. The baseline for determining percent change was determined by subtracting the starting aggregate percent of the fresh IgG control (3.9%) from all samples.

[0049] FIG. 31, panels a-b. Panel a depicts injection force curves for injection of 300 mg / mL IgG, 5 wt% MoNi suspensions at 1mL / min through BD Insulin syringes (28G,Attorney Docket No.38821-63329 (008WO) 12.7mm needle) with triacetin as a non-solvent, and panel b shows a graph of corresponding plateau injection force.

[0050] FIG. 32, panels a-b show SEC traces of insulin before and after spray drying. Panel a shows the insulin SEC Trace of spray dried insulin and pre-spray dried insulin over 22 minutes. Panel b is a zoomed in portion of minutes 14-17 of the SEC trace in panel a.

[0051] FIG. 33, panels a-b show SEC traces of pramlintide before and after spray drying. (Panel a) shows the pramlintide SEC Trace of spray dried pramlintide and pre-spray dried pramlintide over 20 minutes. (Panel b) is a zoomed in portion of minutes 14-17 of the SEC trace in panel a.

[0052] FIG. 34 shows SEC trace of pramlintide (“pram”), insulin, and controls before and after spray drying.

[0053] FIG. 35 panels a-b. SEM images of insulin and pramlintide spray dried particles resuspended in triacetin (panel a) and trehalose and MoNi (95:5) particles (panel b). Particles in panel b do not contain either insulin or pramlintide, so protein may affect particle morphology.

[0054] FIG. 36 shows insulin and pramlintide spray dried particles resuspended in triacetin at a solids content of 350 mg / mL. Particle suspension flows like a liquid.

[0055] FIG. 37, panels a and b show injection force of insulin pramlintide coformulation (350 mg / mL solids) in triacetin. Injection measurements were performed using a 1 mL syringe at 1 mL / min through a 26 G ½ inch needle.

[0056] FIG. 38 is an image depicting the insulin pramlintide coformulation redissolved in cell grade water.

[0057] FIG. 39, panels a-c shows graphs of the syringe force profiles for exemplary BSA formulations with various liquid carriers. Panel a depicts the syringe force profile for formulation 12 (benzyl benzoate as liquid carrier). Panel b depicts the syringe force profile for formulation 13 (Miglyol 840 as liquid carrier). Panel c depicts the syringe force profile for formulation 16 (ethyl oleate as liquid carrier).Attorney Docket No.38821-63329 (008WO)

[0058] FIG. 40 is a graph showing the syringe force profile for exemplary BSA formulation 17 (triacetin:DMAc (75:25) as liquid carrier).

[0059] FIG. 41A is a SEM image of batch 010A-01 (pre-vacuum dried) particles of IgG:MoNi (95.25:4.75 w / w).

[0060] FIG. 41B is a SEM image of batch 010A-01 (post-vacuum dried) particles of IgG:MoNi (95.25:4.75 w / w).

[0061] FIG. 42 illustrates the exemplary vehicles with batch 028B-01 (post-vacuum dried) particles of IgG:MoNi (95.25:4.75 w / w) in benzyl benzoate, ethyl oleate, benzyl benzoate : DMAc (75:25), and triacetin : DMAc (75:25) at 500 mg / mL at T = 0 and T = 96.

[0062] FIG. 43, panels A-B, illustrates SEC traces of IgG Standard at 1mg / mL (Panel A – Injection 3; Panel B – Injection 24).

[0063] FIG. 44A illustrates SEC traces of the spray dried batch 028B-01 of IgG:MoNi (95.25:4.75 w / w) at 1 mg / mL.

[0064] FIG. 44B illustrates SEC traces of the spray dried powder 028B-01 of IgG:MoNi (95.25:4.75 w / w) upon suspension in ethyl oleate for 120 hours at 500 mg / mL (diluted for SEC HPLC analysis at 1mg / mL).

[0065] FIG. 45A illustrates the exemplary vehicles with batch 031A-01 (post-vacuum dried) particles of IgG:MoNi (95.25:4.75 w / w) in ethyl oleate at 500 mg / mL at T = 0.

[0066] FIG. 45B illustrates the exemplary vehicles with batch 031A-01 (post-vacuum dried) particles of IgG:MoNi (95.25:4.75 w / w) in ethyl oleate at 500 mg / mL at T = 3 days at 2-8oC.

[0067] FIG. 46 illustrates SEC traces of the spray dried batch 031A-01 of IgG:MoNi (95.25:4.75 w / w) at 1 mg / mL at T=0 and T=3 days at 2-8oC.

[0068] FIG. 47A illustrates the exemplary vehicles with batch 031A-01 (post-vacuum dried) particles of IgG:MoNi (95.25:4.75 w / w) in ethyl oleate at 500 mg / mL at T = 0.

[0069] FIG. 47B illustrates the exemplary vehicles with batch 031A-01 (post-vacuum dried) particles of IgG:MoNi (95.25:4.75 w / w) in ethyl oleate at 500 mg / mL at T = 7 days at 2-8oC.Attorney Docket No.38821-63329 (008WO)

[0070] FIG. 48A illustrates the exemplary vehicles with batch 031A-01 (post-vacuum dried) particles of IgG:MoNi (95.25:4.75 w / w) in ethyl oleate at 500 mg / mL at T = 0.

[0071] FIG. 48B illustrates the exemplary vehicles with batch 031A-01 (post-vacuum dried) particles of IgG:MoNi (95.25:4.75 w / w) in ethyl oleate at 500 mg / mL at T = 2 weeks at 2-8oC.

[0072] FIG. 49 illustrates SEC traces of the spray dried batch 031A-01 of IgG:MoNi (95.25:4.75 w / w) at 1 mg / mL at T=3 days, T=1 week, and T=2 weeks at 2-8oC.

[0073] FIG. 50A illustrates the exemplary vehicles at T=0 days with batches 023A-01 (IgG:MoNi:Trehalose (90.48:4.76:4.76 w / w)) at 500 mg / mL, 023B-01 (IgG:MoNi:Trehalose (85.72:4.76:9.67 w / w)) at 500 mg / mL, 023B-01 (IgG:MoNi:Trehalose (85.72:4.76:9.67 w / w)) at 600 mg / mL, 023C-01 (IgG:MoNi:Trehalose (80.96:4.76:14.28 w / w)) at 500 mg / mL in ethyl oleate.

[0074] FIG. 50B illustrates the exemplary vehicles at T=16 days with batches 023A-01 (IgG:MoNi:Trehalose (90.48:4.76:4.76 w / w)) at 500 mg / mL, 023B-01 (IgG:MoNi:Trehalose (85.72:4.76:9.67 w / w)) at 500 mg / mL, 023B-01 (IgG:MoNi:Trehalose (85.72:4.76:9.67 w / w)) at 600 mg / mL, 023C-01 (IgG:MoNi:Trehalose (80.96:4.76:14.28 w / w)) at 500 mg / mL in ethyl oleate.

[0075] FIGs. 51A-51C show SEM images of particles of including 3 different amounts of the excipient stabilizer trehalose: 4.76% (FIG. 51A), 9.52% (FIG. 51B), and 14.28% (FIG. 51C). The particles further include IgG and MoNi (4.76%).

[0076] FIG. 52A illustrates hIgG serum concentration in human FcRn transgenic mice following hIgG administered via a PBS bolus injection or a UHC protein suspension hIgG:MoNi (95:5 w / w) (n=5-6).

[0077] FIG. 52B, panels a-c, illustrate comparative a) Cmax, b) serum half-life, and c) bioavailability of human IgG (hIgG) in a standard aqueous formulation at 100mg / mL and in a hIgG:MoNi (95:5 w / w) suspension formulation at 350 mg / mL.

[0078] FIG. 53 illustrates the injection force of suspensions containing particles with 100:0:5, 90:10:5, 95:5:5 and 85:15:5 IgG: Trehalose:MoNi.Attorney Docket No.38821-63329 (008WO)

[0079] FIG. 54 illustrates the injection force of 500 mg / mL IgG suspensions in ethyl oleate containing particles with 90:10:5 IgG:Trehalose:MoNi, 90:10:5 IgG:Glycine:MoNi, 90:5:5:5 IgG:Glycine:Trehalose:MoNi, and 90:5:5:5 IgG:Isoleucine:Trehalose:MoNi.

[0080] FIG. 55A illustrates the injection force of suspensions in ethyl oleate containing 100:5 IgG:MoNi particles. FIG. 55B illustrates the injection force of suspensions in benzyl benzoate containing 100:5 IgG:MoNi particles. FIG. 55C illustrates the injection force of suspensions in Miglyol 840 containing 100:5 IgG:MoNi particles.

[0081] FIG. 56A illustrates the injection force of 450 mg / mL IgG suspensions containing particles with 90:10:5 IgG:Trehalose:MoNi. Suspensions are prepared in benzyl benzoate (BB) with varied ratios of ethyl oleate (EO) added to reduce viscosity. Data is presented as EO fraction where 0 is pure benzyl benzoate and 1 is pure ethyl oleate. FIG. 56B illustrates the injection force of 450 mg / mL IgG suspensions containing particles with 90:10:5 IgG:Trehalose:MoNi. Suspensions are prepared in Miglyol 840 with varied ratios of EO added to reduce viscosity. Data is presented as EO fraction where 0 is pure Miglyol 840 and 1 is pure ethyl oleate.

[0082] FIG. 57A illustrates the injection force of 400, 450 and 500 mg / mL of BSA suspensions in ethyl oleate containing 100:5 BSA:MoNi particles. Injection force of each suspension through a 1 mL Schott syringe with a 27G ½ in needle was quantified using flow rates of 4, 6, and 8 mL / min. FIG. 57B illustrates the injection force of 400, 450 and 500 mg / mL of BSA suspensions in ethyl oleate containing 100:5 BSA:MoNi particles. Injection force of each suspension through a 2.25 mL Schott syringe with a 27G ½ in needle was quantified using flow rates of 4, 6, and 8 mL / min.

[0083] FIG. 58 illustrates the ratio of injection force from 2.25 mL and 1 mL syringes. Injection force was quantified for 400, 450 and 500 mg / mL biopharmaceutical agent suspensions in ethyl oleate containing 100:5 BSA:MoNi particles. Injection force was quantified using flow rates of 4, 6, and 8 mL / min.

[0084] FIG. 59A illustrates a commercial IV antibody drug product (ADP) requiring time- intensive delivery in a hospital setting while ADP reformulated as a UHC protein suspension provides delivery with an auto-injector at home.Attorney Docket No.38821-63329 (008WO)

[0085] FIG. 59B illustrates SEM images of spray dried mAb with MoNi particle morphology

[0086] FIG. 59C illustrates a SEC trace of fresh mAb control and spray-dried mAb with 5 wt% MoNi.

[0087] FIG. 59D illustrates injection force of 400 mg / mL mAb microparticles with MoNi in triacetin (n=3). Bar graph shows mean ± SD.

[0088] FIG. 59E illustrates comparative volume of administration and mAb dose for bolus injections and UHC protein suspension.

[0089] FIG. 59F illustrates mAb serum concentration in human BL6 mice following mAb administered via a bolus injection or a UHC protein suspension (n=5-7).

[0090] FIG. 59G illustrates corresponding Cmax values of bolus injections and UHC protein suspension.

[0091] FIG. 59H illustrates corresponding bioavailability of bolus injections and UHC protein suspension.

[0092] FIG. 59I illustrates corresponding day 1 infectivity percent from neutralization for bolus injections and UHC protein suspension. 4. DETAILED DESCRIPTION

[0093] As summarized above, the present disclosure provides pharmaceutical compositions including particles, such as particles suspended in a liquid carrier. The particles generally include a biopharmaceutical active agent to be administered to a subject in need thereof. In some embodiments, the particles and compositions further include a polyacrylamide-based copolymer that confers a benefit upon the resulting composition, such as a stability benefit, and / or provides for formulation of the biopharmaceutical agent at a concentration suitable for administration via injection. Thus, certain of the pharmaceutical compositions of this disclosure can be referred to as injectable pharmaceutical compositions.

[0094] Reference will now be made in detail to certain embodiments of the disclosed subject matter. While the disclosed subject matter will be described in conjunction with theAttorney Docket No.38821-63329 (008WO) enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter. 4.1. Particles

[0095] The pharmaceutical compositions can include particles including a biopharmaceutical agent and a polyacrylamide-based copolymer, and one or more optional excipients, such as a stabilizer. The particles of the formulations of this disclosure can provide a beneficial particle shape, particle size, particle distribution, and uniformity, and impart benefits on a resulting composition in terms of dispersibility in a suspension, injectability, and / or stability.

[0096] The particles can be prepared (e.g., as descried herein) from a precursor composition including the biopharmaceutical agent, polyacrylamide-based copolymer, and one or more optional excipients, where the composition can be subjected to a variety of processes for preparing a microparticulate form of the precursor composition, including processes such as lyophilization, spray-drying, freeze-drying, spray-freeze drying, milling, encapsulation, microglassification, flash nanoprecipitation, hot homogenization, or a combination thereof. The particles can then be suspended in a carrier liquid.

[0097] In some embodiments, the particles include 70 wt% or more of a biopharmaceutical agent. In some embodiments, the particles further include 5 wt% or less of a polyacrylamide- based copolymer. In some embodiments, the particles further may include 25 wt% or less of a stabilizing agent.

[0098] In some embodiments, the particles comprise 75 wt% or more of the biopharmaceutical agent. In some embodiments, the particles comprise 80 wt% or more of the biopharmaceutical agent. In some embodiments, the particles comprise 85 wt% or more of the biopharmaceutical agent. In some embodiments, the particles comprise 90 wt% or more of the biopharmaceutical agent.

[0099] In some embodiments, the particles comprise 25 wt% or less of the biopharmaceutical agent. In some embodiments, the particles comprise 20 wt% or less of the biopharmaceutical agent. In some embodiments, the particles comprise 15 wt% or less of the biopharmaceutical agent. In some embodiments, the particles comprise 10 wt% or less of the biopharmaceutical agent. In some embodiments, the particles comprise 5 wt% or less of the biopharmaceutical agent.Attorney Docket No.38821-63329 (008WO)

[0100] In some embodiments, the particles comprising a weight ratio of a biopharmaceutical agent to a polyacrylamide-based copolymer of 10:1 or greater.

[0101] In some embodiments, the particles comprising a weight ratio of a biopharmaceutical agent to a polyacrylamide-based copolymer of 1:10 or greater.

[0102] In some embodiments, the particles comprise 20 wt% or less of a stabilizing agent. In some embodiments, the particles comprise 15 wt% or less of a stabilizing agent. In some embodiments, the particles comprise 10 wt% or less of a stabilizing agent. In some embodiments, the particles comprise 5 wt% or less of a stabilizing agent.

[0103] In some embodiments, the particles comprise 70 wt% or more of a stabilizing agent. In some embodiments, the particles comprise 80 wt% or more of a stabilizing agent. In some embodiments, the particles comprise 90 wt% or more of a stabilizing agent.

[0104] In some embodiments, the particles comprise 90 wt% or more of the biopharmaceutical agent, 5 wt% or less of the polyacrylamide-based copolymer, and 15 wt% or less of the stabilizing agent.

[0105] In some embodiments, the particles comprise 80 wt% or more of the biopharmaceutical agent, 5 wt% or less of the polyacrylamide-based copolymer, and 15 wt% or less of the stabilizing agent.

[0106] In some embodiments, the particles comprise 80 to 95 wt% of the biopharmaceutical agent, 0.1 to 5 wt% of the polyacrylamide-based copolymer, and 5 to 15 wt% of the stabilizing agent.

[0107] In some embodiments, the particles comprise 0.1 to 5 wt% of the biopharmaceutical agent, 0.1 to 5 wt% of the polyacrylamide-based copolymer, and 80 to 95 wt%of the stabilizing agent.

[0108] In some embodiments, the particles comprise 5 wt% or less of an optional aqueous component. In some embodiments, the aqueous component optionally includes a buffer.

[0109] The particles size can depend on the particular composition, and selected method of preparation. Characterization of particle(s) size and / or dispersity in a composition can be performed using methods such as optical microscopy imaging.Attorney Docket No.38821-63329 (008WO)

[0110] The particles of the present disclosure can be solid particles. The solid particles may be amorphous or crystalline. In some embodiments, a plurality of solid particles comprises amorphous particles. In some embodiments, a plurality of solid particles may comprise crystalline particles such as, e.g., when small molecules (e.g., salts) are present that can be crystalized.

[0111] The plurality of solid particles may be uniform in size or may be polydisperse. In some embodiments, at least a portion of the plurality of solid particles have a size that is within about ±5%, 10%, 15%, 20%, 25%, 50%, 75%, 100%, 150%, 200% or more of the average particle size. In some embodiments, the composition comprises discrete particles.

[0112] The particles according to the disclosure are circular. Circularity can serve as an indicator of the shape of the particle. The particles described herein, can have a characteristic circularity, e.g., have a relative shape, that is substantially circular. This characteristic describes and defines the form of a particle on the basis of its circularity. The circularity is 1.0 when the particle has a completely circular structure. Particles as described herein, can have a circularity of about 0.8, 0.85, 0.9, 0.95, 0.96, 0.97, 0.98, or about 0.99. The diameter and the circularity of the particles can be determined by the image processing of an image observed under an electron microscope or the like or a flow-type particle image analyzer. The circularity can also be determined by subjecting particles to circularity measurement and averaging the resulting values.

[0113] In some embodiments, the particles exhibit a skeletal density of about 1 to about 6 g / cm3, e.g., about 1 to about 5 g / cm3, about 1 to about 3 g / cm3, about 1 to about 2 g / cm3, about 1 to about 1.5 g / cm3, or about 1. 1 to about 1 .4 g / cm3. Exemplary methods of skeletal density measurements include gas displacement pycnometry. In certain embodiments, the particles exhibit a density of about 0.1 to about 5 g / cm3, e.g., about 0.1 to about 2.5 g / cm3, about 0.1 to about 1.4 g / cm3, about 0.5 to about 1.4 g / cm3, or about 1.0 to about 1.4 g / cm3.

[0114] In some embodiments, the particle outer surface is smooth. The particle surface composition can be determined by the relative surface-activity of a biopharmaceutical agent and a polyacrylamide-based copolymer.

[0115] In some embodiments, the particles are microspheres.Attorney Docket No.38821-63329 (008WO)

[0116] In some embodiments, the particles are uniform-sized particles. In some embodiments, the particles are substantially monodisperse.

[0117] In some embodiments, particles have a substantially spherical morphology.

[0118] The particles can include microparticles and / or nanoparticles.

[0119] In some embodiments, the particles have a mean diameter of 100 microns or less. In some embodiments, the particles have a mean diameter of 95 microns or less, for example, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5 microns or less.

[0120] In some embodiments, the particles have a mean diameter of from 0.01 to 100 microns, such as from 0.01 to 100 microns, from 0.01 to 50 microns, from 0.01 to 20 microns, from 0.01 to 10 microns, or from 0.01 to 1 micron.

[0121] The particle size can depend on the particular composition, and selected method of preparation. Characterization of particle(s) size and / or dispersity in a composition can be performed using methods such as optical microscopy imaging.

[0122] In some embodiments, the particles are microparticles.

[0123] In some embodiments, the particles have a mean diameter of from 0.1 to 100 microns, such as from 0.1 to 50 microns, or for example, a mean diameter from 0.1 to 20 micron, 0.1 to 10 microns, 10 to 20 microns, 20 to 30 microns, 30 to 40 microns, 40 to 50 microns, 50 to 60 microns, 60 to 70 microns, 70 to 80 microns, 80 to 90 microns, or 90 to 100 microns.

[0124] In some embodiments, the particles have a mean diameter of from 1 to 100 microns, for example, a mean diameter from 10 to 100 microns, 1 to 5 microns, 5 to 10 microns, 10 to 20 microns, 10 to 15 microns, 15 to 20 microns, 20 to 25 microns, 25 to 30 microns, 30 to 35 microns, 35 to 40 microns, 40 to 45 microns, 45 to 50 microns, 50 to 55 microns, 55 to 60 microns, 60 to 65 microns, 65 to 70 microns, 70 to 75 microns, 75 to 80 microns, 80 to 85 microns, 85 to 90 microns, 90 to 95 microns and 95 to 100 microns.

[0125] In some embodiments, the particles have a mean diameter of from 1 to 50 microns. In some embodiments, the particles have a mean diameter of from 10-20 microns, for example, a mean diameter of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 microns.Attorney Docket No.38821-63329 (008WO)

[0126] In some embodiments, the particles have a mean diameter of 20 microns or less (e.g., 10 microns or less, 9 microns or less, 8 microns or less, 7 microns or less, 6 microns or less, or 5 microns or less).

[0127] In some embodiments, at least 70% (e.g., at least 80%, at least 90%, or at least 95%) of the particles have a diameter of 10 to 100 microns (e.g., 10 to 50 microns, 10 to 25 microns, or 50 to 100 microns).

[0128] In some embodiments, the particles have a mean diameter of from 0.2 to 10 microns (e.g., from 0.2 to 9 microns, from 0.2 to 8 microns, from 0.2 to 7 microns, from 0.2 to 6 microns, or from 0.2 to 5 microns).

[0129] In some embodiments, the particles have a mean diameter of from 1 to 10 microns (e.g., from 1 to 9 microns, from 1 to 8 microns, from 1 to 7 microns, from 1 to 6 microns, or from 1 to 5 microns).

[0130] In some embodiments, the particles are polydisperse. The dispersity of the particles can be assessed using a variety of methods, e.g., laser diffraction, microscopy, dynamic light scattering (DLS), and the like. The particles can have a particle size distribution width (also referred to as span, i.e., (D90-D10) / D50) that provides for injectability of the particles. D90 refers to the point in the size distribution, up to and including which, 90% of the total volume of material in the sample is contained.

[0131] In some embodiments, the particles have a particle size distribution width of 1.1 or more (e.g., 1.1 or more, 1.2 or more, 1.3 or more, 1.4 or more, 1.5 or more, 1.6 or more, 1.7 or more, 1.8 or more, 1.9 or more, 2.0 or more, 2.1 or more, 2.2 or more, 2.3 or more, 2.4 or more, 2.5 or more, or 3.0 or more).

[0132] In some embodiments, at least 80% (e.g., at least 90%, at least 92%, at least 93%, at least 94%, or at least 95%) of the particles have a diameter of less than 10 microns (e.g., less than 9 microns, less than 8 microns, less than 7 microns, less than 6 microns, or less than 5 microns). In some embodiments, at least 90% of the particles have a diameter of 0.2 to 10 microns. In some embodiments, at least 95% of the particles have a diameter of less than 5 microns.Attorney Docket No.38821-63329 (008WO)

[0133] In some embodiments, the particles have a particle size distribution characterized by at least 90% of the particles having a diameter (D90) of 50 microns or less (e.g., 40 microns or less, 30 microns or less, 25 microns or less, 20 microns or less, 15 microns or less, 10 microns or less, 9 microns or less, 8 microns or less, 7 microns or less, 6 microns or less, or 5 microns or less).

[0134] In some embodiments, the particles have a particle size distribution characterized by at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, or at least 95%) of the particles having a diameter of less than 10 microns. In some embodiments, the particle size distribution is characterized by at least 96% (e.g., at least 97%) of the particles having a diameter of less than 10 microns. In some embodiments, the particle size distribution is characterized by at least 98% (e.g., at least 99%) of the particles having a diameter of less than 10 microns.

[0135] In some embodiments, the particles have a particle size distribution width (i.e., (D90- D10) / D50) of 1.1 or more (e.g., 1.1 or more, 1.2 or more, 1.3 or more, 1.4 or more, 1.5 or more, 1.6 or more, 1.7 or more, 1.8 or more, 1.9 or more, 2.0 or more, 2.1 or more, 2.2 or more, 2.3 or more, 2.4 or more, 2.5 or more, or 3.0 or more).

[0136] In some embodiments, the particles have a volume median diameter (VMD) of between 1 and 10 microns (e.g., between 1 and 5 microns, or between 2 and 3 microns).

[0137] In some embodiments, the particles are microparticles. In some embodiments, the particles have a particle size distribution width of 50 microns or less (e.g., 45 microns or less, 40 microns or less, 35 microns or less, 30 microns or less, etc.).

[0138] The particles may be uniform in shape and size. In some embodiments, the particles are spherical. In some embodiments, the particles have a substantially spherical morphology. In some embodiments, the particles are microspheres. Examples of the spherical particles are shown in the figures.

[0139] Indices which can be used to characterize the morphology or shape of the particles include Wadell's circularity and sphericity which have been used in the field of the powder industry.Attorney Docket No.38821-63329 (008WO)

[0140] Sphericity “s” is defined as s=(surface area of sphere having the same volume as particle) / (surface area of particle). As “s” is closer to 1, the particle is more spherical. Particles as described herein, can have an average Sphericity of 0.5 or more, such as 0.6 or more, 0.7 or more, 0.8 or more, or 0.9 or more.

[0141] Circularity “c” is defined as c=(circumference of the same area as projected area of particle) / (circumference of plane of projection of particle) As “c” is closer to 1, the particle is more circular. Circularity can serve as an indicator of the shape of the particle. In some embodiments, the particles according to the disclosure can be referred to as circular, and / or characterized by their circularity. The particles described herein, can have a characteristic circularity, e.g., have a relative shape, that is substantially circular or spherical. The circularity is 1.0 when the particle has a completely circular structure. Particles as described herein, can have an average circularity of 0.5 or more, such as 0.6 or more, 0.7 or more, 0.8 or more, or 0.9 or more. The diameter and the circularity of the particles can be determined by the image processing of an image observed under an electron microscope or the like or a flow-type particle image analyzer. The circularity can also be determined by subjecting particles to circularity measurement and averaging the resulting values.

[0142] In some embodiments, the particles are nanoparticles. In some embodiments, the particles have a mean diameter of less than 100 nm.

[0143] The terms “particle” or “particles” or “particulate” as used herein, interchangeably in the broadest sense, refer to a discrete body or bodies. The particles may be uniform in size or may be polydisperse. In some embodiments, the particles are uniform-sized particles.

[0144] In some embodiments, the particles have a size that is within about ±5%, ±10%, ±15%, ±20%, ±25%, ±50%, ±75%, ±100%, ±150%, or ±200% of the mean particle size.

[0145] Dispersity can be quantified using techniques such as dynamic light scattering (DLS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM), to provide information on the size distribution and shape of the particles, to provide an assessment of a sample of particles.

[0146] In some embodiments, the particles have a particle size distribution characterized by at least 80% (e.g., at least 90%, or at least 95%) of the particles having a size parameter (e.g.,Attorney Docket No.38821-63329 (008WO) diameter) that is within ±20% (e.g., within ±10%) of the mean particle size (e.g., mean diameter).

[0147] In certain embodiments, the particles include from 0.1 wt to 50 wt% of the biopharmaceutical agent (such as, from 0.1 wt% to 40 wt%, 0.1 wt% to 30 wt%, from 0.1 wt% to 20 wt%, from 0.1 wt% to 10 wt%, from 0.1 wt% to 5 wt%, from 1 wt% to 50 wt%, from 1 wt% to 40 wt%, from 1 wt% to 30 wt%, from 1 wt% to 20 wt%, from 1 wt% to 10 wt%, from 1 wt% to 5 wt%, from 5 wt% to 50 wt%, from 5 wt% to 40 wt%, from 5 wt% to 30 wt%, from 5 wt% to 20 wt%, from 5 wt% to 10 wt%, from 10 wt% to 50 wt%, from 10 wt% to 40 wt%, from 10 wt% to 30 wt%, from 10 wt% to 20 wt%, from 20 wt% to 50 wt%, from 20 wt% to 40 wt%, from 20 wt% to 30 wt%, from 30 wt% to 50 wt%, from 30 wt% to 40 wt%, or from 40 wt% to 50 wt%.

[0148] In certain embodiments, the particles include at least 50 wt% of the biopharmaceutical agent, such as at least 60 wt%, at least 70 wt%, at least 80 wt% or at least 90 wt% of the biopharmaceutical agent. In some embodiments, the particles include 10 wt% or less of a polyacrylamide-based copolymer, such as 9 wt% or less, 8 wt% or less, 7 wt% or less, 6 wt% or less, 5 wt% or less, 4 wt% or less, 3 wt% or less, 2 wt% or less or 1 wt% or less of a polyacrylamide-based copolymer.

[0149] In some embodiments, the particles comprise 90 wt% or more of a biopharmaceutical agent and 5 wt% or less of a polyacrylamide-based copolymer. In some embodiments, the particles may further comprise 5 wt% or less of an optional aqueous component. In some embodiments, the aqueous component optionally includes a buffer. In some embodiments, the particles comprise 5 wt% or less of an aqueous component consisting of a buffer (e.g., 4 wt% or less, 3 wt% or less, 2 wt% or less, or 1 wt% or less).

[0150] In some embodiments, the particles comprise a weight ratio of a biopharmaceutical agent to a polyacrylamide-based copolymer of 10:1 or greater. In some embodiments, the particles comprise 91 wt% or more (e.g., 92 wt% or more, 93 wt% or more, 94 wt% or more, 95 wt% or more, 96 wt% or more, 97 wt% or more, 98 wt% or more, or 99 wt% or more) of the the biopharmaceutical agent. In some other embodiments, the particles comprise 4.5 wt% or less (e.g., 4 wt% or less, 3.5 wt% or less, 3 wt% or less, 2.5 wt% or less, 2 wt% or less, 1.5 wt% or less, or 1 wt% or less) of the polyacrylamide-based copolymer. In some embodiments, the ratio of the polyacrylamide-based copolymer to the biopharmaceuticalAttorney Docket No.38821-63329 (008WO) agent in the particles is 5:95 or less (e.g., 4:96 or less, 3:97 or less, 2:98 or less, or 1:99 or less).

[0151] In some embodiments, the particles have a density from 1 g / cm3to 1.5 g / cm3(e.g., from 1.1 g / cm3to 1.5 g / cm3, from 1.2 g / cm3to 1.5 g / cm3, from 1.3 g / cm3to 1.5 g / cm3, or from 1.4 g / cm3to 1.5 g / cm3, from 1 g / cm3to 1.4 g / cm3, from 1 g / cm3to 1.3 g / cm3, from 1.1 g / cm3to 1.4 g / cm3, from 1.2 g / cm3to 1.4 g / cm3, or from 1.25 g / cm3to 1.35 g / cm3).

[0152] In some embodiments, the particles have a density of 1.2 g / cm3to 1.4 g / cm3, such as 1.25 g / cm3to 1.35 g / cm3(e.g., 1.25 g / cm3, 1.26 g / cm3, 1.27 g / cm3, 1.28 g / cm3, 1.29 g / cm3, 1.3 g / cm3, 1.31 g / cm3, 1.32 g / cm3, 1.33 g / cm3, 1.34 g / cm3, or 1.35 g / cm3).

[0153] In some embodiments, the particles comprise 5 wt% or less of an aqueous component consisting of a buffer (e.g., 4 wt% or less, 3 wt% or less, 2 wt% or less, or 1 wt% or less).

[0154] In some embodiments, the particles comprise 5 wt% or less (e.g., 4.5 wt% or less, 4 wt% or less, 3.5 wt% or less, 3 wt% or less, 2.5 wt% or less, 2 wt% or less, 1.5 wt% or less, or 1 wt% or less) of the polyacrylamide-based copolymer.

[0155] In some embodiments, as noted above, the particles comprise a weight ratio of a biopharmaceutical agent to a polyacrylamide-based copolymer of 10:1 or greater. In some embodiments, the weight ratio of the biopharmaceutical agent to the polyacrylamide-based copolymer in a particle is 11:1 or greater (e.g., 12:1 or greater, 13:1 or greater, 14:1 or greater, 15:1 or greater, 16:1 or greater, 17:1 or greater, 18:1 or greater, 19:1 or greater, 20:1 or greater, 21:1 or greater, 22:1 or greater, 23:1 or greater, 24:1 or greater, or 25:1 or greater).

[0156] In some embodiments, the particles are composed primarily of the biopharmaceutical agent, the polyacrylamide-based copolymer, and one or more optional excipients (e.g., as described herein).

[0157] The particles can be suspended in a liquid carrier (e.g., as described herein). In some embodiments, a particle composition is provided separately from a liquid carrier and can be formulated as a suspension in the liquid carrier prior to use. In some embodiments, an amount of the particle composition is provided already formulated as a suspension in the liquid carrier at a suitable amount and concentration ready for use. In some embodiments, the suspension needs to be resuspended prior to injection, e.g., after storage for an extendedAttorney Docket No.38821-63329 (008WO) period of time. In some embodiments, the suspension does not need to be resuspended prior to injection. 4.1.1. Biopharmaceutical Agents

[0158] The particles of the pharmaceutical composition also include a biopharmaceutical agent. In some embodiments, the amount of biopharmaceutical agent present in the pharmaceutical composition is sufficient to provide a unit dose suitable for administration via injection. In some embodiments, the particles include a single biopharmaceutical agent. In some embodiments, the particles include a co-formulation of two or more biopharmaceutical agents.

[0159] In some embodiments, the particles are formulated at a weight percent of the biopharmaceutical agent in a volume suitable for injection (e.g., SC or IM) of a unit dose to a patient in need thereof. In some embodiments, the biopharmaceutical agent is a biologic. In some embodiments, the biopharmaceutical agent has a high MW, e.g., a large biologic. In some embodiments, a high MW biopharmaceutical agent is one having a MW of 20 kDa or more, such as 30 kDa or more, 40 kDa or more, 50 kDa or more, 60 kDa or more, 70 kDa or more, 80 kDa or more, 90 kDa or more, or 100 kDa or more.

[0160] In some embodiments, the particles include about 20 wt% or more of the biopharmaceutical agent, for example, about 25 wt% or more, about 30 wt% or more, about 40 wt% or more, about 50 wt% or more, about 60 wt% or more, about 65 wt% or more, about 70 wt% or more, about 75 wt% or more, about 80 wt% or more, about 85 wt% or more, about 90 wt% or more, about 95 wt% or more of the biopharmaceutical agent. In some embodiments, the particles include about 90 wt% to 95 wt% of the biopharmaceutical agent. In some embodiments, the particles comprise 90 wt% or more of a biopharmaceutical agent. In some embodiments, the particles comprise 91 wt% or more (e.g., 92 wt% or more, 93 wt% or more, 94 wt% or more, 95 wt% or more, 96 wt% or more, 97 wt% or more, 98 wt% or more, or 99 wt% or more) of the biopharmaceutical agent. In some embodiments, the particles include 95 wt% or more of a biopharmaceutical agent.

[0161] In some embodiments, the particles include about 20 wt% or less of the biopharmaceutical agent, for example, 15 wt% or less, 10 wt% or less, or 5 wt% or less. In some embodiments, the particles include about 5 wt% or less of the biopharmaceutical agent, for example, 4 wt% or less, 3 wt% or less, 2 wt% or less, or 1 wt% or less. In someAttorney Docket No.38821-63329 (008WO) embodiments, the particles include about 1 wt% or less of the biopharmaceutical agent, for example, 0.9 wt% or less, 0.8 wt% or less, 0.7 wt% or less, 0.6 wt% or less, 0.5 wt% or less, 0.4 wt% or less, 0.3 wt% or less, 0.2 wt% or less, or 0.1 wt% or less.

[0162] In some embodiments, the particles are formulated to contain a therapeutically effective amount of a biopharmaceutical agent, where the biopharmaceutical agent has a MW of 10 kDa or less, such as 5 kDa or less. In some embodiments, the particles are formulated to contain a therapeutically effective amount of a biopharmaceutical agent, where the biopharmaceutical agent has a MW of 5 kDa or more, such as 10 kDa or more. In some embodiments, the particles include no more than 20 wt% of the biopharmaceutical agent, for example, no more than 15 wt%, no more than 10 wt%, no more than 9 wt%, no more than 8 wt%, no more than 7 wt%, no more than 6 wt%, no more than 5 wt%, no more than 4 wt%, no more than 3 wt%, no more than 2 wt%, or no more than 1 wt% of the biopharmaceutical agent. In some embodiments, the particles include about 1 wt% to 20 wt% of the biopharmaceutical agent, for example about 1 wt% to aboutIn some embodiments, the particles include 1 wt% to 20 wt% of the biopharmaceutical agent, for example 1 wt% to 10 wt%. In such cases, the remainder of the particle composition can be composed of the polyacrylamide-based copolymer, and / or one or more optional components such as a stabilizing agent (e.g., as described herein).

[0163] In some embodiments, the biopharmaceutical agent includes a polypeptide. In some embodiments, the polypeptide is susceptible to aggregation in an aqueous medium. In some embodiments, the polypeptide is a protein. In some embodiments, the polypeptide is a peptide. In some embodiments, the polypeptide is an enzyme. In some embodiments, the polypeptide is hyaluronidase.

[0164] In some embodiments, the biopharmaceutical agent is selected from antibodies and fragments thereof, chimeric fusion proteins, cytokines, chemokines, hormones, vaccine antigens, cancer antigens, adjuvants, and combinations thereof, and conjugates thereof. In some embodiments, the biopharmaceutical agent is a polypeptide.

[0165] In some embodiments, the biopharmaceutical agent is an antibody. In some cases, the biopharmaceutical agents of the present disclosure are commercially available and can be further purified.Attorney Docket No.38821-63329 (008WO)

[0166] The term “antibody” is used herein in its broadest sense and includes certain types of immunoglobulin molecules comprising one or more antigen-binding domains that specifically bind to an antigen or epitope. An antibody specifically includes, but is not limited to, full length antibodies (e.g., intact immunoglobulins), antibody fragments, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized fully human antibodies, chimeric antibodies, and single domain antibodies.

[0167] In some embodiments, the biopharmaceutical agent is a monoclonal antibody or fragment thereof. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is monospecific, i.e., binds a single antigen. In some embodiments, the monoclonal antibody is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, an IgG4 antibody, an IgM antibody, and IgA antibody, or any hybrid thereof. In some embodiments, the monoclonal antibody is a Rec-MC Antibody. In some embodiments, the monoclonal antibody is trastuzumab.

[0168] In some embodiments, the antibody is a chimeric antibody. The term “chimeric antibody” refers to an antibody that contains one or more regions from one antibody and one or more regions from one or more other antibodies.

[0169] In some embodiments, the antibody is multispecific, i.e., binds multiple antigens, e.g., a bispecific antibody.

[0170] In some embodiments, the antibody is an antibody fragment. An “antibody fragment” includes a portion of an intact antibody, such as the antigen-binding or variable region of an intact antibody. Antibody fragments suitable for use in the present compositions include, for example, Fv fragments, Fab fragments, F(ab’)2fragments, Fab’ fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0171] In some embodiments, the biopharmaceutical agent is a chimeric protein. In some embodiments, the chimeric protein isa recombinant fusion protein. The chimeric protein can include two or more domains connected via optional linkers or spacers. In some embodiments, the chimeric protein comprises an antibody fragment, such as an Fc or fragment or variant thereof. In some embodiments, the chimeric protein comprises an antibody fragment fused to a protein domain, e.g., a protein domain that specifically binds to a therapeutic target of a biopharmaceutical agent. In some embodiments, the chimeric protein is an Fc fusion protein.Attorney Docket No.38821-63329 (008WO)

[0172] In some embodiments, the antibody is a single domain antibody, e.g., a camelid antibody, or nanobody. In some embodiments, the antibody is a bispecific antibody immunoconjugate. In some embodiments, the antibody is an antibody fragment. In some embodiments, the antibody includes one or more single-chain variable fragments (scFv) of a monoclonal antibody. In some embodiments, the monoclonal antibody is a humanized antibody, a human antibody, a murine antibody, or a chimeric (mouse / human) antibody.

[0173] In some embodiments, the antibody is an antibody conjugate, e.g., an antibody or fragment thereof conjugated to one or more heterologous molecule(s). The heterologous molecule can be an additional active agent. The heterologous molecule can be a small molecule (e.g., an organic compound with a molecular weight of less than 1000, 900, 800, 700, 600, or 500 Daltons). In some embodiments, the antibody conjugate is an antibody-drug conjugate (ADC). In some embodiments, the heterologous molecule is a small molecule drug such as a cytotoxic agent, a chemotherapeutic agent, or a cytostatic agent. In some embodiments, the heterologous molecule is a small molecule drug for inflammatory condition or disease. In some embodiments, the small molecule drug is a steroid.

[0174] In some embodiments, the small molecule that is conjugated to the antibody is an inhibitor. An inhibitor is a compound capable of inhibiting the function of a target protein.

[0175] In some embodiments, the small molecule that is conjugated to the antibody of the antibody-conjugate (e.g., via an optional linker) is a degrader. A degrader is a protein- degrading molecule that is capable of targeting proteins via targeted protein degradation (TPD). The degrader can be a bifunctional molecule including a target binding moiety linked to a moiety that facilitates target degradation. In some embodiments, the degrader may be selected from, proteolysis-targeting chimera (PROTAC) degrader, lysosome-targeting chimera (LYTAC) degrader, autophagy-targeting chimaera (AUTAC), and the like.

[0176] In some embodiments, the antibody conjugate is itself a degrader where the antibody or fragment thereof specifically binds a target protein, and is conjugated via an optional linker to a small molecule that facilitates target degradation. In some embodiments, the antibody conjugate includes a binding moiety for a cell surface receptor that targets the lysosome, such as an asialoglycoprotein receptor (ASGPR), or mannose-6-phosphate receptor (M6PR). In some embodiments, the antibody conjugate includes a moiety that binds a E3Attorney Docket No.38821-63329 (008WO) ligase, such as cereblon or VHL. In some embodiments, antibody conjugate is a molecular glue–antibody conjugate (MAC) that includes a conjugated molecular glue.

[0177] In some embodiments, the antibody conjugate includes a conjugated imaging agent. In some embodiments, the antibody conjugate includes a radiolabeled imaging agent. In some embodiments, the antibody conjugate includes a therapeutic radionuclide for targeted cancer therapy.

[0178] The antibody can be targeted to a variety of target proteins, e.g., a therapeutic target protein.

[0179] In some embodiments, the antibody has a molecular weight of about 100 kDa to about 200 kDa, for example, about 120 kDa to about 180 kDa. In some embodiments, the antibody has a molecular weight of about 150 kDa. In some embodiments, the antibody has a molecular weight of 100 kDa to 200 kDa, for example, 120 kDa to 180 kDa. In some embodiments, the antibody has a molecular weight of 150 kDa. In some embodiments, the antibody has a molecular weight of 100 kDa or less, such as 40 kDa to 80 kDa, for example, about 50 kDa.

[0180] In some embodiments, the biopharmaceutical agent is a conjugate, e.g., a biopharmaceutical agent (e.g., a nucleic acid, peptide or protein) conjugated to one or more heterologous molecule(s). The heterologous molecule can be an additional active agent (e.g., as described herein). It is understood that any of the heterologous molecules described above can be incorporated in to a biopharmaceutical agent conjugate.

[0181] In some embodiments, the particles include 5 wt% or more of the antibody, for example, 10 wt% or more, 20 wt% or more, 30 wt% or more, 40 wt% or more, 50 wt% or more, 60 wt% or more, 70 wt% or more, 80 wt% or more, 90% or more, or 95% or more of the antibody. In some embodiments, the composition includes 95 wt% or less, 90 wt% or less, or 80 wt% or less of the antibody. In some embodiments, the antibody is a monoclonal antibody or fragment thereof.

[0182] In some embodiments, the particles includes about 60 wt% to about 99 wt% of the antibody, for example, about 65 wt% to about 95 wt%, about 70 wt% to about 95 wt%, about 75 wt% to about 95 wt%, about 80 wt% to about 95 wt%, about 85 wt% to about 95 wt%, or about 90 wt% to about 95 wt% of the antibody. In some embodiments, the particles includeAttorney Docket No.38821-63329 (008WO) about 90 wt%, or about 95 wt% of the antibody. In some embodiments, the particles include 60 wt% to 99 wt% of the antibody, for example, 65 wt% to 95 wt%, 70 wt% to 95 wt%, 75 wt% to 95 wt%, 80 wt% to 95 wt%, 85 wt% to 95 wt%, or 90 wt% to 95 wt% of the antibody. In some embodiments, the antibody is a monoclonal antibody or fragment thereof.

[0183] In certain embodiments, the biopharmaceutical agent comprises a protein that is a growth factor. Exemplary growth factors include, but are not limited to, humatrope, genotropin, omnitrope, pharmaceutically acceptable salts of the foregoing, and combinations thereof.

[0184] In some embodiments, the biopharmaceutical agent is insulin.

[0185] The term “insulin” refers to a hormone produced by the beta cells in the pancreatic islets that regulates the amount of glucose in the blood. Many eukaryotes, including humans, primates, pigs, cows, cats, dogs, and rodents, produce insulin. Thus, “insulin,” as used herein, includes insulin produced by humans, and analogs thereof, as well as insulin, and analogs thereof, produced by other eukaryotes, including, but not limited to, primates, pigs, cows, cats, dogs, and rodents, and also includes recombinant, purified or synthetic insulin or insulin analogs having similar function and structure, unless otherwise specified. The human insulin protein consists of 51 amino acids and has a molecular weight of approximately 5.8 kilodalton (kDa). Human insulin is a heterodimer of an A-chain and a B-chain that are connected by disulfide bonds.

[0186] Insulin can be isolated from the pancreatic islets extracts of an animal that produces insulin or expressed recombinantly in a suitable expression system such as E. coli, yeast, insect cells, and mammalian cells (e.g., Chinese hamster ovary (CHO) cells). Depending upon their specific pharmacokinetics and pharmacodynamics (PK / PD) properties (e.g., duration of action, maximum concentration observed (Cmax), time-to-onset, area under the curve (AUC)), insulin can be further characterized as a rapid-acting insulin, a short-acting insulin, an intermediate-acting insulin, a long-acting insulin, and a pre-mixed insulin.

[0187] Insulin also includes monomeric and oligomeric forms, such as dimeric and hexameric forms. Insulin can exist as a monomer as it circulates in the plasma, and it also binds to its receptor while in a monomeric form. Insulin formulations (or insulin analog formulations) containing a predominance of protein molecules in the form of monomers and dimers ordinarily have a strong tendency to aggregate and form inactive fibrils. InsulinAttorney Docket No.38821-63329 (008WO) hexamers are too large to be absorbed, and so hexameric insulin formulations must disassemble into dimers or monomers before the insulin can be absorbed and function in the body. The active form of insulin in the blood stream is the monomeric form.

[0188] In some embodiments, the particles include about 0.5 wt% to about 20 wt%, about 1 wt% to about 20 wt%, about 1 wt% to about 15 wt%, about 1to about 10 wt%, about 1 wt% to about 9 wt%, about 1 wt% to about 8 wt% of the insulin or the analog thereof. In some embodiments, the particles include about 7 wt%, about 8about 9 wt%, or about 10 wt% of the insulin or the analog thereof. In some embodiments, the particles include 1 wt% to 20 wt%, 1 wt% to 15 wt%, 1 wt% to 10 wt%, 1 wt% to 9 wt%, or 1 wt% to 8 wt% of the insulin or the analog thereof. In some embodiments, the particles include 7 wt%, 8 wt%, 9 wt%, or 10 wt% of the insulin or the analog thereof.

[0189] In some embodiments, the insulin or the analog thereof is selected from insulin lispro, HUMALOG®(fast-acting insulin lispro), insulin glargine, LANTUS®(insulin glargine), insulin detemir, LEVEMIR®(insulin detemir), ACTRAPID®(fast-acting human insulin), modern insulin, NOVORAPID®(insulin aspart), VELOSULIN®(human insulin), HUMULIN®M3 (a mixture of soluble insulin and isophane insulin called biphasic isophane insulin), HYPURIN®(neutral bovine insulin), INSUMAN®(recombinant human insulin), INSULATARD®(long-acting isophane human insulin), MIXTARD®30 (a mixture of 30% soluble insulin and 70% isophane insulin), MIXTARD®40 (a mixture of 40% soluble insulin and 60% isophane insulin), MIXTARD®50 (a mixture of 50% soluble insulin and 50% isophane insulin), insulin aspart, insulin glulisine, insulin isophane, insulin degludec, insulin icodec, insulin zinc extended, NOVOLIN®R (human insulin), HUMULIN®R (human insulin), HUMULIN®R regular U-500 (concentrated regular insulin), NOVOLIN®N (intermediate-acting human insulin), HUMULIN®N (intermediate-acting human insulin), RELION®(over-the-counter brand of NOVOLIN®R, NOVOLIN®N, and NOVOLIN®70 / 30), AFREZZA®(rapid-acting inhaled insulin), HUMULIN®70 / 30 (a mixture of 70% human insulin isophane suspension and 30% human insulin injection), NOVOLIN®70 / 30 (a mixture of 70% NPH, human insulin isophane suspension and 30% regular, human insulin injection), NOVOLOG®70 / 30 (a mixture of 70% insulin aspart protamine suspension and 30% insulin aspart injection), HUMULIN®50 / 50 (a mixture of 50% human insulin isophane suspension and 50% human insulin injection), HUMALOG®Mix 75 / 25 (a mixture of 75% insulin lispro protamine suspension and 25% insulin lispro injection), insulin aspartAttorney Docket No.38821-63329 (008WO) protamine-insulin aspart, insulin lispro protamine-insulin lispro, human insulin NPH-human insulin regular, insulin degludec-insulin aspart, and combinations thereof. In some embodiments, the insulin or the analog thereof is a human insulin or a recombinant human insulin. In some embodiments, the insulin or the analog thereof is a non-human (e.g., primate, pig, cow, cat, dog, or rodent) insulin or a recombinant non-human insulin. In some embodiments, the insulin or the analog thereof is a purified or synthetic insulin. In some embodiments, the insulin or the analog thereof is selected from a rapid-acting insulin, a short- acting insulin, an intermediate-acting insulin, a long-acting insulin, and a pre-mixed insulin. In some embodiments, the insulin or the analog thereof is insulin lispro. In some embodiments, the insulin or the analog thereof is insulin aspart. In some embodiments, the insulin, or an analog thereof, is recombinant human insulin.

[0190] In some embodiments, the biopharmaceutical agent is a peptide, a peptide analogue, or peptide conjugate. The formulation approaches described herein should be particularly useful in preparing storage stable injectable pharmaceutical compositions of a variety of therapeutic peptides, including but not limited to glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), a GLP-1 receptor agonist, GLP-2, adrenocorticotropic hormone (ACTH), leuprolide, hirudin, insulin, pramlintide, exendins, exenatide, gastric inhibitory peptide, calcitonin, calcitonin gene related peptide, amylin, adrenomedullin, angiotensin, an immunogenic peptide (e.g., a peptide or peptide complex derived from a virus, a bacterium, or any prokaryotic or eukaryotic organism or cell thereof), and the like, and analogues thereof.

[0191] In some embodiments, the pharmaceutical agent is a peptide conjugate (e.g., a peptide-small molecule conjugate, or a peptide-fatty acid conjugate). In some embodiments, the biopharmaceutical agent comprises a macrocyclic peptide. In some embodiments, the biopharmaceutical agent is a peptide-fatty acid conjugate. In some embodiments, the biopharmaceutical agent is an oligonucleotide containing therapeutic agent. In some embodiments, the biopharmaceutical agent is an oligonucleotide conjugate (e.g., an oligonucleotide-peptide conjugate, an oligonucleotide-antibody conjugate, or an oligonucleotide-targeting agent conjugate). In some embodiments, the oligonucleotide is selected from antisense oligonucleotide (ASO), aptamer, RNAi, siRNA, shRNA, antagomir, microRNA (miRNA), a pre-miRNA, miR mimic, and splice switching oligonucleotideAttorney Docket No.38821-63329 (008WO) (SSO). In some embodiments, the biopharmaceutical agent an antibody-siRNA conjugate or peptide-siRNA conjugate.

[0192] In some embodiments, the biopharmaceutical agent is glucagon peptide, glucagon analog, glucagon mimetic, or salt thereof.

[0193] In some embodiments, the biopharmaceutical agent is a conjugate of any one of peptides described herein. A peptide conjugate can include a peptide conjugated to variety of moieties, such as conjugated to a half-life extending moiety, e.g., a fatty acid, conjugated to a targeting moiety, or conjugated to an oligonucleotide (e.g., as described herein), such as an siRNA.

[0194] In some embodiments, the biopharmaceutical agent is a peptide analog. In some embodiments, the peptide analog is a macrocyclic peptide, a peptide-small molecule conjugate, or a peptide-fatty acid conjugate. In some embodiments, peptide analog is an analog of glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), a GLP-1 receptor agonist, GLP-2, adrenocorticotropic hormone (ACTH), leuprolide, hirudin, insulin, pramlintide, exendins, exenatide, gastric inhibitory peptide, calcitonin, calcitonin gene related peptide, amylin, adrenomedullin, angiotensin, or an immunogenic peptide. In some embodiments, peptide analog comprises a peptidic sequence corresponding to glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), a GLP-1 receptor agonist, GLP-2, adrenocorticotropic hormone (ACTH), leuprolide, hirudin, insulin, pramlintide, exendins, exenatide, gastric inhibitory peptide, calcitonin, calcitonin gene related peptide, amylin, adrenomedullin, angiotensin, an immunogenic peptide, or a biologically active fragment thereof.

[0195] In some embodiments, the biopharmaceutical agent is a GLP-1 receptor agonist. In some embodiments, the GLP-1 receptor agonist (GLP-1RA) is a polypeptide or polypeptide analog. A GLP-1RA can be an incretin mimetic, or GLP-1 analog. In some embodiments, the GLP-1RA is a fusion protein, or fusion of a protein and peptide. In some embodiments, the GLP-1RA is a recombinant polypeptide. In some embodiments, the GLP-1RA is a synthetic polypeptide. Such GLP1RA’s can be used to treat obesity related diseases or conditions, or Type 2 diabetes. In some embodiments, the GLP-1RA has additional agonist activity at one or more receptors or relevant biological targets. In some embodiments, the GLP-1RA is a dual agonist (also referred to as a twincretin). In some embodiments, the dual agonist is anAttorney Docket No.38821-63329 (008WO) agonist of GLP-1R and glucose-dependent insulinotropic peptide (GIP) receptor. Tirzepatide is an exemplary dual agonist.

[0196] In some embodiments, the GLP-1RA is an agonist of GLP-1R, and GIP receptor and / or glucagon receptor. In some embodiments, the GLP-1RA is an agonist of GLP-1R and glucagon receptor (GL R or GCGR). In some embodiments, the GLP-1RA is an agonist of GLP-1R and GIP receptor.

[0197] In some embodiments, the GLP-1RA is a peptide drug for diabetes and / or obesity that agonizes GLP-1 and GCGR.

[0198] In some embodiments, the GLP-1RA is a triple agonist (also referred to as a triple G agonist), e.g., an agonist of GLP-1R, GIP receptor and glucagon receptor. Retatrutide (LY3437943) is an exemplary triple G agonist. Other triple G agonists of interest include those described by Knerr et al. (Next generation GLP-1 / GIP / glucagon triple agonists normalize body weight in obese mice, Mol. Metab. 2022 Sep; 63: 101533).

[0199] In some embodiments, the GLP-1RA is selected from: dulaglutide, exenatide, semaglutide, liraglutide, insulin degludec + liraglutide, insulin glargine + lixisenatide, tirzepatide, cagrilintide [INN] + semaglutide, albenatide [INN], cotadutide, CT-868, PF 06882961, efocipegtrutide, LY-3502970, NLY-001, pegapamodutide, pemvidutide, PF- 07081532, retatrutide, RGT-075, TTP-273, vurolenatide, GZR-18, mazdutide, PB-119, AMG-133, dapiglutide, DD-01, DR-10627, ECC-5004, exenatide biobetter, GL-0034, GMA- 105, HEC-88473, LY-3493269, NN-6177, NN-9847, NNC0519-0130, PB-1023, Peptides to Agonize GLP-1 and GCGR for Diabetes and Obesity, Peptides to Agonize GLP-1 and GCGR for Diabetes and Obesity, SCO-094, semaglutide, VK-2735, YH-25724, YN-012, and YN- 015.

[0200] In some embodiments, the GLP-1RA is dulaglutide. Dulaglutide reduces fasting glucose concentrations and reduces postprandial glucose (PPG) concentrations in patients with type 2 diabetes mellitus through the agonism of the GLP-1 receptor. This drug primarily acts as an incretin mimetic hormone or analog of human glucagon-like peptide-1, which normally acts on the GLP-1 receptor. Dulaglutide activates the GLP-1 receptor found in pancreatic beta cells, increasing intracellular cyclic AMP (cAMP) in beta cells, leading to insulin release and subsequent reduction of blood glucose concentrations. Additionally, dulaglutide decreases glucagon secretion and slows gastric emptying.Attorney Docket No.38821-63329 (008WO)

[0201] In some embodiments, the GLP-1RA is exenatide. In some embodiments, the GLP-1RA is Byetta. Exenatide binds to the intact human Glucagon-like peptide-1 receptor (GLP-1R) in a similar way to the human peptide glucagon-like peptide-1 (GLP-1).

[0202] In some embodiments, the GLP-1RA is semaglutide. Semaglutide is a recombinant DNA produced polypeptide analogue of human glucagon-like peptide-1 (GLP- 1) which is typically used in combination with diet and exercise in the therapy of type 2 diabetes, either alone or in combination with other antidiabetic agents. It is an agonist of glucagon-like peptide-1 receptors (GLP-1 AR) and used for the treatment of type 2 diabetes. semaglutide is a polypeptide that contains a linear sequence of 31 amino acids joined together by peptide linkages. It has a role as a hypoglycemic agent, a glucagon-like peptide-1 receptor agonist, an anti-obesity agent, a neuroprotective agent and an appetite depressant. It is a polypeptide and a lipopeptide.

[0203] In some embodiments, the GLP-1RA is liraglutide. Liraglutide is a lipopeptide that is an analogue of human GLP-1 in which the lysine residue at position 27 is replaced by arginine and a hexadecanoyl group attached to the remaining lysine via a glutamic acid spacer. Liraglutide is typically used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It has a role as a glucagon-like peptide-1 receptor agonist and a neuroprotective agent. It is a lipopeptide and a polypeptide.

[0204] In some embodiments, theGLP-1RA is liraglutide. In certain embodiments, the method further comprises administering an additional therapeutic agent. In certain embodiments, the additional therapeutic agent is insuline degludec. Insulin degludec is typically used with a proper diet and exercise program to control high blood sugar in people with diabetes. The combination therapy of insulin degludec and liraglutide gives a robust glycemic control with a low risk for hypoglycemia and less weight gain or even weight loss.

[0205] In some embodiments, the GLP-1RA is lixisenatide. In some embodiments, the method further comprises administering GLP-1RA in combination with insulin glargine. In some embodiments, the insulin glargine in combination with lixisenatide is Soliqua 100 / 33. Insulin glargine and lixisenatide is a combination medicine that is typically used together with diet and exercise to improve blood sugar control in adults with type 2 diabetes. Insulin glargine is a long-acting insulin that starts to work several hours after injection and keeps working evenly for 24 hours. Lixisenatide is a drug that helps the pancreas produce insulin more efficiently.Attorney Docket No.38821-63329 (008WO)

[0206] In some embodiments, the GLP-1RA is tirzepatide. tirzepatide is a dual glucose- dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA). Tirzepatide works by activating both the GLP-1 and GIP receptors in the body. This triggers the release of insulin from the pancreas that blocks glucagon, a hormone that increases blood sugar levels.

[0207] In some embodiments, the GLP-1RA is semaglutide.

[0208] In some embodiments, the GLP-1RA is albenatide.

[0209] In some embodiments, the GLP-1RA is albiglutide.

[0210] In some embodiments, the GLP-1RA is cotadutide. Cotadutide (MEDI0382), a dual GLP-1 and glucagon receptor agonist, is currently under development for type 2 diabetes and NASH.

[0211] In some embodiments, the GLP-1RA is CT-868. CT-868 is a dual GLP-1 and GIP receptor modulator that is optimized for improved tolerability at the GLP-1 receptor. The combined action of GLP-1 and GIP result in greater body weight loss and glucose control.

[0212] In some embodiments, the GLP-1RA is efocipegtrutide. Efocipegtrutide is a glucagon, gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptors agonist. Efocipegtrutide shares sequence homology with glucagon, glucagon-like peptide 1 (GLP1) and gastric inhibitory polypeptide (GIP, glucose-dependent insulinotropic polypeptide, incretin hormone), where the gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) triple full agonist is chemically conjugated with constant region of human immunoglobulin via non-peptidyl flexible linker.

[0213] In some embodiments, the GLP-1RA is NLY-001. NLY-001 is a microglia- targeted GLP-1RA. NLY-001 is a pegylated exendin-4 analogue of Glucagon Like Peptide-1 Receptor (GLP-1R) agonist.

[0214] In some embodiments, the GLP-1RA is pegapamodutide.

[0215] In some embodiments, the GLP-1RA is pemvidutide. Pemvidutide is a peptide- based GLP-1 / glucagon dual receptor agonist developed for the treatment of obesity and non- alcoholic steatohepatitis (NASH). Pemvidutide has been shown to substantially decrease the amount of fat within the liver which could have beneficial effects on insulin resistance and cardiorenal risk, common problems in people with obesity. In clinical trials, pemvidutideAttorney Docket No.38821-63329 (008WO) demonstrated striking reductions in body weight, liver fat, serum lipids and markers of liver inflammation.

[0216] In some embodiments, the GLP-1RA is retatrutide. Retatrutide stimulates GIPR, GLP-1, and GLP-1 receptors.

[0217] In some embodiments, the GLP-1RA is TTP-273.

[0218] In some embodiments, the GLP-1RA is vurolenatide. Vurolenatide is a GLP-1 receptor agonist that is administered via injection.

[0219] In some embodiments, the GLP-1RA is GZR-18. GZR-18 is an analog of glucagon-like peptide-1 (GLP-1). In vitro pharmacology and activity of GZR18 were previously characterized by a binding assay of GZR18 using human serum albumin (HSA), an activation assay in human GLP-1 receptor-expressing cell lines, and its effect on glucose- stimulated insulin secretion (GSIS) in primary mice islets.

[0220] In some embodiments, the GLP-1RA is mazdutide. Mazdutide (IBI362) is a glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist. Mazdutide is a long- acting synthetic peptide related to mammalian oxyntomodulin (OXM), which uses a fatty acid side chain to prolong the duration of action and allow once-weekly administration. Mazdutide is thought to exert its biological effects by activating GLP-1 receptor and glucagon receptor in human beings, which is estimated to improve glucose tolerance and induce weight loss, mimicking the effects of endogenous oxyntomodulin.

[0221] In some embodiments, the GLP-1RA is PB-119. PB-119 is a pegylated human glucagon-like peptide-1 (GLP-1) receptor agonist.

[0222] In some embodiments, the GLP-1RA is AMG-133. AMG 133 is a bispecific glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonist and glucagon-like peptide-1 (GLP-1) receptor agonist molecule. AMG 133 mimics the agonist effects of GLP-1 and antagonizes the effects of glucose-dependent insulinotropic polypeptide (GIP).

[0223] In some embodiments, the GLP-1RA is dapiglutide. Dapiglutide promotes significant intestinal growth, as indicated by significantly increased villus height as well as intestinal length. Dapiglutide reduces stool water losses, resulting in reduced plasma aldosterone. It has been shown that dapiglutide possesses specific and potent GLP-1R and GLP-2R agonist effects in rodents.Attorney Docket No.38821-63329 (008WO)

[0224] In some embodiments, the GLP-1RA is DD-01. DD-01 is a pegylated, long- acting, peptide based dual agonist of glucagon-like peptide 1 (GLP-1) receptor and glucagon receptor (GCGR).

[0225] In some embodiments, the GLP-1RA is DR-10627.

[0226] In some embodiments, the GLP-1RA is ECC-5004. ECC-5004 is an orally administered small-molecule GLP-1 RA.

[0227] In some embodiments, the GLP-1RA is exenatide biobetter.

[0228] In some embodiments, the GLP-1RA is GL-0034. GL0034 is a glucagon-like peptide-1 receptor (GLP-1R) agonist that has been shown to have glucose-lowering effects with increased insulin and C-peptide levels, reduced plasma glucagon levels, long-term reduction in HbA1C, and reduced body weight when tested in type 2 diabetic mice.

[0229] In some embodiments, the GLP-1RA is GMA-105. GMA-105 is a humanized anti-GLP-1R monoclonal antibody carrying a GLP-1 fragment.

[0230] In some embodiments, the GLP-1RA is HEC-88473. HEC88473 is a GLP- 1 / FGF21 dual agonist.

[0231] In some embodiments, the GLP-1RA is LY-3493269. LY-3493269 is a GIP / GLP coagonist peptide.

[0232] In some embodiments, the GLP-1RA is NN-6177. NN-6177 acts by targeting glucagon receptor (GCGR) and glucagon like peptide 1 receptor (GLP1R).

[0233] In some embodiments, the GLP-1RA is NN-9847.

[0234] In some embodiments, the GLP-1RA is NNC0519-0130.

[0235] In some embodiments, the GLP-1RA is PB-1023. PB-1023 is a recombinant GLP- 1 analogue used to treat sarcopenia-related diseases.

[0236] In some embodiments, the GLP-1RA is SCO-094. SCO-094 is a dual agonist for GLP-1R and GIPR. Preclinical studies have shown that SCO-094 is more effective in improving diabetes and obesity than the GLP-1R mono-agonist.

[0237] In some embodiments, the GLP-1RA is semaglutide. semaglutide is a GLP-1 agonist and works by increasing insulin release, lowering the amount of glucagon released, delaying gastric emptying and reducing appetite.Attorney Docket No.38821-63329 (008WO)

[0238] In some embodiments, the GLP-1RA is VK-2735. VK-2735 is a dual agonist of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors for the potential treatment of various metabolic disorders such as diabetes, obesity and NASH.

[0239] In some embodiments, the GLP-1RA is YH-25724. YH-25724 is a long-acting GLP-1 / FGF21 dual agonist that lowers both non-alcoholic fatty liver disease activity score and fibrosis stage in a diet-induced obese mouse model of biopsy-confirmed non-alcoholic steatohepatitis.

[0240] In some embodiments, the GLP-1RA is YN-012. In some embodiments, the GLP- 1RA is and YN-015.

[0241] In some embodiments, the biopharmaceutical agent comprises an oligonucleotide. In some embodiments, the biopharmaceutical agent is an oligonucleotide containing therapeutic agent. In some embodiments, the biopharmaceutical agent comprises an oligonucleotide conjugated or linked to another agent, such as a targeting moiety, a protein (e.g., antibody), peptide or peptide analog. In some embodiments, the oligonucleotide is selected from antisense oligonucleotide (ASO), aptamer, RNAi, siRNA, antagomir, microRNA (miRNA), miR mimic, and splice switching oligonucleotide (SSO).

[0242] In some embodiments, the biopharmaceutical agent is a conjugate of an oligonucleotide and a protein or peptide or analog thereof. The polynucleotide component of the conjugate molecules can be an siRNA, an shRNA, a miRNA, a pre-miRNA, a miRNA mimetic, an anti-miRNA oligonucleotide, or an antisense oligonucleotide. The protein component of the conjugate molecule can be an antibody, antigen-binding fragment (e.g. a some embodiments, the antibody, antigen-binding fragment, or ligand specifically bind to a receptor expressed by a particular cell type or tissue. In some embodiments, the biopharmaceutical agent is a peptide-siRNA conjugate. In some embodiments, the biopharmaceutical agent is a mAb-siRNA conjugate. 4.1.1.1 Additional active agents

[0243] The particles of the present disclosure can include a combination of biopharmaceutical agents and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are useful for treating a diseaseAttorney Docket No.38821-63329 (008WO) or condition that is targeted by biopharmaceutical agent. In some embodiments, administration of the agents from the pharmaceutical composition can provide for delivery to a cell in the subject’s body so as to exert their biological or therapeutic effect at the same time. In some embodiments, the agents in the particles are co-formulated to provide pharmacokinetic profiles that are substantially similar.

[0244] In some embodiments, the one or more additional therapeutic agent is an active agent that provides a synergistic effect with the biopharmaceutical agent. In some embodiments, the additional therapeutic agent is a small molecule drug.

[0245] In some embodiments, the stable formulations and particles used in accordance with the present disclosure include co-formulations or mixtures of the types of biopharmaceutical agent described herein, such as at least one peptide, at least one small molecule, and combinations thereof.

[0246] In some embodiments, the particles are co-formulated to contain a first biopharmaceutical agent that is a protein, and a second biopharmaceutical agent that is a peptide. In some embodiments, the particles are co-formulated to contain first and second biopharmaceutical agents that are peptides. In some embodiments, the particles are co- formulated to contain a first biopharmaceutical agent that is a peptide hormone or analog thereof, and a second therapeutic agent that is a small molecule. In some embodiments, the second therapeutic agent is a steroid. In some embodiments, the co-formulation is a mixture of a first batch of particles containing a biopharmaceutical that is a protein, and a second batch of particles containing a biopharmaceutical that is a peptide.

[0247] In some embodiments, the particles are co-formulated to contain a first biopharmaceutical agent that is insulin, and a second biopharmaceutical agent that is a peptide. In some embodiments, the co-formulation is a mixture of a first batch of particles containing insulin, and a second batch of particles containing a peptide. In some embodiments, the peptide is pramlintide.

[0248] The amounts of active agent(s) that may be combined with each other and the carrier materials of the particles to produce a dosage form will vary depending upon the subject in need and the particular mode of administration.Attorney Docket No.38821-63329 (008WO) 4.1.2. Polyacrylamide-based Copolymers

[0249] The particles provided in the present disclosure can include a polyacrylamide-based copolymer that is formulated with the biopharmaceutical agent of interest.

[0250] Polyacrylamide-based copolymers of interest and that can be used in the particles and particle suspensions described herein include those described in International Publication Nos. WO 2021 / 211976 and WO 2023 / 230046, the disclosures of which are herein incorporated by reference.

[0251] In some embodiments, the polyacrylamide-based copolymer contains a water-soluble carrier monomer and a functional dopant monomer. In some embodiments, the polyacrylamide-based copolymer is amphiphilic.

[0252] In some embodiments, the polyacrylamide-based copolymer includes a non-ionic water-soluble acrylamide monomer and a functional dopant monomer. In some embodiments, the polyacrylamide-based copolymer further includes 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.

[0253] 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- methoxypropoyl)acrylamide (MPAM), 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 MPAM and MORPH. In some embodiments, the water-soluble carrier monomer is N- (3-methoxypropoyl)acrylamide (MPAM). 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 includes a water-soluble carrier monomer selected from N-(3-methoxypropoyl)acrylamide (MPAM) and 4-acryloylmorpholine (MORPH).Attorney Docket No.38821-63329 (008WO)

[0254] The polyacrylamide-based copolymers of the present disclosure also include 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-N- diethylacrylamide (DEA), N-tert-butylacrylamide (TBA), N-phenylacrylamide (PHE), and combinations thereof. In some embodiments, a functional dopant monomer is selected from 2-acrylamido-2-methylpropane sulfonic acid (AMP), (3- acrylamidopropyl)trimethylammonium chloride (TMA), N-tert-butylacrylamide (TBA), N- phenylacrylamide (PHE), and combinations thereof. In some embodiments, a functional dopant monomer is selected from N-N-diethylacrylamide (DEA), N-phenylacrylamide (PHE), N-isopropylacrylamide (NIP), and combinations thereof.

[0255] In some embodiments, the polyacrylamide-based copolymer includes a 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 includes 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 includes 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 includes an ionic functional acrylamide dopant monomer. In some embodiments, the ionic functional acrylamide 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). In some embodiments, the functional dopant monomer is N,N-diethylacrylamide (DEA).

[0256] In some embodiments, the polyacrylamide-based copolymer includes a water-soluble carrier monomer selected from N-(3-methoxypropoyl)acrylamide (MPAM), 4-Attorney Docket No.38821-63329 (008WO) acryloylmorpholine (MORPH), N,N-dimethylacrylamide (DMA), N-hydroxyethylacrylamide (HEAM), and acrylamide (AM); and 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-N-diethylacrylamide (DEA), N-tert-butylacrylamide (TBA), and N- phenylacrylamide (PHE).

[0257] In some embodiments, the water-soluble carrier monomer is N-(3- methoxypropoyl)acrylamide (MPAM). In some embodiments, the water-soluble carrier monomer is N-(3-methoxypropoyl)acrylamide (MPAM) and the functional dopant monomer is N-phenylacrylamide (PHE).

[0258] 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-isopropylacrylamide (NIP), or N-phenylacrylamide (PHE).

[0259] 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 selected from 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), N-phenylacrylamide (PHE), and combinations thereof.

[0260] In some embodiments, the water-soluble carrier monomer is N-hydroxyethyl acrylamide (HEAM). In some embodiments, the water-soluble carrier monomer is N- hydroxyethyl acrylamide (HEAM) and the functional dopant monomer is selected from 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), N-phenylacrylamide (PHE), and combinations thereof.

[0261] 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 selected from N-[tris(hydroxymethyl)-methyl]acrylamideAttorney Docket No.38821-63329 (008WO) (TRI), 2-acrylamido-2-methylpropane sulfonic acid (AMP), (3- acrylamidopropyl)trimethylammonium chloride (TMA), N-isopropylacrylamide (NIP), N-N- diethylacrylamide (DEA), N-tert-butylacrylamide (TBA), N-phenylacrylamide (PHE), and combinations thereof.

[0262] In some embodiments, the polyacrylamide-based copolymer includes N-(3- methoxypropoyl)acrylamide (MPAM) or 4-acryloylmorpholine (MORPH) as the water- soluble carrier monomer, and the functional dopant monomer includes one or more of 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).

[0263] In some embodiments, the polyacrylamide-based copolymer includes N-(3- methoxypropoyl)acrylamide (MPAM), 4-acryloylmorpholine (MORPH) or combinations thereof as the water-soluble carrier monomer, and the functional dopant monomer includes one or more N-isopropylacrylamide (NIP) and N-phenylacrylamide (PHE), or combinations thereof.

[0264] In some embodiments, the polyacrylamide-based copolymer includes N-(3- methoxypropoyl)acrylamide (MPAM), 4-acryloylmorpholine (MORPH) or combinations thereof as the water-soluble carrier monomer, and the functional dopant monomer includes one or more of 2-acrylamido-2-methylpropane sulfonic acid (AMP), (3- acrylamidopropyl)trimethylammonium chloride (TMA), N-tert-butylacrylamide (TBA), N- phenylacrylamide (PHE), or combinations thereof.

[0265] In some embodiments, the polyacrylamide-based copolymer includes N,N- dimethylacrylamide (DMA), N-hydroxyethyl acrylamide (HEAM), or acrylamide (AM) as the water-soluble carrier monomer, and the functional dopant monomer is selected from 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), N-phenylacrylamide (PHE), and combinations thereof.

[0266] In some embodiments, the amount of functional dopant monomer used in the copolymerization reaction is designed to maximize dopant loading while yielding functionalAttorney Docket No.38821-63329 (008WO) 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 includes 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 includes 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 polyacrylamide-based copolymer includes 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 includes 2%, 5%, 8%, 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, or 30% by weight of a functional dopant monomer.

[0267] In some embodiments, the polyacrylamide-based copolymer includes 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 includes 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 includes 70% to 98% by weight of a water-soluble carrier monomer, for example, 75% to 98%, 80% to 98%, 85% to 98%, 90%Attorney Docket No.38821-63329 (008WO) 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 includes 70%, 72%, 75%, 78%, 80%, 82%, 85%, 88%, 90%, 92%, 95%, or 98% by weight of a water-soluble carrier monomer.

[0268] In some embodiments, the polyacrylamide-based copolymer includes 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 95%, 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 2% to about 17%, 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.

[0269] In some embodiments, the polyacrylamide-based copolymer includes 70% to 98% by weight of a water-soluble carrier monomer and 2% to 30% by weight of a functional dopant monomer. For example, the polyacrylamide-based copolymer can contain 70% to 98%, 70% to 95%, 70% to 80%, 80% to 95%, 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%, 2% to 17%, 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.

[0270] In some embodiments, the polyacrylamides-based copolymer includes about 2% to about 30% by weight of the functional dopant monomer NIP. In some embodiments, the polyacrylamides-based copolymer includes about 5% to about 30% by weight of the functional dopant monomer NIP. In some embodiments, the polyacrylamides-based copolymer includes about 10% to about 28% by weight of the functional dopant monomer NIP. In some embodiments, the polyacrylamide-based copolymer includes about 5% to about 26% by weight of the functional dopant monomer NIP. In some embodiments, theAttorney Docket No.38821-63329 (008WO) polyacrylamides-based copolymer includes about 5% to about 10% by weight of the functional dopant monomer NIP. In some embodiments, the polyacrylamides-based copolymer includes about 10% to about 15% by weight of the functional dopant monomer NIP. In some embodiments, the polyacrylamides-based copolymer includes about 15% to about 20% by weight of the functional dopant monomer NIP. In some embodiments, the polyacrylamides-based copolymer includes about 20% to about 26% by weight of the functional dopant monomer NIP.

[0271] In some embodiments, the polyacrylamides-based copolymer includes 2% to 30% by weight of the functional dopant monomer NIP, 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 NIP.

[0272] In some embodiments, the polyacrylamides-based copolymer includes about 2% to about 30% by weight of the functional dopant monomer PHE. In some embodiments, the polyacrylamides-based copolymer includes about 5% to about 30% by weight of the functional dopant monomer PHE. In some embodiments, the polyacrylamides-based copolymer includes about 10% to about 28% by weight of the functional dopant monomer PHE. In some embodiments, the polyacrylamide-based copolymer includes about 5% to about 26% by weight of the functional dopant monomer PHE. In some embodiments, the polyacrylamides-based copolymer includes about 5% to about 10% by weight of the functional dopant monomer PHE. In some embodiments, the polyacrylamides-based copolymer includes about 10% to about 15% by weight of the functional dopant monomer PHE. In some embodiments, the polyacrylamides-based copolymer includes about 15% to about 20% by weight of the functional dopant monomer PHE. In some embodiments, the polyacrylamides-based copolymer includes about 20% to about 26% by weight of the functional dopant monomer PHE.

[0273] In some embodiments, the polyacrylamides-based copolymer includes 2% to 30% by weight of the functional dopant monomer PHE, 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 PHE.

[0274] In some embodiments, the polyacrylamides-based copolymer includes about 2% to about 30% by weight of the functional dopant monomer DEA. In some embodiments, theAttorney Docket No.38821-63329 (008WO) polyacrylamides-based copolymer includes about 5% to about 30% by weight of the functional dopant monomer DEA. In some embodiments, the polyacrylamides-based copolymer includes about 10% to about 28% by weight of the functional dopant monomer DEA. In some embodiments, the polyacrylamide-based copolymer includes about 5% to about 26% by weight of the functional dopant monomer DEA. In some embodiments, the polyacrylamides-based copolymer includes about 5% to about 10% by weight of the functional dopant monomer DEA. In some embodiments, the polyacrylamides-based copolymer includes about 10% to about 15% by weight of the functional dopant monomer DEA. In some embodiments, the polyacrylamides-based copolymer includes about 15% to about 20% by weight of the functional dopant monomer DEA. In some embodiments, the polyacrylamides-based copolymer includes about 20% to about 26% by weight of the functional dopant monomer DEA.

[0275] In some embodiments, the polyacrylamides-based copolymer includes 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.

[0276] In some embodiments, the polyacrylamides-based copolymer includes MORPH as the water-soluble carrier monomer and about 2% to about 30% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the copolymer includes MORPH and from about 5% to about 30% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the copolymer includes MORPH and about 10% to about 28% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the copolymer includes MORPH and about 5% to about 26% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the copolymer includes MORPH and about 5% to about 10% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the copolymer includes MORPH and about 10% to about 15% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the copolymer includes MORPH and about 15% to about 20% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the copolymer includes MORPH and about 20% to about 25% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the copolymer includes MORPH and about 25% toAttorney Docket No.38821-63329 (008WO) about 30% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the copolymer includes MORPH and about 20% to about 28% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the copolymer includes MORPH and about 21% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the copolymer includes MORPH and about 22% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the copolymer includes MORPH and about 23% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the copolymer includes MORPH and about 24% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the copolymer includes MORPH and about 25% by weight of a functional dopant monomer selected from NIP, PHE and DEA.

[0277] In some embodiments, the polyacrylamides-based copolymer includes MORPH as the water-soluble carrier monomer and 2% to 30% by weight of a functional dopant monomer selected from NIP, PHE and DEA, 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 a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the copolymer includes MORPH and 21% by weight of a functional dopant monomer selected from NIP, PHE and DEA, such as 22, 23%, 24%, or 25% by weight of a functional dopant monomer selected from NIP, PHE and DEA.

[0278] In some embodiments, the polyacrylamide-based copolymer includes MPAM as the water-soluble carrier monomer and about 2% to about 16% by weight of a functional dopant monomer selected from NIP, PHE or DEA. In some embodiments, the polyacrylamide-based copolymer includes MPAM as the water-soluble carrier monomer and about 5% to about 15% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the polyacrylamide-based copolymer includes MPAM as the water-soluble carrier monomer and about 6% to about 10% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the polyacrylamide-based copolymer includes MPAM as the water-soluble carrier monomer and about 7% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the polyacrylamide-based copolymer includes MPAM as the water-soluble carrier monomer and about 8% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the polyacrylamide-based copolymer includes MPAM as the water-Attorney Docket No.38821-63329 (008WO) soluble carrier monomer and about 9% by weight of a functional dopant monomer selected from NIP, PHE and DEA.

[0279] In some embodiments, the polyacrylamide-based copolymer includes MPAM as the water-soluble carrier monomer and 2% to 16% by weight of a functional dopant monomer selected from NIP, PHE and DEA, such as 5% to 15%, or 6% to 10% by weight of a functional dopant monomer selected from NIP, PHE and DEA. In some embodiments, the polyacrylamide-based copolymer includes MPAM as the water-soluble carrier monomer and 7% by weight of a functional dopant monomer selected from NIP, PHE and DEA, such as 8%, or 9% by weight of a functional dopant monomer selected from NIP, PHE and DEA.

[0280] In some embodiments, the polyacrylamide-based copolymer further includes TRI, AMP, TMA, or TBA as a functional dopant monomer. In some embodiments, AMP, TMA, or TBA functional dopant monomer is present at about 2% to about 16% by weight of the copolymer. In some embodiments, TRI, AMP, TMA, or TBA functional dopant monomer is present at about 5% to about 15% by weight of the copolymer. In some embodiments, TRI, AMP, TMA, or TBA functional dopant monomer is present at about 6% to about 14% by weight of the copolymer. In some embodiments, TRI, AMP, TMA, or TBA functional dopant monomer is present at about 12% to about 15% by weight of the copolymer. In some embodiments, TRI, AMP, TMA, or TBA functional dopant monomer is present at about 2% to about 5% by weight of the copolymer. In some embodiments, TRI, AMP, TMA, or TBA functional dopant monomer is present at about 5% to about 10% by weight of the copolymer.

[0281] In some embodiments, the polyacrylamide-based copolymer further includes AMP, TMA, or TBA 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, TRI, AMP, TMA, or TBA functional dopant monomer is present at 2% to 5% by weight of the copolymer. In some embodiments, TRI, AMP, TMA, or TBA functional dopant monomer is present at 5% to 10% by weight of the copolymer.

[0282] In some embodiments, the polyacrylamide-based copolymer includes 70% to 85% by weight of MORPH as the water-soluble carrier monomer and 15% to 30% by weight of NIP as the functional dopant monomer. In some embodiments, the polyacrylamides-based copolymer includes 74% to 80% by weight of MORPH as the water-soluble carrier monomer and 20% to 26% by weight of NIP as the functional dopant monomer. In some embodiments,Attorney Docket No.38821-63329 (008WO) the polyacrylamide-based copolymer includes 70% by weight of MORPH and 30% by weight of NIP. In some embodiments, the polyacrylamide-based copolymer includes 71% by weight of MORPH and 29% by weight of NIP. In some embodiments, the polyacrylamide-based copolymer includes 72% by weight of MORPH and 28% by weight of NIP. In some embodiments, the polyacrylamide-based copolymer includes 73% by weight of MORPH and 27% by weight of NIP. In some embodiments, the polyacrylamide-based copolymer includes 74% by weight of MORPH and 26% by weight of NIP. In some embodiments, the polyacrylamide-based copolymer includes 75% by weight of MORPH and 25% by weight of NIP. In some embodiments, the polyacrylamide-based copolymer includes 76% by weight of MORPH and 24% by weight of NIP. In some embodiments, the polyacrylamide-based copolymer includes 77% by weight of MORPH and 23% by weight of NIP. In some embodiments, the polyacrylamide-based copolymer includes 78% by weight of MORPH and 22% by weight of NIP. In some embodiments, the polyacrylamide-based copolymer includes 79% by weight of MORPH and 21% by weight of NIP. In some embodiments, the polyacrylamide-based copolymer includes 80% by weight of MORPH and 20% by weight of NIP. In some embodiments, the polyacrylamide-based copolymer includes 81% by weight of MORPH and 19% by weight of NIP. In some embodiments, the polyacrylamide-based copolymer includes 82% by weight of MORPH and 18% by weight of NIP. In some embodiments, the polyacrylamide-based copolymer includes 83% by weight of MORPH and 17% by weight of NIP. In some embodiments, the polyacrylamide-based copolymer includes 84% by weight of MORPH and 16% by weight of NIP. In some embodiments, the polyacrylamide-based copolymer includes 85% by weight of MORPH and 15% by weight of NIP.

[0283] In some embodiments, the polyacrylamide-based copolymer includes 70 wt% to 98 wt% of the water-soluble carrier monomer; and 2 wt% to 30 wt% of the functional dopant monomer. In some embodiments, the polyacrylamide-based copolymer includes 80 wt% to of the water-soluble carrier monomer; and 5 wt% to 20 wt% of the functional dopant monomer. In some embodiments, the polyacrylamide-based copolymer includes 83 wt% to 98 wt% of the water-soluble carrier monomer; and 2 wt% to 17 wt% of the functional dopant monomer.

[0284] In some embodiments, the polyacrylamide-based copolymer includes a random copolymer consisting of a water-soluble carrier monomer selected from N-(3-Attorney Docket No.38821-63329 (008WO) methoxypropyl)acrylamide (MPAM) and 4-acryloylmorpholine (MORPH); and a functional dopant monomer that is N-isopropylacrylamide (NIP). In some embodiments, the random copolymer comprises from 10% to 28% by weight of NIP. In some embodiments, the water- soluble carrier monomer is MORPH. In some embodiments, the polyacrylamide-based copolymer comprises 70 wt% to 85 wt% of MORPH; and 15 wt% to 30 wt% of NIP. In some embodiments, the polyacrylamide-based copolymer comprises 74 wt% to 80 wt% of MORPH; and 20 wt% to 26 wt% of NIP.

[0285] 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.

[0286] 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.

[0287] 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 toAttorney Docket No.38821-63329 (008WO) about 4,000 g / mol, about 1,000 g / mol to about 3,000 g / mol, about 2,000 g / mol to about 10,000 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 35,000 g / 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.Attorney Docket No.38821-63329 (008WO) 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. 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, 2,000 g / mol to 10,000 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 to 20,000 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 toAttorney Docket No.38821-63329 (008WO) 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 1,000 g / mol to 20,000 g / mol. In some embodiments, the molecular weight of the copolymer is 1,000 g / mol to 15,000 g / mol. In some embodiments, the molecular weight of the copolymer is 3,000 g / mol to 12,000 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 4,000 g / mol to 8,000 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.

[0288] In some embodiments, the polyacrylamide-based copolymer contains a water-soluble carrier monomer comprising an acrylamide reactive moiety, and a functional dopant monomer (as described herein). In some embodiments, the polyacrylamide-based copolymer includes about 70% to about 98% of a water-soluble carrier monomer with an acrylamide reactive moiety and about 2% to about 30% of a functional dopant monomer. 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 10 to about 250. In some embodiments, the polyacrylamide-based copolymer includes 70% to 98% of a water-soluble carrier monomer with an acrylamide reactive moiety and 2% to 30% of a functional dopant monomer. 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.

[0289] In some embodiments, the polyacrylamide-based copolymer includes 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 NIP, 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, theAttorney Docket No.38821-63329 (008WO) polyacrylamide-based copolymer includes 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 NIP, 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 includes about 77% by weight of the water-soluble carrier monomer MORPH and about 23% by weight of the functional dopant monomer NIP, wherein the number-averaged molecular weight (Mn) of the copolymer is about 3,200 g / mol and the degree of polymerization is about 26.

[0290] In some embodiments, the polyacrylamide-based copolymer includes 70% to 95% by weight of the water-soluble carrier monomer MORPH and 5% to 30% by weight of the functional dopant monomer NIP, 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 includes 74% to 80% by weight of the water-soluble carrier monomer MORPH and 20% to 26% by weight of the functional dopant monomer NIP, 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 includes 77% by weight of the water-soluble carrier monomer MORPH and 23% by weight of the functional dopant monomer NIP, wherein the number-averaged molecular weight (Mn) of the copolymer is 3,200 g / mol and the degree of polymerization is 26.

[0291] In some embodiments, the particles include about 0.01 wt% to about 25 wt% of the polyacrylamide-based copolymer, for example, about 0.01 wt% to about 20 wt%, about 0.01 wt% to about 10 wt%, about 0.01 wt% to about 5 wt%, about 0.1 wt% to about 5 wt%, about 0.2 wt% to about 5 wt%, about 0.3 wt% to about 5 wt%, about 0.4 wt% to about 5 wt%, about 0.5 wt% to about 5 wt%, about 0.6 wt% to about 5 wt%, about 0.7 wt% to about 5 wt%, about 0.8 wt% to about 5 wt%, about 0.9 wt% to about 5 wt%, about 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%, or about 0.1 wt% to about 1 wt% of the polyacrylamide-based copolymer. In some embodiments, the particles includes about 5 wt% of the polyacrylamide-based copolymer.

[0292] In some embodiments, the particles include 0.1 wt% to 25 wt% of the polyacrylamide-based copolymer, for example, 0.1 wt% to 20 wt%, 0.1 wt% to 10 wt%, 0.1Attorney Docket No.38821-63329 (008WO) wt% to 5 wt%, 0.2 wt% to 5 wt%, 0.3 wt% to 5 wt%, 0.4 wt% to 5 wt%, 0.5 wt% to 5 wt%, 0.6 wt% to 5 wt%, 0.7 wt% to 5 wt%, 0.8 wt% to 5 wt%, 0.9 wt% to 5 wt%, 1 wt% to 5 wt%, 0.1 wt% to 4 wt%, 0.1 wt% to 3 wt%, 0.1 wt% to 2 wt%, or 0.1 wt% to 1 wt% of the polyacrylamide-based copolymer. In some embodiments, the particles include 5 wt% to 25 wt% of the polyacrylamide-based copolymer, for example, about 5 wt% to about 10 wt%. In some embodiments, the particles include 5 wt% of the polyacrylamide-based copolymer. 4.1.3. Optional Particle Components

[0293] The pharmaceutical composition of this disclosure can further include one or more additional components, such as excipients. In some embodiments, such additional components, or excipients are formulated into the particles of the composition.

[0294] The term “excipient” refers to a natural or synthetic substance formulated alongside the active biopharmaceutical agent of a composition, included for the purpose of stabilization, bulking, and / or to confer a therapeutic enhancement on the biopharmaceutical agent in the final dosage form, such as facilitating drug absorption, reducing viscosity, enhancing or reducing aqueous or non-aqueous solubility, adjusting tonicity, mitigating injection site discomfort, depressing the freezing point, or enhancing stability. Excipients can also be useful in the manufacturing process, to aid in the handling of the biopharmaceutical agent concerned such as by facilitating powder flowability or non-stick properties, in addition to aiding stability such as prevention of denaturation or aggregation over the expected shelf life.

[0295] The term “pharmaceutically acceptable” ingredient, excipient or component is one that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio.

[0296] Additional components, or excipients, of interest include a variety of materials for modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, color, tonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. Suitable formulation materials include, but are not limited to, amino acids; antimicrobials; antioxidants; buffers (e.g., a phosphate buffer, an acetate buffer, a citrate buffer, a histidine buffer, a TRIS buffer); chelating agents; complexing agents; saccharides (monosaccharides, disaccharides, polysaccharides, and other carbohydrates (e.g., mannitol, sorbitol, sucrose, trehalose, lactose, melibiose, cyclodextrins, stachyose,Attorney Docket No.38821-63329 (008WO) lactosucrose, melezidose, raffinose, inulin, chitosan, alginate, hyaluronan cellulosics, dextrans, alginates, etc.)); synthetic polymers (e.g., polyoxamers, polyvinylalcohol, polyvinylpyrrolidone, pluronics, etc.); emulsifying agents (e.g., polysorbates); salt-forming counterions; preservatives; solvents; sugar alcohols; suspending agents; surfactants or wetting agents; stability enhancing agents; tonicity enhancing agents; delivery vehicles; diluents; other excipients and / or pharmaceutical adjuvants. In accordance with appropriate industry standards, preservatives may also be added. The composition may be formulated as a lyophilizate using appropriate excipient solutions as diluents. Suitable components are nontoxic to recipients at the dosages and concentrations employed. Further examples of components that may be employed in pharmaceutical formulations are presented in Remington’s Pharmaceutical Sciences, 16thEd. (1980) and 20thEd. (2000), Mack Publishing Company, Easton, PA.

[0297] In some embodiments, the composition (e.g., particles) further comprises one or more of stabilizing agent, preservative, filler, bulking agent, sugar, polysaccharide, or viscosity modifier.

[0298] In some embodiments, the composition further comprises a tonicity agent. In some embodiments, the tonicity agent is selected from, but is not limited to, saline, glycerol, propylene glycol, sucrose, and trehalose. In some embodiments, the tonicity agent is saline. In some embodiments, the tonicity agent is glycerol. In some embodiments, the tonicity agent is propylene glycol. In some embodiments, the tonicity agent is sucrose. In some embodiments, the tonicity agent is trehalose.

[0299] In certain embodiments, the particles include a stabilizing agent. In some embodiments, the stabilizing agent is selected from surfactants, poloxamers, povidones, polyvinylpyrrolidone (PVP) polymer, polyvinyl alcohol (PVA) polymer, carbohydrates, polysaccharides (e.g., dextrans, alginates), cellulosics (e.g., hydroxypropyl methyl cellulose (HPMC), methyl cellulose (MC)), amphoteric compounds, salts, amino acids, and combinations thereof.

[0300] In some embodiments, the stabilizing agent is a carbohydrate. In some embodiments, the stabilizing agent is selected from monosaccharide, reduced sugar, disaccharide, cyclodextrin and dextrin. In some embodiments, the carbohydrate is a disaccharide. In some embodiments, the stabilizing agent is selected from, but is not limited to, sucrose, lactose,Attorney Docket No.38821-63329 (008WO) glucose, fructose, arabinose, xylose, ribose, mannose, galactose, dextrose, sorbose, sorbitol, mannitol, maltose, cellobiose, xylitol, trehalose, or a combination thereof. In some embodiments, wherein the disaccharide is selected from lactose, sucrose, trehalose, and cellobiose. In some embodiments, the stabilizing agent is trehalose. In some embodiments, the stabilizing agent is sucrose.

[0301] In some embodiments, the stabilizing agent is a monosaccharide or a reduced sugar. In some embodiments, the stabilizing agent is selected from glucose, mannose, and mannitol.

[0302] In some embodiments, the particles comprise at least 0.5 wt% stabilizing agent (e.g., at least 1 wt%, at least 2 wt%, at least 3 wt%, at least 4 wt%, at least 5 wt%, at least 7.5 wt%, at least 10 wt%, at least 12.5 wt%, at least 14 wt%, at least 16.5 wt%, etc.). In some embodiments, the particles comprise from 0.5 to 25 wt% stabilizing agent, such as from 0.5 to 20 wt%, from 0.5 to 10 wt%, or from 0.5 to 5 wt%.

[0303] In some embodiments, the particles comprise from 5 to 99 wt% stabilizing agent (e.g., from 5 to 25 wt%, from 5 to 20 wt%, from 5 to 15 wt%, or from 10 to 15 wt%, etc.). In some embodiments, the particles comprise75 to 95% stabilizing agent (e.g., from 75 to 80 wt%, from 80 to 85 wt%, from 85 to 90 wt%, from 90 to 95 wt%, or from 95 to 99 wt%.

[0304] In some embodiments, the composition comprises a particular ratio by weight of biopharmaceutical agent to stabilizer in the composition, such as a ratio by weight of 1:2 or higher, or 1:1 or higher. In some embodiments, the ratio by weight of biopharmaceutical agent to stabilizer in the composition is in the range between 20:1 and 1:2, such as in the range between 20:1 and 1:1, 10:1 and 1:1, 9:1 and 1:1, 8:1 and 1:1, 7:1 and 1:1, 6:1 and 1:1, 5:1 and 1:1, 4:1 and 1:1, 3:1 and 1:1, or 2:1 and 1:1. In some embodiments, the ratio by weight of biopharmaceutical agent to stabilizer in the composition is in the range between 1:1000 and 1:50, such as in the range between 1:800 and 1:50, 1:600 and 1:50, 1:400 and 1:50, 1:200 and 1:50, and 1:100 and 1:50. In some embodiments, the ratio by weight of biopharmaceutical agent to stabilizer in the composition is in the range between 1:600 and 1:50, such as in the range between 1:500 and 1:100, 1:400 and 1:100, 1:300 and 1:100, and 1:200 and 1:100.

[0305] In some embodiments, the weight ratio of the biopharmaceutical agent to the polyacrylamide-based copolymer to the stabilizer is 15:1:1 or greater (e.g., 16:1:1 or greater, 17:1:1 or greater, 18:1:1 or greater, 19:1:1 or greater, 20:1:1 or greater, 15:1:2 or greater,Attorney Docket No.38821-63329 (008WO) 16:1:2 or greater, 17:1:2 or greater, 18:1:2 or greater, 19:1:2 or greater, 20:1:2 or greater, 15:1:3 or greater, 16:1:3 or greater, 17:1:3 or greater, 18:1:3 or greater, 19:1:3 or greater, or 20:1:3 or greater). In some embodiments, the weight ratio of the biopharmaceutical agent to the polyacrylamide-based copolymer to the stabilizer is 1:10:100 or greater (e.g., 1:15:100 or greater, 1:20:100 or greater, 1:25:100 or greater, 1:25:200 or greater, 1:25:300 or greater, 1:25:400 or greater, or 1:25:500 or greater).

[0306] In some embodiments, the composition comprises a particular ratio by weight of polyacrylamide-based copolymer to stabilizer in the composition, such as a ratio by weight of 1:5 or higher, such as 1:10 or higher. In some embodiments, the stabilizing agent is a carbohydrate. In some embodiments, the stabilizing agent is trehalose. In some embodiments, the ratio by weight of polyacrylamide-based copolymer to stabilizing agent in the composition is in the range between 1:100 and 1:1, such as in the range between 1:50 and 1:1, 1:30 and 1:1, 1:20 and 1:1, or 1:20 and 1:5. In some embodiments, the polyacrylamide- based copolymer is MoNi.

[0307] In some embodiments, the composition comprises a particular ratio by weight of biopharmaceutical agent to stabilizing agent to polyacrylamide-based copolymer in the solid composition, such as a ratio by weight in the range between 20:20:1 and 1:1:1, such as 10:10:1. In some embodiments, the stabilizing agent is a carbohydrate. In some embodiments, the stabilizing agent is trehalose. In some embodiments, the stabilizing agent is sucrose. In some embodiments, the ratio by weight of biopharmaceutical agent to stabilizing agent to polyacrylamide-based copolymer in the solid composition is in the range between 20:20:1 and 2:2:1, such as in the range between 20:10:1 and 1:1:1, 20:5:1 and 1:1:1, 10:20:1 and 1:1:1, 5:20:1 and 1:1:1, 10:10:1 and 5:5:1, or 20:20:1 to 10:10:1. In some embodiments, the ratio by weight of biopharmaceutical agent to stabilizing agent to polyacrylamide-based copolymer in the solid composition is in the range between 1:1000:100 and 1:50:1, such as in the range between 1:500:100 and 1:50:1, 1:250:100 and 1:50:1, 1:100:50 and 1:50:1, 1:100:10 and 1:50:1, or 1:100:5 and 1:50:1. In some embodiments, the polyacrylamide-based copolymer is MoNi.

[0308] In some embodiments, the stabilizing agent is an amino acid (e.g., naturally occurring or non-naturally occurring). In some embodiments, the amino acid is selected from arginine, histidine, isoleucine, leucine, glutamic acid, glycine, methionine, phenylalanine, proline, tryptophan and tyrosine. In some embodiments, the amino acid is arginine. In someAttorney Docket No.38821-63329 (008WO) embodiments, the amino acid is glycine, histidine, or proline. In some embodiments, the amino acid is histidine. In some embodiments, the amino acid is glycine. In some embodiments, the amino acid is proline. In some embodiments, the amino acid is isoleucine.

[0309] In some embodiments, the ratio by weight of biopharmaceutical agent to amino acid to stabilizing agent to polyacrylamide-based copolymer in the solid composition is in the range between 20:20:1:1 and 2:2:1:1, such as in the range between 20:10:1:1 and 2:2:1:1, 20:5:1:1 and 2:2:1:1, and 20:1:1:1 and 2:2:1:1. In some embodiments, the polyacrylamide- based copolymer is MoNi. In some embodiments, the amino acid is glycine. In some embodiments, the amino acid is isoleucine.

[0310] In some embodiments, the particles comprise less than 5 wt% amino acid stabilizer (e.g., less than 4 wt%, less than 3 wt%, less than 2 wt%, or less than 1 wt%). In some embodiments, the particles comprise less than 1 wt% amino acid stabilizer (e.g., from 0.1 to 1 wt%, from 0.1 to 0.8 wt%, ofrom 0.1 to 0.6 wt%, from 0.1 to 0.4 wt%, or from 0.1 to 0.2 wt%).

[0311] In some embodiments, the composition comprises an antioxidant. In some embodiments, the antioxidant is selected from, but is not limited to methionine, carotenes (e.g., beta carotene), ascorbates (e.g., vitamin C, ascorbic acid), tocopherols (e.g., vitamin E), tocotrienols, ascorbic acid, fumaric acid, maleic acid, sodium edetate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), thiols (e.g., glutathione), polyphenols (e.g., resveratrol), sodium metabisulfite, and citric acid. In some embodiments, the ratio by weight of polyacrylamide-based copolymer to antioxidant in the composition is in the range between 1:100 and 1:1, such as in the range between 1:50 and 1:1, 1:30 and 1:1, 1:20 and 1:1, or 1:20 and 1:5. In some embodiments, the polyacrylamide-based copolymer is MoNi.

[0312] In some embodiments, the composition further comprises one or more of solubilizing agent, permeation enhancer, buffering agent, pH regulator, surfactant, lipid, preservative, filler, bulking agent, or viscosity modifier.

[0313] In some embodiments, the composition further comprises a tonicity agent. In some embodiments, the tonicity agent is selected from saline, glycerol, and propylene glycol.

[0314] In some embodiments, the composition is biodegradable.Attorney Docket No.38821-63329 (008WO) 4.2. Solid Compositions of Particles

[0315] Also provided are solid pharmaceutical compositions containing a plurality of particles that include the biopharmaceutical agent. Described herein is a solid composition comprising a plurality of particles, the particles comprising 90 wt% or more of a biopharmaceutical agent. In some embodiments, the particles compriseor less of the polyacrylamide-based copolymer. In some embodiments, the particles consist of 90 wt% or more of a biopharmaceutical agent, 5 wt% or less of a polyacrylamide-based copolymer; and 5 wt% or less of an optional aqueous component. In some embodiments, the aqueous component optionally includes a buffer. In some embodiments, the buffer is an acetate buffer. In some embodiments, the buffer is a citrate buffer. In some embodiments, the buffer is a histidine buffer. In some embodiments, the buffer is a phosphate buffer. In some embodiments, the buffer is a TRIS buffer.

[0316] In some embodiments, a solid composition comprising a plurality of particles is provided wherein the particles comprise a weight ratio of a biopharmaceutical agent to a polyacrylamide-based copolymer of 10:1 or greater. In some embodiments, the weight ratio of the biopharmaceutical agent to the polyacrylamide-based copolymer is 11:1 or greater (e.g., 12:1 or greater, 13:1 or greater, 14:1 or greater, 15:1 or greater, 16:1 or greater, 17:1 or greater, 18:1 or greater, 19:1 or greater, 20:1 or greater, 21:1 or greater, 22:1 or greater, 23:1 or greater, 24:1 or greater, or 25:1 or greater).

[0317] In some embodiments, the composition is a spray dried powder. In some embodiments, the spray dried powder is a vacuum dried powder.

[0318] In some embodiments, the composition includes 91 wt% or more (e.g., 92 wt% or more, 93 wt% or more, 94 wt% or more, 95 wt% or more, 96 wt% or more, 97 wt% or more, 98 wt% or more, or 99 wt% or more) of the biopharmaceutical agent in a particle. In certain embodiments, the biopharmaceutical agent is 95 wt % or more of the particles.

[0319] In some embodiments, the composition includes 4.5 wt% or less (e.g., 4 wt% or less, 3.5 wt% or less, 3 wt% or less, 2.5 wt% or less, 2 wt% or less, 1.5 wt% or less, or 1 wt% or less) of the polyacrylamide-based copolymer in a particle.Attorney Docket No.38821-63329 (008WO)

[0320] In some embodiments, the composition has ratio of the polyacrylamide-based copolymer to the biopharmaceutical agent in the particles that is 5:95 or less (e.g., 4:96 or less, 3:97 or less, 2:98 or less, or 1:99 or less).

[0321] In some embodiments, the composition is storage stable.

[0322] In some embodiments, there is provided a storage stable solid composition comprising a plurality of particles, the particles comprising: a biopharmaceutical agent (e.g., as described herein); a polyacrylamide-based copolymer (e.g., as described herein); and a stabilizer (e.g., as described herein).

[0323] In some embodiments, the weight ratio of the biopharmaceutical agent to the polyacrylamide-based copolymer to the stabilizer is 15:1:1 or greater (e.g., 16:1:1 or greater, 17:1:1 or greater, 18:1:1 or greater, 19:1:1 or greater, 20:1:1 or greater, 15:1:2 or greater, 16:1:2 or greater, 17:1:2 or greater, 18:1:2 or greater, 19:1:2 or greater, 20:1:2 or greater, 15:1:3 or greater, 16:1:3 or greater, 17:1:3 or greater, 18:1:3 or greater, 19:1:3 or greater, or 20:1:3 or greater). 4.3. Injectable Compositions of Particles

[0324] Also provided are injectable pharmaceutical compositions containing a suspension of the particles described in the present disclosure in a liquid carrier. Described herein are exemplary components of the particles, and methods of making particles which are utilized in the pharmaceutical compositions suitable for injection. Also described are the components of the injectable pharmaceutical compositions, other than the particles, such as the liquid carrier. It is understood that the components of the compositions can be described in terms of their content in the solid particles, and / or in reference to their content in the final injectable pharmaceutical compositions, which includes both an amount of the solid particles and an amount of the liquid carrier. In some embodiments, the injectable pharmaceutical composition includes a solid composition as described herein. In some embodiments, the injectable pharmaceutical composition includes a spray-dried solid composition.Attorney Docket No.38821-63329 (008WO)

[0325] In some embodiments, the composition comprises a 3:1 to 1:3 weight to weight ratio of the liquid carrier to the particles (e.g., 2:1, 1:1, or 1:2).

[0326] In some embodiments, the composition that contains suspended particles of the present disclosure has a copolymer concentration of about 0.01% to about 10% by weight of the composition, such as about 0.01% to about 5% by weight of the composition. In some embodiments, the copolymer concentration is about 0.1% to about 5% by weight of the composition.

[0327] In some embodiments, the composition that contains suspended particles of the present disclosure has about 20 wt% or more, for example, about 25 wt% or more, about 30 wt% or more, about 40 wt% or more, about 50 wt% or more, about 60 wt% or more, about 65 wt% or more, about 70 wt% or more, about 75 wt% or more, about 80 wt% or more, about 85 wt% or more, about 90 wt% or more, about 95 wt% or more of the biopharmaceutical agent. In some embodiments, the composition includes about 20 wt% to 65 wt% of the biopharmaceutical agent, for example, about 40 wt% to 65 wt%, or 35 wt% to 50 wt% of the biopharmaceutical agent. In some embodiments, the particles of the present disclosure contain 90 wt% or more of a biopharmaceutical agent. In some embodiments, the particles of the present disclosure contain 91 wt% or more (e.g., 92 wt% or more, 93 wt% or more, 94 wt% or more, 95 wt% or more, 96 wt% or more, 97 wt% or more, 98 wt% or more, or 99 wt% or more) of the biopharmaceutical agent. In some embodiments, the particles contain 95 wt% or more of the biopharmaceutical agent.

[0328] In some embodiments, the composition that contains suspended particles of the present disclosure has 20 wt% or more, for example, 25 wt% or more, 30 wt% or more, 40 wt% or more, 50 wt% or more, 60 wt% or more, 65 wt% or more, 70 wt% or more, 75 wt% or more, 80 wt% or more, 85 wt% or more, 90 wt% or more, 95 wt% or more of the biopharmaceutical agent. In some embodiments, the composition includes 20 wt% to 80 wt% of the biopharmaceutical agent, for example, 35 wt% to 80 wt%, such as 40 wt% to 65 wt%, or 35 wt% to 50 wt% of the biopharmaceutical agent.

[0329] In some embodiments, the biopharmaceutical agent is an antibody.

[0330] In some embodiments, the suspended particles contain an antibody. In some embodiments, the antibody is a monoclonal antibody or fragment thereof. In some embodiments, the composition has an antibody concentration of about 20 wt% or more, forAttorney Docket No.38821-63329 (008WO) example, about 25 wt% or more, about 30 wt% or more, about 40 wt% or more, about 50 wt% or more, about 60 wt% or more, about 65 wt% or more, about 70 wt% or more, about 75 wt% or more, about 80 wt% or more, about 85 wt% or more, about 90 wt% or more, about 95 wt% or more of the antibody. In some embodiments, the composition includes about 20 wt% to 65 wt% of the antibody, for example, about 40 wt% to 65 wt%, or 35 wt% to 50 wt% of the antibody.

[0331] In some embodiments, the composition has 20 wt% or more, for example, 25 wt% or more, 30 wt% or more, 40 wt% or more, 50 wt% or more, 60 wt% or more, 65 wt% or more, 70 wt% or more, 75 wt% or more, 80 wt% or more, 85 wt% or more, 90 wt% or more, 95 wt% or more of an antibody or fragment thereof. In some embodiments, the composition includes 20 wt% to 80 wt% of the biopharmaceutical agent, for example, 35 wt% to 80 wt%, 40 wt% to 65 wt%, or 35 wt% to 50 wt% of the antibody.

[0332] In some embodiments, the composition that contains suspended particles of the present disclosure has no more than 20 wt% of the biopharmaceutical agent, for example, no more than 15 wt%, no more than 10 wt%, no more than 9 wt%, no more than 8 wt%, no more than 7 wt%, no more than 6 wt%, no more than 5 wt%, no more than 4 wt%, no more than 3 wt%, no more than 2 wt%, or no more than 1 wt% of the biopharmaceutical agent. In some embodiments, the composition includes 0.1 wt% to 20 wt% of the biopharmaceutical agent, for example 0.1 wt% to about 10 wt%, or 0.1 wt% to about 5 wt%. In some embodiments, the composition includes 1 wt% to 20 wt% of the biopharmaceutical agent, for example 1 wt% to 10 wt%.

[0333] In some embodiments, the biopharmaceutical agent is a peptide or peptide analogue.

[0334] In some embodiments, the suspended particles contain insulin or an analog thereof. In some embodiments, the composition includes about 1 wt% to about 20 wt%, about 1 wt% to about 15 wt%, about 1 wt% to about 10 wt%, about 1 wt% to about 9 wt%, about 1 wt% to about 8 wt% of the insulin or the analog thereof. In some embodiments, the composition includes about 7 wt%, about 8 wt%, about 9 wt%, or about 10 wt% of the insulin or the analog thereof. In some embodiments, the composition includes 1 wt% to 20 wt%, 1 wt% to 15 wt%, 1 wt% to 10 wt%, 1 wt% to 9 wt%, or 1 wt% to 8 wt% of the insulin or the analog thereof. In some embodiments, the composition includes 7 wt%, 8 wt%, 9 wt%, or 10 wt% of the insulin or the analog thereof.Attorney Docket No.38821-63329 (008WO)

[0335] In some embodiments, the concentration of the insulin or the insulin analog in the composition is about U50 (that is, 50 U / mL) to about U1000, about U50 to about U500, about U50 to about U200, about U50 to about U100, about U100 to about U500, or about U100 to about U200. In some embodiments, the concentration of the insulin or the insulin analog in the composition is about U50, about U100, about U200, about U500, or about U1000. In some embodiments, the composition includes about 1.7 mg / mL to about 17.5 mg / mL, about 1.7 mg / mL to about 7 mg / mL, about 1.7 mg / mL to about 3.5 mg / mL, about 3.5 wt% to about 17.5 mg / mL, or about 3.5 mg / mL to about 7 mg / mL of the insulin or the analog thereof. In some embodiments, the composition includes about 1.7 mg / mL, about 3.5 mg / mL, about 7 mg / mL, or about 17.5 mg / mL of the insulin or the analog thereof. In some embodiments, the concentration of the insulin or the insulin analog in the composition is U50 (that is, 50 U / mL) to U500, U50 to U200, U50 to U100, U100 to U500, or U100 to U200. In some embodiments, the concentration of the insulin or the insulin analog in the composition is U50, U100, U200, or U500. In some embodiments, the composition includes 1.7 mg / mL to 17.5 mg / mL, 1.7 mg / mL to 7 mg / mL, 1.7 mg / mL to 3.5 mg / mL, 3.5 mg / mL to 17.5 mg / mL, or 3.5 mg / mL to 7 mg / mL of the insulin or the analog thereof. In some embodiments, the composition includes 1.7 mg / mL, 3.5 mg / mL, 7 mg / mL, or 17.5 mg / mL of the insulin or the analog thereof.

[0336] In some embodiments, the suspended particles comprise a co-formulation of particles comprising biopharmaceutical agents. In some embodiments the suspended particles comprise a co-formulation of a first batch of particles comprising a biopharmaceutical agent that is insulin or an insulin analog, and a second batch of particles biopharmaceutical agent that is a peptide or a peptide analog. In some embodiments, the suspended particles comprise a co-formulation of particles comprising insulin or an insulin analog, and particles comprising pramlintide. In some embodiments, the composition includes 1.0 mg / mL to 35 mg / mL, 1.0 mg / mL to 17.5 mL, 1.0 mg / mL to 7.0 mg / mL, 1.5 mg / mL to 5.0 mg / mL, 2.0 mg / mL to 5.0 mg / mL, 2.5 mg / mL to 4.5 mg / mL, or 3.0 mg / mL to 4.0 mg / mL of the insulin or the analog thereof; and 0.2 mg / mL to 2.0 mg / mL, 0.2 mg / mL to 1.5 mg / mL, 0.2 mg / mL to 1.0 mg / mL, 0.2 mg / mL to 1.2 mg / mL, 0.5 mg / mL to 1.0 mg / mL, or 0.6 mg / mL to 0.9 mg / mL of the pramlintide. In some embodiments, the composition includes 1.5 mg / mL, 3.5 mg / mL, 5 mg / mL, 7 mg / mL, 17.5 mg / mL or 35 mg / mL of the insulin or the analog thereof; and 0.2, 0.5, 0.6, 0.8, 1.0, or 1.2 mg / mL of pramlintide.Attorney Docket No.38821-63329 (008WO)

[0337] In some embodiments, the composition includes a 1:500 to 1:1 weight to weight ratio of the polyacrylamide-based copolymer to the biopharmaceutical agent.

[0338] In some embodiments, the composition includes a 1:10 to 1:2 weight to weight ratio (e.g., a 1:5 weight to weight ratio) of the polyacrylamide-based copolymer to the biopharmaceutical agent.

[0339] In some embodiments, the composition includes a 1:25 to 1:15 weight to weight ratio (e.g., a 1:20 weight to weight ratio) of the polyacrylamide-based copolymer to the biopharmaceutical agent.

[0340] In some embodiments, the composition includes a 1:10 weight to weight ratio of the polyacrylamide-based copolymer to the biopharmaceutical agent.

[0341] In some embodiments, the composition includes 400 to 800 mg / mL of the biopharmaceutical agent (e.g., 425 to 800 mg / mL, 450 to 800 mg / mL, 475 to 800 mg / mL, 500 to 800 mg / mL, 525 to 800 mg / mL, 550 to 800 mg / mL, 575 to 800 mg / mL, 600 to 800 mg / mL, 625 to 800 mg / mL, 650 to 800 mg / mL, 675 to 800 mg / mL, 700 to 800 mg / mL, 750 to 800 mg / mL, 425 to 800 mg / mL, 775 to 800 mg / mL, 425 to 750 mg / mL, 450 to 750 mg / mL, 475 to 750 mg / mL, 500 to 750 mg / mL, 525 to 750 mg / mL, 550 to 750 mg / mL, 575 to 750 mg / mL, 600 to 750 mg / mL, 625 to 750 mg / mL, 650 to 750 mg / mL, 675 to 750 mg / mL, 700 to 750 mg / mL, 725 to 750 mg / mL, 425 to 700 mg / mL, 450 to 700 mg / mL, 475 to 700 mg / mL, 500 to 700 mg / mL, 525 to 700 mg / mL, 550 to 700 mg / mL, 575 to 700 mg / mL, 600 to 700 mg / mL, 625 to 700 mg / mL, 650 to 700 mg / mL, 675 to 700 mg / mL, 425 to 650 mg / mL, 450 to 650 mg / mL, 475 to 650 mg / mL, 500 to 650 mg / mL, 525 to 650 mg / mL, 550 to 650 mg / mL, 575 to 650 mg / mL, 600 to 650 mg / mL, 625 to 650 mg / mL, 400 to 600 mg / mL, 425 to 600 mg / mL, 450 to 600 mg / mL, 475 to 600 mg / mL, 500 to 600 mg / mL, 525 to 600 mg / mL, 550 to 600 mg / mL, 575 to 600 mg / mL, 400 to 550 mg / mL, 425 to 550 mg / mL, 450 to 550 mg / mL, 475 to 550 mg / mL, 500 to 550 mg / mL, 525 to 550 mg / mL, 400 to 500 mg / mL, 425 to 500 mg / mL, 450 to 500 mg / mL, 475 to 500 mg / mL, 400 to 450 mg / mL, or 425 to 450 mg / mL). In some embodiments, the composition includes at least 500 mg / mL of the biopharmaceutical agent.

[0342] In some embodiments, the composition includes at least 510 mg / mL (e.g., at least 520 mg / mL, at least 530 mg / mL, at least 540 mg / mL, at least 550 mg / mL, at least 560 mg / mL, at least 570 mg / mL, at least 580 mg / mL, at least 590 mg / mL, at least 600 mg / mL, at least 610Attorney Docket No.38821-63329 (008WO) mg / mL, at least 620 mg / mL, at least 630 mg / mL, at least 640 mg / mL, or at least 650 mg / mL) of the biopharmaceutical agent.

[0343] In some embodiments, the composition is injectable with a glide force of 500 to 8000 g (e.g., 1000 to 8000 g, 1500 to 8000 g, 2000 to 8000 g, 2500 to 8000 g, 3000 to 8000 g, 3500 to 8000 g, 4000 to 8000 g, 4500 to 8000 g, 5000 to 8000 g, 5500 to 8000 g, 6000 to 8000 g, 6500 to 8000 g, 7000 to 8000 g, 7500 to 8000 g, 1000 to 7500 g, 1500 to 7500 g, 2000 to 7500 g, 2500 to 7500 g, 3000 to 7500 g, 3500 to 7500 g, 4000 to 7500 g, 4500 to 7500 g, 5000 to 7500 g, 5500 to 7500 g, 6000 to 7500 g, 6500 to 7500 g, 7000 to 7500 g, 1000 to 7000 g, 1500 to 7000 g, 2000 to 7000 g, 2500 to 7000 g, 3000 to 7000 g, 3500 to 7000 g, 4000 to 7000 g, 4500 to 7000 g, 5000 to 7000 g, 5500 to 7000 g, 6000 to 7000 g, 6500 to 7000 g, 1000 to 6500 g, 1500 to 6500 g, 2000 to 6500 g, 2500 to 6500 g, 3000 to 6500 g, 3500 to 6500 g, 4000 to 6500 g, 4500 to 6500 g, 5000 to 6500 g, 5500 to 6500 g, 6000 to 6500 g, 1000 to 6000 g, 1500 to 6000 g, 2000 to 6000 g, 2500 to 6000 g, 3000 to 6000 g, 3500 to 6000 g, 4000 to 6000 g, 4500 to 6000 g, 5000 to 6000 g, 5500 to 6000 g, 1000 to 5500 g, 1500 to 5500 g, 2000 to 5500 g, 2500 to 5500 g, 3000 to 5500 g, 3500 to 5500 g, 4000 to 5500 g, 4500 to 5500 g, 5000 to 5500 g, 1000 to 5000 g, 1500 to 5000 g, 2000 to 5000 g, 2500 to 5000 g, 3000 to 5000 g, 3500 to 5000 g, 4000 to 5000 g, 4500 to 5000 g, 1000 to 4500 g, 1500 to 4500 g, 2000 to 4500 g, 2500 to 4500 g, 3000 to 4500 g, 3500 to 4500 g, 4000 to 4500 g, 1000 to 4000 g, 1500 to 4000 g, 2000 to 4000 g, 2500 to 4000 g, 3000 to 4000 g, 3500 to 4000 g, 1000 to 3500 g, 1500 to 3500 g, 2000 to 3500 g, 2500 to 3500 g, 3000 to 3500 g, 1000 to 3000 g, 1500 to 3000 g, 2000 to 3000 g, 2500 to 3000 g, 1000 to 2500 g, 1500 to 2500 g, 2000 to 2500 g, 1000 to 2000 g, 1500 to 2000 g, or 1000 to 1500 g).

[0344] In some embodiments, the composition comprises 500 to 750 mg / mL (e.g., 500 to 700 mg / mL, 550 to 700 mg / mL, 600 to 700 mg / mL, 650 to 700 mg / mL, 500 to 650 mg / mL, 550 to 650 mg / mL, 600 to 650 mg / mL, 500 to 600 mg / mL, 550 to 600 mg / mL, or 500 to 550 mg / mL) of the biopharmaceutical agent. In some embodiments, the composition is injectable with a glide force of 1000 to 4500 g (e.g., 1000 to 4000 g, 1500 to 4000 g, 2000 to 4000 g, 2500 to 4000 g, 3000 to 4000 g, 3500 to 4000 g, 1000 to 3500 g, 1500 to 3500 g, 2000 to 3500 g, 3000 to 3500 g, 1000 to 3000 g, 1500 to 3000 g, 2000 to 3000 g, 2500 to 3000 g, 1000 to 2500 g, 1500 to 2500 g, 2000 to 2500 g, 1000 to 2000 g, 1500 to 2000 g, or 1000 to 1500 g).Attorney Docket No.38821-63329 (008WO)

[0345] In some embodiments, the composition is formulated for injection at a rate of 1 mL / min or more (e.g., 2 mL / min or more, 3 mL / min or more, 4 mL / min or more, 5 mL / min or more, 6 mL / min or more, 7 mL / min or more, 8 mL / min or more, 9 mL / min or more, or 10 mL / min or more). In some embodiments, the composition is formulated for injection at a rate of 5 mL / min or more (e.g., 4 mL / min or more, 6 mL / min or more, 6 mL / min or more, or 7 mL / min or more). In some embodiments, the composition is formulated for injection through a 27 G needle. In some embodiments, the needle is ultra-thin walled. In some embodiments, the needle is a ½'' staked needle. In some embodiments, the needle is a 1 mL long needle. In some embodiments, the needle is a glass needle. In some embodiments, the position is formulated for injection through a glass syringe with a staked, 27 G ultra thin-walled, ½'' needle with an injection force of 50 N or less.

[0346] In some embodiments, the composition is formulated for injection with an injection force of 50 N or less, such as 45 N or less, 40 N or less, 35 N or less, 30 N or less, 25 N or less, or 20 N or less.

[0347] In some embodiments, the injection force of a suspension may be dependent on total solids fraction. In some embodiments, the injection force of a suspension is dependent on total solids fraction rather than particle composition when suspensions contain particles with similar morphology. In some embodiments, a suspension including total solids fraction of 0.4 or greater, such as 0.5 or greater, 0.6 or greater, or 0.7 or greater, exhibits the injection force of 9000 gf or less, such as 8000 gf or less, 7000 gf or less, 6000 gf or less, 5000 gf or less, 4000 gf or less, 3000 gf or less, 2000 gf or less, or 1000 gf or less.

[0348] In some embodiments, a suspension with a solids concentration of 400 mg / ml or greater, such as 500 mg / ml or greater, 600 mg / ml or greater, or 700 mg / ml or greater, exhibits injection force of 9000 gf or less, such as 8000 gf or less, 7000 gf or less, 6000 gf or less, 5000 gf or less, 4000 gf or less, 3000 gf or less, 2000 gf or less, or 1000 gf or less.

[0349] In some embodiments, the injection force may be fit to a particle jamming model. The jamming model considers the injection force of the pure non-solvent, the intrinsic viscosity which is dictated by particle morphology (shape / roughness / compressibility), and the maximum solids faction prior to jamming.

[0350] In some embodiments, a sugar may be added to a formulation to alter the injection force. In some embodiments, the sugar is trehalose.Attorney Docket No.38821-63329 (008WO)

[0351] In some embodiments, an amino acid may be further added to a formulation to alter the injection force. In some embodiments, the amino acid is glycine. In some embodiments, the amino acid is isoleucine.

[0352] In some embodiments, formulations with matched solids content but varied sugar and amino acid composition may show comparable injection force.

[0353] In some embodiments, injection force of a suspension may be dependent on non- solvent carrier fluid. In some embodiments, the non-solvent carrier fluid is selected from ethyl oleate, benzyl benzoate, and Miglyol 840.

[0354] In some embodiments, the non-solvent carrier fluid is ethyl oleate. In some embodiments, a suspension including a total solids fraction of 0.40 or greater, such as 0.50 or greater, or 0.60 or greater, exhibits an injection force of 2500 gf or less, such as 2000 gf or less, 1500 gf or less, 1000 gf or less, or 500 gf or less.

[0355] In some embodiments, the non-solvent carrier fluid is benzyl benzoate. In some embodiments, a suspension including a total solids fraction of 0.40 or greater, such as 0.50 or greater, or 0.60 or greater, exhibits an injection force of 3500 gf or less, such as 3000 gf or less, such as 2500 gf or less, such as 2000 gf or less, 1500 gf or less, 1000 gf or less, or 500 gf or less.

[0356] In some embodiments, the non-solvent carrier fluid is Miglyol 840. In some embodiments, a suspension including a total solids fraction of 0.40 or greater, such as 0.50 or greater, or 0.60 or greater, exhibits an injection force of 4000 gf or less, such as 3500 gf or less, such as 3000 gf or less, such as 2500 gf or less, such as 2000 gf or less, 1500 gf or less, 1000 gf or less, or 500 gf or less.

[0357] In some embodiments, a formulation of a suspension with a non-solvent with a lower viscosity may result in a suspension with a lower glide force.

[0358] In some embodiments, a combination of non-solvent carrier fluids may be used. In some embodiments, a combination of benzyl benzoate and ethyl oleate may be used. In some embodiments, a combination of Miglyol 840 and ethyl oleate may be used.

[0359] In some embodiments, a low viscosity non-solvent may be added to a higher viscosity non-solvent. In some embodiments, the fraction of the low viscosity non-solvent is 0.5 orAttorney Docket No.38821-63329 (008WO) less, such as 0.4 or less, 0.3 or less, 0.2 or less, or 0.1 or less. In some embodiments, a glide force may decrease with addition of the low viscosity non-solvent to the higher viscosity non- solvent.

[0360] In some embodiments, the injection force of a suspension is dependent on a flow rate. In some embodiments, the dependence is linear. In some embodiments, the injection force through a 1 ml syringe in ethyl oleate at 8 ml / min or less is 20 N or less, such as 15 N or less, 10 N or less, or 5N or less. In some embodiments, the injection force through a 5 ml syringe in ethyl oleate at 8 ml / min or less is 40 N or less, such as 35 N or less, such as 30 N or less, such as 20 N or less, such as 15 N or less, 10 N or less, or 5N or less.

[0361] In some embodiments, the injection force of a suspension may be dependent on syringe barrel dimensions. In some embodiments, the injection force of a suspension may scale with syringe barrel dimensions. In some embodiments, the injection force of a suspension may scale at least 1.5 times or more with syringe barrel dimensions.

[0362] In some embodiments, an inner diameter of a syringe is 5 mm or more, such as 6.35 mm or 8.65 mm. In some embodiments, a cross-sectional area of a syringe is at least 30 mm2, such as 31.67 mm2 or 58.77 mm2.

[0363] In some embodiments, the injectable pharmaceutical composition comprises a plurality of particles and a liquid carrier in which the particles are suspended, wherein the particles comprise 95 wt% (e.g., 96 wt%, 97 wt%, 98 wt%, or 99%) or more of a biopharmaceutical agent. In some embodiments, the injectable pharmaceutical composition further comprises a polyacrylamide-based copolymer. In some embodiments, the composition comprises at least 500 mg / mL (e.g., at least 510 mg / mL, at least 520 mg / mL, at least 530 mg / mL, at least 540 mg / mL, at least 550 mg / mL, at least 560 mg / mL, at least 570 mg / mL, at least 580 mg / mL, at least 590 mg / mL, at least 600 mg / mL, at least 610 mg / mL, at least 620 mg / mL, at least 630 mg / mL, at least 640 mg / mL, or at least 650 mg / mL) of the biopharmaceutical agent.

[0364] In some embodiments, the injectable pharmaceutical composition comprises a plurality of particles and a liquid carrier in which the particles are suspended, wherein the particles comprise 70 wt% (e.g., 75 wt%, 80 wt%, 85 wt%, or 90%) or more of a biopharmaceutical agent. In some embodiments, the injectable pharmaceutical composition further comprises an optional polyacrylamide-based copolymer. In some embodiments, theAttorney Docket No.38821-63329 (008WO) injectable pharmaceutical composition further comprises an optional stabilizing agent. In some embodiments, the injectable pharmaceutical composition comprises at least 500 mg / mL (e.g., at least 510 mg / mL, at least 520 mg / mL, at least 530 mg / mL, at least 540 mg / mL, at least 550 mg / mL, at least 560 mg / mL, at least 570 mg / mL, at least 580 mg / mL, at least 590 mg / mL, at least 600 mg / mL, at least 610 mg / mL, at least 620 mg / mL, at least 630 mg / mL, at least 640 mg / mL, or at least 650 mg / mL) of the biopharmaceutical agent.

[0365] In some embodiments, the injectable pharmaceutical composition includes a plurality of particles and a liquid carrier in which the particles are suspended, wherein the particles include: 95 wt% or more (e.g., 96 wt% or more, 97 wt% or more, 98 wt% or more, or 99 wt% or more) of a biopharmaceutical agent; and an optional polyacrylamide-based copolymer; and the composition includes at least 500 mg / mL of the biopharmaceutical agent (e.g., at least 510 mg / mL, at least 520 mg / mL, at least 530 mg / mL, at least 540 mg / mL, at least 550 mg / mL, at least 560 mg / mL, at least 570 mg / mL, at least 580 mg / mL, at least 590 mg / mL, at least 600 mg / mL, at least 610 mg / mL, at least 620 mg / mL, at least 630 mg / mL, at least 640 mg / mL, or at least 650 mg / mL of the biopharmaceutical agent). In some embodiments, the particles include the polyacrylamide-based copolymer.

[0366] In some embodiments, the injectable pharmaceutical composition includes a plurality of particles and a liquid carrier in which the particles are suspended, wherein the particles include: 95 wt% or more (e.g., 96 wt% or more, 97 wt% or more, 98 wt% or more, or 99 wt% or more) of a biopharmaceutical agent; and an optional polyacrylamide-based copolymer; and the composition includes at least 500 mg / mL of the biopharmaceutical agent (e.g., at least 510 mg / mL, at least 520 mg / mL, at least 530 mg / mL, at least 540 mg / mL, at least 550 mg / mL, at least 560 mg / mL, at least 570 mg / mL, at least 580 mg / mL, at least 590 mg / mL, at least 600 mg / mL, at least 610 mg / mL, at least 620 mg / mL, at least 630 mg / mL, at least 640 mg / mL, or at least 650 mg / mL of the biopharmaceutical agent); and the composition is formulated for injection at a rate of 6 mL / min with an injection force of 50 N or less, such as 45 N or less, 40 N or less, 35 N or less, 30 N or less, 25 N or less, or 20 N or less. In some embodiments, the particles include the polyacrylamide-based copolymer. In some embodiments, the injection rate of 6mL / min is via injection through a 18Attorney Docket No.38821-63329 (008WO) to 32 Gauge (G) ultra-thin walled needle, such as a 22G, 24G, 25G, 26G, 27G, 30G, or 32G needle.

[0367] In some embodiments, the injectable pharmaceutical composition includes a plurality of particles and a liquid carrier in which the particles are suspended, wherein the particles include: 95 wt% or more (e.g., 96 wt% or more, 97 wt% or more, 98 wt% or more, or 99 wt% or more) of a biopharmaceutical agent; and 5 wt% or less (e.g., 4.5 wt% or less, 4 wt% or less, 3.5 wt% or less, 3 wt% or less, 2.5 wt% or less, 2 wt% or less, 1.5 wt% or less, or 1 wt% or less) of a polyacrylamide-based copolymer; and the composition includes at least 500 mg / mL of the biopharmaceutical agent (e.g., at least 510 mg / mL, at least 520 mg / mL, at least 530 mg / mL, at least 540 mg / mL, at least 550 mg / mL, at least 560 mg / mL, at least 570 mg / mL, at least 580 mg / mL, at least 590 mg / mL, at least 600 mg / mL, at least 610 mg / mL, at least 620 mg / mL, at least 630 mg / mL, at least 640 mg / mL, or at least 650 mg / mL of the biopharmaceutical agent); and the composition is formulated for injection at a rate of 6 mL / min with an injection force of 50 N or less, such as 45 N or less, 40 N or less, 35 N or less, 30 N or less, 25 N or less, or 20 N or less, where the injection rate of 6mL / min is via injection through a glass syringe with 27 Gauge (G) x 1 / 2inch ultra-thin walled staked needle.

[0368] In some embodiments, the injectable pharmaceutical composition comprises a polyacrylamide-based copolymer and a biopharmaceutical agent that is an enzyme. In some embodiments, the injectable pharmaceutical composition further includes hyaluronidase. In some embodiments, the enzyme is hyaluronidase. In some embodiments, the copolymer comprises 77 wt% of MORPH and 23 wt% of NIP.

[0369] In some embodiments, the injectable pharmaceutical composition comprises a polyacrylamide-based copolymer and a biopharmaceutical agent that is an enzyme, wherein the copolymer comprises 77 wt% of MORPH and 23 wt% of NIP, and the injectable pharmaceutical composition further includes hyaluronidase. In another embodiment, the injectable pharmaceutical composition comprises a polyacrylamide-based copolymer and a biopharmaceutical agent that hyaluronidase, wherein the copolymer comprises 77 wt% of MORPH and 23 wt% of NIP.Attorney Docket No.38821-63329 (008WO)

[0370] In some embodiments, the injectable pharmaceutical composition is storage stable. In some embodiments, the injectable pharmaceutical composition demonstrates less than 10 mol % (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) degradation of the bioactivity of the biopharmaceutical agent after storage at 2-8oC for 4 weeks or longer (e.g., 3, 6, or 12 months). In some embodiments, the injectable pharmaceutical composition demonstrates less than 10 mol % (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) degradation of the bioactivity of the biopharmaceutical agent after storage at ambient conditions for 4 weeks or longer (e.g., 3, 6, or 12 months). In some embodiments, storage at ambient conditions is at 25oC. 4.3.1. Liquid carrier

[0371] As summarized above, the injectable compositions described herein include particles suspended in a liquid carrier. In some embodiments, the liquid carrier is non-aqueous. In some embodiments, the liquid carrier is an organic liquid. In some embodiments, the liquid carrier includes an organic liquid and an aqueous solution. In some embodiments, the liquid carrier is referred to as a pharmaceutically acceptable liquid carrier.

[0372] The term “pharmaceutically acceptable liquid carrier” means a pharmaceutically acceptable solvent, liquid suspending agent or liquid vehicle for delivering a biopharmaceutical agent of the present disclosure to the animal or human.

[0373] In some embodiments the organic liquid includes an organic solvent, an oil, or a combination thereof. In some embodiments, the liquid carrier is an organic solvent. It is understood that in the present disclosure an organic “solvent” does not necessarily dissolve the suspended particles of biopharmaceutical agent and polyacrylamide-based copolymer, but rather is a term of art that refers to organic liquids of interest which can be utilized in the present injectable pharmaceutical compositions.

[0374] In some embodiments, the liquid carrier includes an organic solvent, and an aqueous solution, such as water or a buffer. In some embodiments, the liquid carrier is a mixture of an organic liquid miscible with water that does not dissolve the particles and / or the biopharmaceutical agent. In some embodiments, an amount of water is included in the liquid carrier as a viscosity reducer. In some embodiments, the liquid carrier includes 10% by weight or less of the aqueous solution (e.g., water) in a miscible organic solvent such that theAttorney Docket No.38821-63329 (008WO) resulting liquid carrier mixture does not dissolve the particles and / or the biopharmaceutical agent.

[0375] In some embodiments, the organic liquid includes an organic solvent. An organic solvent refers to a low MW carbon-based substance capable of dissolving or dispersing one or more other substances. In the pharmaceutical compositions of this disclosure, the organic solvent can be a liquid capable of dispersing or suspending, but not dissolving, the suspended particles (e.g., as described herein). It is understood that one or more selected excipients may be dissolved in the organic liquid of the compositions.

[0376] In some embodiments, the organic liquid is selected from triacylglyceride, diacylglyceride, monoacylglyceride, an acetamide, alkyl alcohol, aryl alcohol, aralkyl alcohol, fatty acid or a fatty acid ester, oil, alkane, perfluoroalkane, propylene glycol monoester, propylene glycol diester, butylene glycol monoester, butylene glycol diester, polyethylene glycol diester, and combinations thereof. In some embodiments, the liquid carrier comprises one or more liquids selected from triacylglyceride, acetamide, fatty acid ester, aryl acid ester, and combinations thereof.

[0377] In some embodiments, the organic liquid is a monoacylglyceride. A monoacylglyceride is derived from glycerol and one fatty acid connected to the glycerol via an ester linkage. A monoacylglyceride can be a 1-monoacylglycerol or a 2-monoacylglycerol. In some embodiments, the monoacylglyceride includes a fatty acid chain (saturated or unsaturated, branched or linear) having 4-28 carbon atoms, such as 8-20 carbon atoms. In some embodiments, the fatty acid chain has 8-12 carbon atoms, or 8-10 carbon atoms. In some embodiments, the fatty acid ester groups of the propylene glycol diester are selected from oleic acid, myristic acid, caprylic acid, and capric acid. In some embodiments, the fatty acid is a saturated fatty acid. In some embodiments, the fatty acid is an unsaturated fatty acid, such as linoleic acid, myristoleic acid, palmitoleic acid, or oleic acid. In some embodiments, the fatty acid is selected from hexanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, myristoleic acid, palmitoleic acid, and oleic acid.

[0378] In some embodiments, the organic liquid is a diacylglyceride. A diacylglyceride is derived from glycerol and two fatty acids connected to the glycerol via ester linkages. A diacylglyceride can be a 1,2-diacylglycerol or a 1,3-diacylglycerol. In some embodiments,Attorney Docket No.38821-63329 (008WO) the diacylglyceride includes two fatty acid chains (saturated or unsaturated, branched or linear) each independently having 4-28 carbon atoms, such as 8-20 carbon atoms. In some embodiments, the fatty acid chains each have 8-12 carbon atoms or 8-10 carbon atoms. In some embodiments, the fatty acid ester groups of the propylene glycol diester are selected from oleic acid, myristic acid, caprylic acid, capric acid, or any combination thereof. In some embodiments, the fatty acid is a saturated fatty acid. In some embodiments, the fatty acid is an unsaturated fatty acid, such as linoleic acid, myristoleic acid, palmitoleic acid, or oleic acid. In some embodiments, the fatty acids include both a saturated fatty acid and an unsaturated fatty acid. In some embodiments, the fatty acid is selected from hexanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, myristoleic acid, palmitoleic acid, and oleic acid.

[0379] In some embodiments, the organic liquid includes a triacylglyceride. In some embodiments, the triacylglyceride is triacetin.

[0380] In some embodiments, the organic liquid includes a triacylglyceride having three fatty acid chains. In some embodiments, the organic liquid includes a triacylglyceride having two fatty acid chains. In some embodiments, the organic liquid includes a triacylglyceride that has one fatty acid chain. In some embodiments, the fatty acid chains are hydrocarbon chains (saturated or unsaturated, branched or linear) each independently including from 4 to 28 carbon atoms, such as from 8 to 20, 8 to 12, or 8 to 10 carbon atoms. In some embodiments, the fatty acid chain is selected from caprylic acid and capric acid. In some embodiments, the fatty acid is a saturated fatty acid. In some embodiments, the fatty acid is an unsaturated fatty acid, such as linoleic acid, myristoleic acid, palmitoleic acid, or oleic acid. In some embodiments, the fatty acids include both a saturated fatty acid and an unsaturated fatty acid. In some embodiments, the fatty acid is selected from hexanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, myristoleic acid, palmitoleic acid, and oleic acid. Triacylglyceride liquids of interest include, but are not limited to, Miglyol® 829.

[0381] In some embodiments, the organic liquid includes an acetamide. An acetamide liquid of interest includes, but is not limited to, acetamide (CH3CONH2), N-alkyl-acetamide and N,N-dialkyl-acetamide. In some embodiments, the acetamide is selected from acetamide (CH3CONH2), N-methylacetamide, N-ethylacetamide, N,N-diethylacetamide and N,N-Attorney Docket No.38821-63329 (008WO) dimethylacetamide. In some embodiments, the acetamide is N,N-dimethylacetamide (DMAc).

[0382] In some embodiments, the organic liquid includes an alkyl alcohol, aryl alcohol, an aralkyl alcohol, or a combination thereof. In some embodiments, the organic liquid includes octanol. In some embodiments, the organic liquid includes isopropyl alcohol. In some embodiments, the organic liquid includes ethyl alcohol. In some embodiments, the organic liquid includes benzyl alcohol.

[0383] In some embodiments, the organic liquid includes an alkyl benzoate, an aryl benzoate, an aralkyl benzoate, or any combination thereof. In some embodiments, the organic liquid includes benzyl benzoate.

[0384] In some embodiments, the organic liquid includes a polar aprotic solvent. In some embodiments, the polar aprotic solvent includes dimethyl sulfoxide (DMSO), N-methyl-2- pyrrolidone (NMP), or mixtures thereof.

[0385] In some embodiments, the organic liquid includes a propylene glycol (PG) solvent.

[0386] In some embodiments, the organic liquid includes propylene glycol diester. In some embodiments, the propylene glycol diester is a propylene glycol diester of fatty acid(s). In some embodiments, the fatty acid ester groups of the propylene glycol diester include a hydrocarbon chain (saturated or unsaturated, branched or linear) including from 4 to 28 carbon atoms, such as from 8 to 20 carbon atoms. In some embodiments, the fatty acid ester groups of the propylene glycol diester are selected from oleic acid, myristic acid, caprylic acid, capric acid, or any combination thereof.

[0387] In some embodiments, the propylene glycol diester includes propylene glycol diesters of caprylic acid, propylene glycol diesters of capric acid, or a combination thereof. In some embodiments, the propylene glycol diester includes diester of caprylic acid and / or capric acid. In some embodiments, the propylene glycol diester is propylene glycol dicaprylate. In some embodiments, the propylene glycol diester is propylene glycol dicaprate. Propylene glycol diesters of interest include, but are not limited to, Miglyol® 840.

[0388] In some embodiments, the organic liquid is a propylene glycol monoester. In some embodiments, the propylene glycol monoester includes one fatty acid ester having a chainAttorney Docket No.38821-63329 (008WO) (saturated or unsaturated, branched or linear) of 4-28 carbon atoms, such as 8-20 carbon atoms. In some embodiments, the fatty acid chain has 8-10 carbon atoms. In some embodiments, the fatty acid ester groups of the propylene glycol monoester are selected from oleic acid, myristic acid, caprylic acid, and capric acid. In some embodiments, the fatty acid is a saturated fatty acid. In some embodiments, the fatty acid is an unsaturated fatty acid, such as linoleic acid, myristoleic acid, palmitoleic acid, or oleic acid. In some embodiments, the fatty acid is selected from hexanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, myristoleic acid, palmitoleic acid, and oleic acid.

[0389] In some embodiments, the organic liquid includes a butylene glycol diester. In some embodiments, the butylene glycol diester is a butylene glycol diester of fatty acid(s). In some embodiments, the fatty acid ester groups of the butylene glycol diester include a hydrocarbon chain (saturated or unsaturated, branched or linear) including from 4 to 28 carbon atoms, such as from 8 to 20 carbon atoms, 8 to 12, or 8 to 10. In some embodiments, the fatty acid ester groups of the butylene glycol diester are selected from oleic acid, myristic acid, caprylic acid, capric acid, or any combination thereof. In some embodiments, the butylene glycol solvent includes propylene glycol diester of caprylic acid, propylene glycol diester of capric acid, or a combination thereof. In some embodiments, the butylene glycol diester includes diester of caprylic acid and capric acid (e.g., butylene glycolester of caprylic / capric acid). In some embodiments, the fatty acid is a saturated fatty acid. In some embodiments, the fatty acid is an unsaturated fatty acid, such as linoleic acid, myristoleic acid, palmitoleic acid, or oleic acid. In some embodiments, the fatty acids include both a saturated fatty acid and an unsaturated fatty acid. In some embodiments, the fatty acid is selected from hexanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, myristoleic acid, palmitoleic acid, and oleic acid. Butylene glycol diesters of interest include, but are not limited to, Miglyol® 8810.

[0390] In some embodiments, the organic liquid is a butylene glycol monoester. In some embodiments, the butylene glycol monoester includes one fatty acid ester having a chain (saturated or unsaturated, branched or linear) of 4-28 carbon atoms, such as 8-20 carbon atoms. In some embodiments, the fatty acid chain has 8-10 carbon atoms. In some embodiments, the fatty acid ester groups of the butylene glycol monoester are selected from oleic acid, myristic acid, caprylic acid, and capric acid. In some embodiments, the fatty acid is a saturated fatty acid. In some embodiments, the fatty acid is an unsaturated fatty acid, suchAttorney Docket No.38821-63329 (008WO) as linoleic acid, myristoleic acid, palmitoleic acid, or oleic acid. In some embodiments, the fatty acid is selected from hexanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, myristoleic acid, palmitoleic acid, and oleic acid.

[0391] In some embodiments, the organic liquid includes a polyethylene glycol (PEG) solvent. In some embodiments, the PEG solvent is PEG 200, PEG 400, or a combination thereof.

[0392] In some embodiments, the organic liquid is a polyethylene glycol diester. In some embodiments, the polyethylene glycol portion of the polyethylene glycol diester has an average MW of 500 or less, such as 400 or less, 200-400, or 300-400. In some embodiments, the polyethylene glycol diester has two fatty acid ester groups linked to the linear polyethylene glycol. In some embodiments, the polyethylene glycol diester includes fatty acid esters having a chain (saturated or unsaturated, branched or linear) of 4-28 carbon atoms, such as 8-20 carbon atoms. In some embodiments, the fatty acid chain has 8-10 carbon atoms. In some embodiments, the fatty acid ester groups of the polyethylene glycol diester are selected from oleic acid, myristic acid, caprylic acid, and capric acid. In some embodiments, the fatty acid is a saturated fatty acid. In some embodiments, the fatty acid is an unsaturated fatty acid, such as linoleic acid, myristoleic acid, palmitoleic acid, or oleic acid. In some embodiments, the fatty acids include both a saturated fatty acid and an unsaturated fatty acid. In some embodiments, the fatty acid is selected from hexanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, myristoleic acid, palmitoleic acid, and oleic acid.

[0393] In some embodiments, the organic liquid includes a fatty acid or a fatty acid ester. In some embodiments, the fatty acid or fatty acid ester includes a hydrocarbon chain (saturated or unsaturated, branched or linear) including from 4 to 28 carbon atoms, such as from 8 to 20 carbon atoms, 8 to 16, 8 to 12, or 8 to 10 carbon atoms. In some embodiments, the fatty acid is a saturated fatty acid. In some embodiments, the fatty acid is an unsaturated fatty acid, such as linoleic acid, myristoleic acid, palmitoleic acid, or oleic acid. In some embodiments, the fatty acid is selected from hexanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, myristoleic acid, palmitoleic acid, and oleic acid. In some embodiments, the fatty acid is oleic acid, myristic acid, caprylic acid, capric acid, or any combination thereof. In some embodiments, the fatty acid ester is derived from oleic acid, myristic acid, caprylic acid, or capric acid. In some embodiments, the fatty acid ester isAttorney Docket No.38821-63329 (008WO) derived from hexanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, myristoleic acid, palmitoleic acid, or oleic acid. In some embodiments, the fatty acid ester is an (C1-C6)-alkyl or substituted (C1-C6)-alkyl ester of a fatty acid (e.g., as described herein). In some embodiments, the fatty acid ester includes ethyl oleate, isopropyl myristate, or a combination thereof. In some embodiments, the fatty acid ester is ethyl oleate.

[0394] In some embodiments, the organic liquid includes an oil (e.g., a plant-based oil or an animal-based oil). In some embodiments, the oil includes coconut oil, cottonseed oil, fish oil, grape seed oil, hazelnut oil, hydrogenated vegetable oils, lime oil, olive oil, palm seed oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, sunflower oil, walnut oil, or any combination thereof. In some embodiments, the oil includes sesame oil. In some embodiments, the oil includes safflower oil.

[0395] In some embodiments, the organic solvent includes an alkane or a perfluoroalkane. In some embodiments, the organic solvent includes perfluorohexyl octane, perfluoro octane, octane, perfluoro decalin, perfluoro butyl pentane, tetradecane, and any combination thereof.

[0396] In some embodiments, the organic solvent includes ethyl lactate, ethyl acetate, propyl acetate, or any combination thereof.

[0397] Organic liquids of interest include, but are not limited to, benzyl benzoate, ethyl oleate, triacetin, dimethylacetamide (DMAc), Miglyol 840, Miglyol 829, Miglyol 8810, Miglyol 812, Miglyol 812, and the like.

[0398] In some embodiments, the organic liquid includes a blend of or organic liquids (e.g., as described herein), e.g., a blend of organic solvents. In some embodiments, the organic liquid is a blend comprising an organic selected from triacylglyceride, diacylglyceride, monoacylglyceride, an acetamide, alkyl alcohol, aryl alcohol, aralkyl alcohol, fatty acid or a fatty acid ester, oil, alkane, perfluoroalkane, propylene glycol monoester, propylene glycol diester, butylene glycol monoester, butylene glycol diester, and polyethylene glycol diester. In some embodiments, the organic liquid blend includes an additional organic solvent. In some embodiments, the organic liquid is a blend of two or more organic liquids independently selected from triacylglyceride, diacylglyceride, monoacylglyceride, an acetamide, alkyl alcohol, aryl alcohol, aralkyl alcohol, fatty acid or a fatty acid ester, oil,Attorney Docket No.38821-63329 (008WO) alkane, perfluoroalkane, propylene glycol monoester, propylene glycol diester, butylene glycol monoester, butylene glycol diester, and polyethylene glycol diester.

[0399] In some embodiments, the organic liquid blend has a lower viscosity than one or more of the individual liquids or solvents in the blend alone. In some embodiments, the viscosity of the organic liquid blend is 25 cp or less at 25 °C, such as 23 cp or less, 20 cp or less, 18 cp or less, 15 cp or less, 12 cp or less, 10 cp or less, 8 cp or less, 5 cp or less, or even less. In some embodiments, the organic liquid blend comprises a blend of a triacylglyceride and one or more organic solvents that is less viscous than the triacylglyceride. In some embodiments, the triacylglyceride is triacetin. In some embodiments, the organic liquid blend comprises a blend of a propylene glycol and one or more organic solvents that is less viscous than the propylene glycol. In some embodiments, the propylene glycol is propylene glycol diester or a propylene glycol monoester. In some embodiments, the propylene glycol diester or monoester includes esters that are derived from oleic acid, myristic acid, caprylic acid, capric acid, or any combination thereof. In some embodiments, the ester is an (C4-C20)-alkyl or substituted (C4-C20)-alkyl ester of a fatty acid. In some embodiments, the propylene glycol diester or monoester includes diesters of caprylic acid and capric acid (e.g., propylene glycol, dicaprylate, dicaprate).

[0400] In some embodiments, the organic liquid blend comprises from 50-90% v / v triacetin and from 10-50% v / v of one or more organic solvents that is less viscous than triacetin. In some embodiments, the organic liquid blend comprises 50-90% v / v triacetin, such as 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% v / v triacetin. In some embodiments, the organic liquid blend comprises 10-50% v / v of one or more organic solvents that is less viscous than triacetin, such as 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% v / v of one or more organic solvents that is less viscous than triacetin. In some embodiments, the organic liquid blend comprises 50% v / v triacetin and 50% v / v of one or more organic solvents that is less viscous than triacetin. In some embodiments, the organic liquid blend comprises 55% v / v triacetin and 45% v / v of one or more organic solvents that is less viscous than triacetin. In some embodiments, the organic liquid blend comprises 60%v / v triacetin and 40% v / v of one or more organic solvents that is less viscous than triacetin. In some embodiments, the organic liquid blend comprises 65% v / v triacetin and 35% v / v of one or more organic solvents that is less viscous than triacetin. In some embodiments, the organic liquid blend comprises 70% v / v triacetin and 30% v / v of one or more organic solvents that isAttorney Docket No.38821-63329 (008WO) less viscous than triacetin. In some embodiments, the organic liquid blend comprises 75% v / v triacetin and 25% v / v of one or more organic solvents that is less viscous than triacetin. In some embodiments, the organic liquid blend comprises 80% v / v triacetin and 20% v / v of one or more organic solvents that is less viscous than triacetin. In some embodiments, the organic liquid blend comprises 85% v / v triacetin and 15% v / v of one or more organic solvents that is less viscous than triacetin. In some embodiments, the organic liquid blend comprises 90% v / v triacetin and 10% v / v of one or more organic solvents that is less viscous than triacetin.

[0401] In some embodiments, the organic liquid blend comprises from 50-90% v / v a propylene glycol and from 10-50% v / v of one or more organic solvents that is less viscous than the propylene glycol. In some embodiments, the organic liquid blend comprises 50-90% v / v propylene glycol, such as 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% v / v propylene glycol. In some embodiments, the organic liquid blend comprises 10-50% v / v of one or more organic solvents that is less viscous than propylene glycol, such as 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% v / v of one or more organic solvents that is less viscous that triacetin. In some embodiments, the organic liquid blend comprises 50% v / v propylene glycol and 50% v / v of one or more organic solvents that is less viscous than propylene glycol. In some embodiments, the organic liquid blend comprises 55% v / v propylene glycol and 45% v / v of one or more organic solvents that is less viscous than propylene glycol. In some embodiments, the organic liquid blend comprises 60%v / v propylene glycol and 40% v / v of one or more organic solvents that is less viscous than propylene glycol. In some embodiments, the organic liquid blend comprises 65% v / v propylene glycol and 35% v / v of one or more organic solvents that is less viscous than propylene glycol. In some embodiments, the organic liquid blend comprises 70% v / v propylene glycol and 30% v / v of one or more organic solvents that is less viscous than propylene glycol. In some embodiments, the organic liquid blend comprises 75% v / v propylene glycol and 25% v / v of one or more organic solvents that is less viscous than propylene glycol. In some embodiments, the organic liquid blend comprises 80% v / v propylene glycol and 20% v / v of one or more organic solvents that is less viscous than propylene glycol. In some embodiments, the organic liquid blend comprises 85% v / v propylene glycol and 15% v / v of one or more organic solvents that is less viscous than propylene glycol. In some embodiments, the organic liquid blend comprises 90% v / vAttorney Docket No.38821-63329 (008WO) propylene glycol and 10% v / v of one or more organic solvents that is less viscous than propylene glycol.

[0402] In some embodiments, the organic liquid blend comprises triacetin and an organic solvent that is less viscous than triacetin. In some embodiments, the organic liquid comprises triacetin and two or more organic solvents that are less viscous than triacetin. In some embodiments, the one or more less viscous (than triacetin) solvents is selected from DMAc, benzyl benzoate, benzyl alcohol, ethanol, isopropyl alcohol, ethyl lactate, perfluorohexyl octane, perfluoro octane, octane, perfluoro decalin, perfluoro butyl pentane, methoxyflurane, octanol, ethyl acetate, propyl acetate, ethyl oleate and isopropyl myristate. In some embodiments, the one or more less viscous (than triacetin) solvents is selected from DMAc, benzyl benzoate, and benzyl alcohol. In some embodiments, the solvent that is less viscous than triacetin is DMAc. In some embodiments, the solvent that is less viscous than triacetin is benzyl benzoate. In some embodiments, the solvent that is less viscous than triacetin is benzyl alcohol. In some embodiments, the solvent that is less viscous than triacetin includes a combination of DMAc and benzyl alcohol. As such, in some embodiments, the organic liquid comprises a blend of triacetin, DMAc and benzyl alcohol. In some embodiments, the solvent that is less viscous than triacetin includes a 2:1 to 3:1 v / v ratio of DMAc to benzyl alcohol. In some embodiments, the solvent that is less viscous than triacetin includes a combination of DMAc and benzyl benzoate. In some embodiments, the solvent that is less viscous than triacetin includes a 2:1 to 3:1 v / v ratio of DMAc to benzyl benzoate. In some embodiments, the benzyl alcohol is present in an amount of 10% v / v or less of the total volume of the organic liquid.

[0403] In some embodiments, the organic liquid includes a blend of a triacylglyceride and an acetamide. In some embodiments the triacylglyceride is triacetin. In some embodiments, the acetamide is DMAc. In some embodiments, the organic liquid comprises a 1:1 to 9:1 volume to volume (v / v) ratio of triacetin to DMAc, such as a 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, or 9:1 v / v ratio of triacetin to DMAc. In some embodiments, the organic liquid comprises a 1:1 to 3:1 v / v ratio of triacetin to DMAc, such as 1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, or 3:1 v / v of triacetin to DMAc. In some embodiments, the organic liquid comprises a 3:1 to 5:1 v / v ratio of triacetin to DMAc, such as 3:1, 3.2:1, 3.4:1, 3.6:1, 3.8:1, 4:1, 4.2:1, 4.4:1, 4.6:1, 4.8:1, or 5:1 v / v of triacetin to DMAc. In some embodiments, the organic liquid comprises a 5:1 to 7:1 v / v ratioAttorney Docket No.38821-63329 (008WO) of triacetin to DMAc, such as 5:1, 5.2:1, 5.4:1, 5.6:1, 5.8:1, 6:1, 6.2:1, 6.4:1, 6.6:1, 6.8:1, or 7:1 v / v of triacetin to DMAc. In some embodiments, the organic liquid comprises a 7:1 to 9:1 v / v ratio of triacetin to DMAc, such as 7:1, 7.2:1, 7.4:1, 7.6:1, 7.8:1, 8:1, 8.2:1, 8.4:1, 8.6:1, 8.8:1, or 9:1 v / v of triacetin to DMAc.

[0404] In some embodiments, the organic liquid comprises at least 50% v / v triacetin (e.g., at least 75% v / v, or at least 90% v / v) and dimethylacetamide (DMAC). In some embodiments, the organic liquid comprises a 1:1 v / v ratio of triacetin to DMAc. In some embodiments, the organic liquid comprises a 3:1 v / v ratio of triacetin to DMAc. In some embodiments, the organic liquid comprises a 9:1 v / v ratio of triacetin to DMAc.

[0405] In some embodiments, the organic liquid includes a blend of a triacylglyceride and aralkyl alcohol. In some embodiments, the triacylglyceride is triacetin. In some embodiments, the aralkyl alcohol is benzyl alcohol. In some embodiments, the organic liquid comprises a 1:1 to 9:1 volume to volume (v / v) ratio of triacetin to benzyl alcohol, such as a 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, or 9:1 v / v ratio of triacetin to benzyl alcohol. In some embodiments, the organic liquid comprises a 1:1 to 3:1 v / v ratio of triacetin to benzyl alcohol, such as 1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, or 3:1 v / v of triacetin to benzyl alcohol. In some embodiments, the organic liquid comprises a 3:1 to 5:1 v / v ratio of triacetin to benzyl alcohol, such as 3:1, 3.2:1, 3.4:1, 3.6:1, 3.8:1, 4:1, 4.2:1, 4.4:1, 4.6:1, 4.8:1, or 5:1 v / v of triacetin to benzyl alcohol. In some embodiments, the organic liquid comprises a 5:1 to 7:1 v / v ratio of triacetin to benzyl alcohol, such as 5:1, 5.2:1, 5.4:1, 5.6:1, 5.8:1, 6:1, 6.2:1, 6.4:1, 6.6:1, 6.8:1, or 7:1 v / v of triacetin to benzyl alcohol. In some embodiments, the organic liquid comprises a 7:1 to 9:1 v / v ratio of triacetin to benzyl alcohol, such as 7:1, 7.2:1, 7.4:1, 7.6:1, 7.8:1, 8:1, 8.2:1, 8.4:1, 8.6:1, 8.8:1, or 9:1 v / v of triacetin to benzyl alcohol.

[0406] In some embodiments, the organic liquid includes a blend of a triacylglyceride and aralkyl benzoate. In some embodiments the triacylglyceride is triacetin. In some embodiments, the aralkyl benzoate is benzyl benzoate. In some embodiments, the organic liquid comprises a 1:1 to 9:1 volume to volume (v / v) ratio of triacetin to benzyl benzoate, such as a 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, or 9:1 v / v ratio of triacetin to benzyl benzoate. In some embodiments, the organic liquid comprises a 1:1 to 3:1 v / v ratio of triacetin to benzyl benzoate, such as 1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, or 3:1 v / v of triacetin to benzyl benzoate. InAttorney Docket No.38821-63329 (008WO) some embodiments, the organic liquid comprises a 3:1 to 5:1 v / v ratio of triacetin to benzyl benzoate, such as 3:1, 3.2:1, 3.4:1, 3.6:1, 3.8:1, 4:1, 4.2:1, 4.4:1, 4.6:1, 4.8:1, or 5:1 v / v of triacetin to benzyl benzoate. In some embodiments, the organic liquid comprises a 5:1 to 7:1 v / v ratio of triacetin to benzyl benzoate, such as 5:1, 5.2:1, 5.4:1, 5.6:1, 5.8:1, 6:1, 6.2:1, 6.4:1, 6.6:1, 6.8:1, or 7:1 v / v of triacetin to benzyl benzoate. In some embodiments, the organic liquid comprises a 7:1 to 9:1 v / v ratio of triacetin to benzyl benzoate, such as 7:1, 7.2:1, 7.4:1, 7.6:1, 7.8:1, 8:1, 8.2:1, 8.4:1, 8.6:1, 8.8:1, or 9:1 v / v of triacetin to benzyl benzoate.

[0407] In some embodiments, the organic liquid includes a blend of an aryl benzoate and an acetamide. In some embodiments the aryl benzoate is benzyl benzoate. In some embodiments, the acetamide is DMAc. In some embodiments, the organic liquid comprises at least 50% v / v benzyl benzoate (e.g., at least 75% v / v, or at least 90% v / v) and dimethylacetamide (DMAC).

[0408] In some embodiments, the composition includes a 1:5 to 4:1 weight to weight ratio of the liquid carrier to the particles. In some embodiments, the composition includes a 1:1 to 2:1 weight to weight ratio of the liquid carrier to the particles. In some embodiments, the composition includes a 1:1 to 1.5:1 weight to weight ratio of the liquid carrier to the particles.

[0409] In some embodiments, the composition includes a 3:1 to 1:3 weight to weight ratio of the liquid carrier to the particles (e.g., 2:1, 1:1, or 1:2).

[0410] In some embodiments, the composition includes 200 mg / mL to 850 mg / mL of particles in the liquid carrier. In some embodiments, the composition includes 300 mg / mL to 500 mg / mL of particles in the liquid carrier. In some embodiments, the composition includes 400 mg / mL to 600 mg / mL, such as 450 mg / mL to 550 mg / mL of particles in the liquid carrier.

[0411] In some embodiments, the composition comprises 400 to 800 mg / mL of the biopharmaceutical agent (e.g., 425 to 800 mg / mL, 450 to 800 mg / mL, 475 to 800 mg / mL, 500 to 800 mg / mL, 525 to 800 mg / mL, 550 to 800 mg / mL, 575 to 800 mg / mL, 600 to 800 mg / mL, 625 to 800 mg / mL, 650 to 800 mg / mL, 675 to 800 mg / mL, 700 to 800 mg / mL, 750 to 800 mg / mL, 425 to 800 mg / mL, 775 to 800 mg / mL, 425 to 750 mg / mL, 450 to 750 mg / mL, 475 to 750 mg / mL, 500 to 750 mg / mL, 525 to 750 mg / mL, 550 to 750 mg / mL, 575 to 750 mg / mL, 600 to 750 mg / mL, 625 to 750 mg / mL, 650 to 750 mg / mL, 675 to 750Attorney Docket No.38821-63329 (008WO) mg / mL, 700 to 750 mg / mL, 725 to 750 mg / mL, 425 to 700 mg / mL, 450 to 700 mg / mL, 475 to 700 mg / mL, 500 to 700 mg / mL, 525 to 700 mg / mL, 550 to 700 mg / mL, 575 to 700 mg / mL, 600 to 700 mg / mL, 625 to 700 mg / mL, 650 to 700 mg / mL, 675 to 700 mg / mL, 425 to 650 mg / mL, 450 to 650 mg / mL, 475 to 650 mg / mL, 500 to 650 mg / mL, 525 to 650 mg / mL, 550 to 650 mg / mL, 575 to 650 mg / mL, 600 to 650 mg / mL, 625 to 650 mg / mL, 400 to 600 mg / mL, 425 to 600 mg / mL, 450 to 600 mg / mL, 475 to 600 mg / mL, 500 to 600 mg / mL, 525 to 600 mg / mL, 550 to 600 mg / mL, 575 to 600 mg / mL, 400 to 550 mg / mL, 425 to 550 mg / mL, 450 to 550 mg / mL, 475 to 550 mg / mL, 500 to 550 mg / mL, 525 to 550 mg / mL, 400 to 500 mg / mL, 425 to 500 mg / mL, 450 to 500 mg / mL, 475 to 500 mg / mL, 400 to 450 mg / mL, or 425 to 450 mg / mL).

[0412] In some embodiments, the composition comprises at least 510 mg / mL (e.g., at least 520 mg / mL, at least 530 mg / mL, at least 540 mg / mL, at least 550 mg / mL, at least 560 mg / mL, at least 570 mg / mL, at least 580 mg / mL, at least 590 mg / mL, at least 600 mg / mL, at least 610 mg / mL, at least 620 mg / mL, at least 630 mg / mL, at least 640 mg / mL, or at least 650 mg / mL) of the biopharmaceutical agent.

[0413] In some embodiments, the pharmaceutical composition comprises particles, the particles comprising a biopharmaceutical agent, a polyacrylamide-based copolymer, and a liquid carrier in which the particles are suspended. In some embodiments, the injectable pharmaceutical composition comprises at least 500 mg / mL of the biopharmaceutical agent. In certain embodiments, the liquid carrier is ethyl oleate. In certain embodiments, the liquid carrier is triacetin. In certain embodiments, the liquid carrier is a mixture comprising at least 50% v / v triacetin (e.g., at least 75% v / v, or at least 90% v / v) and dimethylacetamide (DMAC). In certain embodiments, the liquid carrier is benzyl benzoate. In certain embodiments, the liquid carrier is a mixture comprising at least 50% v / v benzyl benzoate (e.g., at least 75% v / v, or at least 90% v / v) and dimethylacetamide (DMAC). 4.4. Loaded Syringe

[0414] Also provided in the present disclosure is a syringe loaded with an injectable pharmaceutical composition (e.g., as described herein), for example, a syringe that is pre- loaded with an injectable pharmaceutical composition as described herein in advance of dispensing of the composition from the syringe.Attorney Docket No.38821-63329 (008WO)

[0415] In some embodiments, the loaded syringe is configured to dispense the composition at a flow rate of 0.1 mL / min or more, such as 0.5 mL / min or more, 1 mL / min or more, 2 mL / min or more, 5 mL / min or more, 10 mL / min or more, 15 mL / min or more, or 20 mL / min or more, in response to a force applied to the syringe of 70 N or less. In some embodiments, the syringe is configured to dispense the composition at a flow rate of 0.1 mL / min or more, such as 0.5 mL / min or more, 1 mL / min or more, 2 mL / min or more, 5 mL / min or more, 10 mL / min or more, 15 mL / min or more, or 20 mL / min or more, in response to a force applied to the syringe of 50 N or less.

[0416] In some embodiments, the loaded syringe has a needle having a size of 18 to 32 Gauge (G). In some embodiments, the needle is an 18G needle. In some embodiments, the needle is a 21G needle. In some embodiments, the needle is a 22G needle. In some embodiments, the needle is a 24G needle. In some embodiments, the needle is a 25G needle. In some embodiments, the needle is a 26G needle. In some embodiments, the needle is a 27G needle. In some embodiments, the needle is a 30G needle. In some embodiments, the needle is a 32G needle.

[0417] In some embodiments of any of the needles described herein, the needle is an ultra- thin-walled needle (UTW). It is understood that the UTW needle can have an inner diameter that is larger than a conventional gauge needle. 4.5. Methods of administration

[0418] Also provided in the present disclosure are methods of administering a biopharmaceutical to a subject by injection. In some embodiments, the method includes injecting a composition (e.g., as described herein) in a subject in need thereof to administer a therapeutically effective dose of the biopharmaceutical agent to the subject.

[0419] In some embodiments of the method, the injecting is performed using a loaded syringe, such as a pre-loaded syringe, that includes the composition. In some embodiments of the method, the therapeutically effective amount of a biopharmaceutical composition is administered via IV administration, subcutaneous injection, or intramuscular injection.

[0420] The methods of this disclosure can provide for administration of a biopharmaceutical composition to a subject with a desirable pharmacokinetic profile. In some embodiments, the pharmacokinetic properties of the biopharmaceutical when administered via a subjectAttorney Docket No.38821-63329 (008WO) composition are at least maintained relative to a control composition containing the biopharmaceutical. In some embodiments, the therapeutically effective dose or amount of a composition comprising a biopharmaceutical agent (e.g., as described herein) results in area under the curve (AUC) of greater than 1,000 μg*hr / mL, 2,000 μg*hr / mL, 3,000 μg*hr / mL, 4,000 μg*hr / mL, 5,000 μg*hr / mL, 6,000 μg*hr / mL, 7,000 μg*hr / mL, 8,000 μg*hr / mL, 9,000 μg*hr / mL, or 10,000 μg*hr / mL. In some embodiments, the therapeutically effective amount of a composition results in AUC of greater than 2,000 μg*hr / mL. In some embodiments, the therapeutically effective amount of composition results in AUC of greater than 3,000 μg*hr / mL. In some embodiments, the therapeutically effective amount of a composition results in AUC of greater than 4,000 μg*hr / mL. In some embodiments, the therapeutically effective amount of a composition results in AUC of greater than 5,000 μg*hr / mL. In some embodiments, the therapeutically effective amount of a composition results in AUC of greater than 6,000 μg*hr / mL. In some embodiments, the therapeutically effective amount of a composition results in AUC of greater than 7,000 μg*hr / mL. In some embodiments, the therapeutically effective amount of a composition results in AUC of greater than 8,000 μg*hr / mL. In some embodiments, the therapeutically effective amount of a composition results in AUC of greater than 9,000 μg*hr / mL. In some embodiments, the therapeutically effective amount of a composition results in AUC of greater than 10,000 μg*hr / mL. In some embodiments, the biopharmaceutical agent is an antibody.

[0421] In some embodiments, the therapeutically effective amount of a composition comprising a biopharmaceutical agent results in Cmax of greater than 400 μg / mL, 600 μg / mL, 800 μg / mL, 1000 μg / mL, 1200 μg / mL, 1400 μg / mL, 1600 μg / mL, 1800 μg / mL, 2000 μg / mL, 2200 μg / mL, 2400 μg / mL, 2600 μg / mL, 2800 μg / mL, or 3000 μg / mL. In some embodiments, the therapeutically effective amount of a composition results in Cmax of greater than 600 μg / mL. In some embodiments, the therapeutically effective amount of a composition results in Cmaxof greater than 800 μg / mL. In some embodiments, the therapeutically effective amount of a composition results in Cmax of greater than 1000 μg / mL. In some embodiments, the therapeutically effective amount of a composition results in Cmax of greater than 1200 μg / mL. In some embodiments, the therapeutically effective amount of a composition results in Cmax of greater than 1400 μg / mL. In some embodiments, the therapeutically effective amount of a composition results in Cmax of greater than 1600 μg / mL. In some embodiments, the therapeutically effective amount of composition results in Cmaxof greater than 1800 μg / mL. In some embodiments, the therapeutically effective amount of aAttorney Docket No.38821-63329 (008WO) composition results in Cmax of greater than 2000 μg / mL. In some embodiments, the therapeutically effective amount of a composition results in Cmax of greater than 2200 μg / mL. In some embodiments, the therapeutically effective amount of a composition results in Cmaxof greater than 2400 μg / mL. In some embodiments, the therapeutically effective amount of a composition results in Cmax of greater than 2600 μg / mL. In some embodiments, the therapeutically effective amount of a composition results in Cmaxof greater than 2800 μg / mL. In some embodiments, the therapeutically effective amount of a composition results in Cmaxof greater than 3000 μg / mL. 4.6. Methods of preparation

[0422] As summarized herein, also provided are methods of preparing an injectable pharmaceutical composition (e.g., as described herein).

[0423] In some embodiments, the method of preparing an injectable pharmaceutical composition includes: a) providing a mixture comprising: a biopharmaceutical agent; a polyacrylamide-based copolymer in aqueous solution; and an optional stabilizing agent, wherein the ratio of the polyacrylamide-based copolymer to the biopharmaceutical agent in the mixture is 5:95 or less (e.g., 4:96 or less, 3:97 or less, 2:98 or less, or 1:99 or less); b) spray drying the mixture to obtain particles comprising the biopharmaceutical agent and the polyacrylamide-based copolymer; and c) contacting a liquid carrier with the particles to form a suspension of the particles in the liquid carrier.

[0424] In some embodiments, the particles obtained in step b) have a mean diameter as described herein, e.g., of 100 microns or less. In some embodiments, the particles obtained in step b) have a mean diameter of 10 microns or less. In some embodiments, the particles have a particle size distribution of at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, or at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of the particles having a diameter of less than 10 microns. In some embodiments, the particles have a particle size distribution of at least 96% of the particles having a diameter of less than 10 microns. In some embodiments, the particles have a particle size distribution of at least 98% of the particles having a diameter of less than 10 microns.Attorney Docket No.38821-63329 (008WO) 4.7. Definitions

[0425] 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; other, suitable methods and materials known in the art in some aspects of this disclosure are also used. 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.

[0426] 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.

[0427] The terms “therapies” and “therapy” are used in their broadest sense understood in the clinical arts.

[0428] 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.

[0429] 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 toAttorney Docket No.38821-63329 (008WO) 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.

[0430] 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.

[0431] 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.

[0432] The term “polymer” refers to a substance or material consisting of repeating monomer subunits.

[0433] 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- methoxypropoyl)acrylamide (MPAM), 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).

[0434] 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 monomersAttorney Docket No.38821-63329 (008WO) 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 are connected 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.

[0435] 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- methoxypropoyl)acrylamide (MPAM), 4-acryloylmorpholine (MORPH), N,N- dimethylacrylamide (DMA), and N-hydroxyethyl acrylamide (HEAM).Attorney Docket No.38821-63329 (008WO)

[0436] 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 the polymers 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.

[0437] 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.

[0438] 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 weight- average 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, size exclusion chromatography (SEC), static light scattering (SLS) analysis, multi-angle laser light scattering (MALLS)Attorney Docket No.38821-63329 (008WO) 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 magnetic spectroscopy (NMR), Fourier Transform infrared spectroscopy (FT-IR) and Raman spectroscopy.

[0439] The term “amphiphilic” refers to chemical substances that possess both hydrophilic (water-loving, polar) and lipophilic or hydrophobic (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. In some embodiments, the co-polymers incorporated into the particles of this disclosure are amphiphilic because they include both hydrophilic co-monomers, and lipophilic or hydrophobic co-monomers.

[0440] 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.

[0441] “Biologic molecule,” as used herein, refers to molecules such as proteins, nucleic acids, polysaccharides, and lipids.

[0442] 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, cytokines, chemokines, enzymes, hormones, vaccine antigens, cancer antigens, adjuvants, nutritional markers, and tissue specific antigens.

[0443] 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).Attorney Docket No.38821-63329 (008WO)

[0444] The term “antibody” refers to large, immunoglobulin 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 be human, humanized and / or affinity matured. “Antibody fragments” include 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 includes 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 includes 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 include an antigen binding arm linked to an Fe sequence capable of conferring in vivo stability to the fragment.

[0445] 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 include an encapsulated species.

[0446] 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.Attorney Docket No.38821-63329 (008WO)

[0447] 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 conditions such 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 , mass spectrometry (MS), optical microscopy, fluorescence microscopy, dynamic light scattering (DLS), multi-angle laser light scattering (MALLS), flow imaging, turbidity / nephelometry, and transmittance measurement.

[0448] 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, mass spectrometry (MS), optical microscopy, fluorescence microscopy, dynamic light scattering (DLS), multi-angle laser light scattering (MALLS), flow imaging, turbidity / nephelometry, and transmittance measurement.Attorney Docket No.38821-63329 (008WO)

[0449] 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.

[0450] 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 aggregates can 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.

[0451] The term “loss on drying” (“LOD”), as used herein, refers to the amount of volatile matter of any kind that is driven off under the specified conditions. Loss on drying is determined by heating the sample below its melting point in an oven and it includes all volatile matter including water content and solvents.

[0452] The term “residual moisture content” (“RMC”), as used herein, refers to the water content in a biological product after drying.

[0453] The term “thermogravimetric analysis” (“TGA”), as used herein, refers to a method of thermal analysis in which the mass of a sample is measured over time as the temperature changes.

[0454] The term “particle size distribution” (“PSD”), as used herein, refers to a list of values or a mathematical function that defines the relative amount, typically by mass, of particles present according to size.Attorney Docket No.38821-63329 (008WO)

[0455] As used herein, “X10” (D10) represents the particle size at which 10% of the particles in a sample are smaller.

[0456] As used herein, “X50” (D50) represents the particle size at which 50% of the particles are smaller and 50% are larger.

[0457] As used herein, “X90” (D90) represents the particle size at which 90% of the particles are smaller.

[0458] The term “particle density”, as used herein, is defined as the mass of the particle divided by the solids volume including the volume occupied by internal pores. The term “true density”, as used herein, is defined as the ratio of particle mass to its actual volume, excluding internal pores. Particle density and true density may be measured by helium pycnometry.

[0459] The term “size exclusion chromatography” (SE-HPLC, SEC), as used herein, refers to a chromatographic method that separates molecules in solution by their size or molecular weight.

[0460] The term “deionized water” (“DI”), as used herein, refers to water that has had almost all of its mineral ions removed, such as cations like sodium, calcium, iron, and copper, and anions such as chloride and sulfate.

[0461] The term “spray drying”, as used herein, refers to a method of forming a dry powder from a liquid or slurry by rapidly drying with a hot gas.

[0462] The term “electrospray drying”, as used herein, refers to a process that uses electrostatic force to disperse a conductive liquid stream into fine charged droplets through the coulomb fission of charges in the liquid and finally dry into fine particles.

[0463] The term “dialysis”, as used herein, refers to a process of separating molecules in solution by the difference in their rates of diffusion through a semipermeable membrane.

[0464] The term “syringeability”, as used herein, refers to the ability to aspirate or withdraw the liquid into a syringe, while injectability refers to the ability to push the withdrawn liquid through a needle.Attorney Docket No.38821-63329 (008WO)

[0465] The term “injectability”, as described herein, refers to the ease of parenteral administration of a dosing solution.

[0466] The term “injection force”, as described herein, refers to the force necessary to inject a solution / suspension via a hollow needle.

[0467] The term “glide force”, as used herein, refers to the force required to maintain plunger movement once static friction has been overcome.

[0468] A liquid composition further comprises a buffer to maintain pH of the pharmaceutical composition. The buffer can include a buffer compound known in the art, such as TAPS, Bicine, Tris, Tricine, TAPSO, HEPES, TES, MPOS, PIPES, Cacodylate, histidine (e.g., L- histidine hydrochloride), or MES. The buffer can contain citric acid, monopotassium phosphate, boric acid, or diethyl barbituric acid. The buffer can be PBS, HEPES, TRIS or TRIS / EDTA buffer. The buffer can be other phosphate buffer. Phosphate buffers can comprise a mixture of monobasic dihydrogen phosphate and dibasic monohydrogen phosphate. In some embodiments, the buffer if L-histidine.

[0469] The term “storage stable”, as used herein, refers to a composition that demonstrates less than 10 mol % degradation of the bioactivity of the biopharmaceutical agent after storage for 4 weeks or longer. The storage stable composition of this disclosure demonstrates less than 10 mol % degradation of the bioactivity of the biopharmaceutical agent after storage for 4 weeks or longer.

[0470] The term “ambient conditions”, as used herein, refers to the surrounding environmental factors of a system or object. These factors include temperature, humidity, air pressure, light intensity, noise amplitude, and vibration magnitude.

[0471] The term “tonicity agent”, as used herein, refers to an excipient used to adjust the tonicity of a composition.

[0472] The term “Cmax”, as used herein, refers to the observed maximum (peak) plasma concentration of a specified compound in the subject after administration of a dose of that compound to the subject.Attorney Docket No.38821-63329 (008WO)

[0473] The term “AUC”, as used herein, refers to the total area under the plasma concentration-time curve, which is a measure of exposure to a compound of interest, and is the integral of the concentration-time curve after a single dose or at steady state.

[0474] The term “volume median diameter”, “volumetric median diameter” or “VMD” of composition is the particle size diameter identified such that half of the mass of the particles is contained in particles with larger diameter than the VMD, and half of the mass of the particles is contained in particles with smaller diameter than the VMD. 5. ADDITIONAL EMBODIMENTS

[0475] This disclosure is further described by the following non-limiting clauses: 1. An injectable pharmaceutical composition comprising: particles, the particles comprising: a biopharmaceutical agent; and a polyacrylamide-based copolymer; and a liquid carrier in which the particles are suspended. 2. The injectable pharmaceutical composition of clause 1, wherein the particles have a mean diameter of 100 microns or less. 3. The injectable pharmaceutical composition of clause 2, wherein the particles have a mean diameter of from 0.01-100 microns. 4. The injectable pharmaceutical composition of clause 3, wherein the particles have a mean diameter of from 0.1-100 microns. 5. The injectable pharmaceutical composition of clause 4, wherein the particles have a mean diameter of from 0.2-20 microns. 6. The injectable pharmaceutical composition of clause 5, wherein the particles have a mean diameter of from 0.2-10 microns. 7. The injectable pharmaceutical composition of clause 1, further comprising one or more of stabilizing agent, preservative, filler, bulking agent, sugar, polysaccharide, or viscosity modifier. 8. The injectable pharmaceutical composition of clause 7, further comprising a stabilizing agent. 9. The injectable pharmaceutical composition of clause 8, wherein the stabilizing agent is selected from surfactants, poloxamers, povidones, polyvinylpyrrolidone (PVP) polymer,Attorney Docket No.38821-63329 (008WO) polyvinyl alcohol (PVA) polymer, carbohydrates, polysaccharides (e.g., dextrans, alginates), cellulosics (e.g., hydroxypropyl methyl cellulose (HPMC), sugars, reduced sugars, methyl cellulose (MC)), amphoteric compounds, salts, amino acids, and combinations thereof. 10. The injectable pharmaceutical composition of any one of clauses 1 to 9, wherein the biopharmaceutical agent is a polypeptide. 11. The injectable pharmaceutical composition of clause 10, wherein the polypeptide is susceptible to aggregation in an aqueous medium. 12. The injectable pharmaceutical composition of clause 10 or 11, wherein the polypeptide is selected from antibodies and fragments thereof, cytokines, chemokines, hormones, vaccine antigens, cancer antigens, adjuvants, and combinations thereof. 13. The injectable pharmaceutical composition of any one of clauses 10 to 12, wherein the polypeptide is a protein. 14. The injectable pharmaceutical composition of clause 13, wherein the protein is an antibody or a fragment thereof. 15. The injectable pharmaceutical composition of clause 14, wherein the protein is a monoclonal antibody, a polyclonal antibody, an immunoglobulin G (IgG) antibody, an IgA antibody, an IgM antibody, a Fc fusion protein, or a fragment thereof. 16. The injectable pharmaceutical composition of any one of clauses 10 to 12, wherein the polypeptide is a hormone or analog thereof. 17. The injectable pharmaceutical composition of clause 16, wherein the polypeptide is insulin or an analog thereof. 18. The injectable pharmaceutical composition of clause 16, wherein the polypeptide is selected from glucagon, GLP-1 receptor agonist, amylin, and analogs thereof. 19. The injectable pharmaceutical composition of any one of clauses 1 to 18, wherein the composition comprises 0.1 to 20% by weight of the biopharmaceutical agent. 20. The injectable pharmaceutical composition of clause 19, wherein the biopharmaceutical agent is insulin or an analog thereof. 21. The injectable pharmaceutical composition of clause 19, wherein the biopharmaceutical agent is a peptide. 22. The injectable pharmaceutical composition of any one of clauses 19 to 21, wherein the particles comprise no more than 20% by weight of the biopharmaceutical agent. 23. The injectable pharmaceutical composition of any one of clauses 1 to 18, wherein the composition comprises 20% or more by weight of the biopharmaceutical agent.Attorney Docket No.38821-63329 (008WO) 24. The injectable pharmaceutical composition of clause 23, wherein the composition comprises 20% to 80% by weight of the biopharmaceutical agent. 25. The injectable pharmaceutical composition of clause 23 or 24, wherein the biopharmaceutical agent is an antibody or fragment thereof, or a Fc fusion protein. 26. The injectable pharmaceutical composition of any one of clauses 23 to 25, wherein the particles comprise 75% or more by weight of the biopharmaceutical agent. 27. The injectable pharmaceutical composition of any one of clauses 1 to 26, wherein the composition comprises 0.01 to 20 wt% of the polyacrylamide-based copolymer. 28. The injectable pharmaceutical composition of clause 27, wherein the composition comprises 0.1 to 10 wt% of the polyacrylamide-based copolymer. 29. The injectable pharmaceutical composition of clause 27, wherein the composition comprises 0.5 to 5 wt% of the polyacrylamide-based copolymer. 30. The injectable pharmaceutical composition of any one of clauses 1 to 29, wherein the particles comprise 0.01 to 25 wt% of the polyacrylamide-based copolymer. 31. The injectable pharmaceutical composition of clause 30, wherein the particles comprise 0.1 to 10 wt% of the polyacrylamide-based copolymer. 32. The injectable pharmaceutical composition of clause 30, wherein the particles comprise 1 to 5 wt% of the polyacrylamide-based copolymer. 33. The injectable pharmaceutical composition of any one of clauses 1 to 32, wherein composition comprises a 1:500 to 2:1 weight to weight ratio of the polyacrylamide-based copolymer to the biopharmaceutical agent. 34. The injectable pharmaceutical composition of clause 33, wherein composition comprises a 1:50 to 1:1 weight to weight ratio of the polyacrylamide-based copolymer to the biopharmaceutical agent. 35. The injectable pharmaceutical composition of clause 33, wherein composition comprises a 1:25 to 1:10 weight to weight ratio of the polyacrylamide-based copolymer to the biopharmaceutical agent. 36. The injectable pharmaceutical composition of any one of clauses 1 to 35, wherein the polyacrylamide-based copolymer comprises: a water-soluble carrier monomer selected from N-(3-methoxypropyl)acrylamide (MPAM), 4-acryloylmorpholine (MORPH), N,N-dimethylacrylamide (DMA), N- hydroxyethyl acrylamide (HEAM), acrylamide (AM), and combinations thereof; and a functional dopant monomer selected from N-[tris(hydroxymethyl)- methyl]acrylamide (TRI), 2-acrylamido-2-methylpropane sulfonic acid (AMP), (3-Attorney Docket No.38821-63329 (008WO) acrylamidopropyl)trimethylammonium chloride (TMA), N-isopropylacrylamide (NIP), N-N- diethylacrylamide (DEA), N-tert-butylacrylamide (TBA), N-phenylacrylamide (PHE), and combinations thereof. 37. The injectable pharmaceutical composition of clause 33, wherein the water-soluble carrier monomer is selected from MORPH, MPAM, and combinations thereof. 38. The injectable pharmaceutical composition of clause 34, wherein the water-soluble carrier monomer comprises MORPH. 39. The injectable pharmaceutical composition of clause 34, wherein the water-soluble carrier monomer comprises MPAM. 40. The injectable pharmaceutical composition of any one of clauses 33-36, wherein the functional dopant monomer is selected from AMP, TMA, TBA, PHE, and combinations thereof. 41. The injectable pharmaceutical composition of any one of clauses 33-36, wherein the functional dopant monomer is selected from DEA, PHE, NIP, and combinations thereof. 42. The injectable pharmaceutical composition of any one of clauses 33-36, wherein the functional dopant monomer comprises TRI. 43. The injectable pharmaceutical composition of any one of clauses 33-36, wherein the functional dopant monomer comprises PHE. 44. The injectable pharmaceutical composition of any one of clauses 33-36, wherein the functional dopant monomer comprises NIP. 45. The injectable pharmaceutical composition of any one of clauses 33-36, wherein the functional dopant monomer comprises DEA. 46. The injectable pharmaceutical composition of clause 33, wherein: the water-soluble carrier monomer is selected from MPAM, MORPH, and combinations thereof; and the functional dopant monomer is selected from NIP, PHE, and combinations thereof. 47. The injectable pharmaceutical composition of clause 33, wherein: the water-soluble carrier monomer is selected from MPAM, MORPH, and combinations thereof; and the functional dopant monomer is selected from AMP, TMA, TBA, PHE, and combinations thereof. 48. The injectable pharmaceutical composition of clause 33, wherein the water-soluble carrier monomer is MPAM, and the functional dopant monomer is PHE.Attorney Docket No.38821-63329 (008WO) 49. The injectable pharmaceutical composition of clause 33, wherein the water-soluble carrier monomer is MORPH, and the functional dopant monomer is PHE. 50. The injectable pharmaceutical composition of clause 33, wherein the water-soluble carrier monomer is MORPH, and the functional dopant monomer is NIP. 51. The injectable pharmaceutical composition of any one of clauses 33-50, wherein the polyacrylamide-based copolymer comprises: 70 wt% to 98 wt% of the water-soluble carrier monomer; and 2 wt% to 30 wt% of the functional dopant monomer. 52. The injectable pharmaceutical composition of any one of clauses 33-50, wherein the polyacrylamide-based copolymer comprises: 80 wt% to 95 wt% of the water-soluble carrier monomer; and 5 wt% to 20 wt% of the functional dopant monomer. 53. The injectable pharmaceutical composition of any one of clauses 33-50, wherein the polyacrylamide-based copolymer comprises: 83 wt% to 98 wt% of the water-soluble carrier monomer; and 2 wt% to 17 wt% of the functional dopant monomer. 54. The injectable pharmaceutical composition of clause 33, wherein the polyacrylamide- based copolymer comprises: 70 wt% to 85 wt% of MORPH; and 15 wt% to 30 wt% of NIP. 55. The injectable pharmaceutical composition of clause 33, wherein the polyacrylamide- based copolymer comprises: 74 wt% to 80 wt% of MORPH; and 20 wt% to 26 wt% of NIP. 56. The injectable pharmaceutical composition of clause 33, wherein the polyacrylamide- based copolymer comprises: 77 wt% of MORPH; and 23 wt% of NIP. 57. The injectable pharmaceutical composition of any one of clauses 33-56, wherein the degree of polymerization of the polyacrylamide-based copolymer is 10 to 500. 58. The injectable pharmaceutical composition of clause 57, wherein the degree of polymerization of the polyacrylamide-based copolymer is 20 to 200. 59. The injectable pharmaceutical composition of clause 58, wherein the degree of polymerization of the polyacrylamide-based copolymer is 50.Attorney Docket No.38821-63329 (008WO) 60. The injectable pharmaceutical composition of any one of clauses 22-59, wherein a number-average molecular weight of the polyacrylamide-based copolymer is 1,000 g / mol to 40,000 g / mol. 61. The injectable pharmaceutical composition of 60, wherein a number-average molecular weight of the polyacrylamide-based copolymer is 2,000 g / mol to 10,000 g / mol. 62. The injectable pharmaceutical composition of 61, wherein a number-average molecular weight of the polyacrylamide-based copolymer is 4,000 g / mol to 6,000 g / mol. 63. The injectable pharmaceutical composition of any one of clauses 1 to 62, wherein the polyacrylamide-based copolymer is amphiphilic. 64. The injectable pharmaceutical composition of any one of clauses 1 to 63, wherein the liquid carrier comprises a mixture of an organic solvent and an aqueous solution. 65. The injectable pharmaceutical composition of any one of clauses 1 to 63, wherein the liquid carrier comprises an organic solvent, an oil, or a combination thereof. 66. The injectable pharmaceutical composition of any one of clauses 1 to 65, wherein the liquid carrier comprises one or more liquids selected from triacylglyceride, diacylglyceride, monoacylglyceride, an acetamide, alkyl alcohol, aryl alcohol, aralkyl alcohol, fatty acid, fatty acid ester, oil, alkane, perfluoroalkane, propylene glycol monoester, propylene glycol diester, butylene glycol monoester, butylene glycol diester, polyethylene glycol diester, and combinations thereof. 67. The injectable pharmaceutical composition of clause 66, wherein the liquid carrier comprises an aralkyl benzoate. 68. The injectable pharmaceutical composition of clause 67, wherein the aralkyl benzoate is benzyl benzoate. 69. The injectable pharmaceutical composition of clause 66, wherein the liquid carrier comprises a triacylglyceride, diacylglyceride, monoacylglyceride, or a combination thereof. 70. The injectable pharmaceutical composition of clause 69, wherein the liquid carrier comprises a triacylglyceride that is triacetin. 71. The injectable pharmaceutical composition of clause 66, wherein the liquid carrier comprises N,N-dimethylacetamide (DMAc). 72. The injectable pharmaceutical composition of clause 66, wherein the liquid carrier comprises a fatty acid ester. 73. The injectable pharmaceutical composition of clause 72, wherein the fatty acid ester is ethyl oleate.Attorney Docket No.38821-63329 (008WO) 74. The injectable pharmaceutical composition of clause 66, wherein the liquid carrier comprises a propylene glycol diester and / or a butylene glycol diester. 75. The injectable pharmaceutical composition of clause 74, wherein the liquid carrier comprises Miglyol 840. 76. The injectable pharmaceutical composition of clause 65 or 66, wherein the liquid carrier comprises a blend of a triacylglyceride and one or more organic solvents that is less viscous than the triacylglyceride. 77. The injectable pharmaceutical composition of clause 76, wherein the triacylglyceride is triacetin. 78. The injectable pharmaceutical composition of clause 77, wherein the liquid carrier comprises a 1:1 to 9:1 volume to volume (v / v) ratio of triacetin to one or more organic solvents that is less viscous than triacetin. 79. The injectable pharmaceutical composition of clause 76, wherein the liquid carrier comprises a 1:1 v / v ratio of triacetin to one or more organic solvents that is less viscous than triacetin. 80. The injectable pharmaceutical composition of clause 76, wherein the liquid carrier comprises a 3:1 v / v ratio of triacetin to one or more organic solvents that is less viscous than triacetin. 81. The injectable pharmaceutical composition of clause 76, wherein the liquid carrier comprises a 9:1 v / v ratio of triacetin to one or more organic solvents that is less viscous than triacetin. 82. The injectable pharmaceutical composition of any one of clauses 76 to 81, wherein the organic solvent that is less viscous that triacetin is selected from an acetamide, an alkyl benzoate, an aryl benzoate, an aralkyl benzoate, an aryl alcohol, an aralkyl alcohol, or any combination thereof. 83. The injectable pharmaceutical composition of clause 82, wherein the organic solvent that is less viscous that triacetin is an acetamide. 84. The injectable pharmaceutical composition of clause 83, wherein the acetamide is DMAc. 85. The injectable pharmaceutical composition of clause 82, wherein the organic solvent that is less viscous that triacetin is an aralkyl alcohol. 86. The injectable pharmaceutical composition of clause 85, wherein the aralkyl alcohol is benzyl alcohol.Attorney Docket No.38821-63329 (008WO) 87. The injectable pharmaceutical composition of clause 82, wherein the organic solvent that is less viscous that triacetin is an aralkyl benzoate. 88. The injectable pharmaceutical composition of clause 87, wherein the aralkyl benzoate is benzyl benzoate. 89. The injectable pharmaceutical composition of clause 82, wherein the organic solvent that is less viscous that triacetin comprises a combination of an acetamide and an aralkyl alcohol. 90. The injectable pharmaceutical composition of clause 89, wherein the acetamide is DMAc, and the aralkyl alcohol is benzyl alcohol. 91. The injectable pharmaceutical composition of clause 90, wherein the less viscous organic solvent comprises a 3:1 to 2:1 v / v ratio of DMAc to benzyl alcohol. 92. The injectable pharmaceutical composition of clause 65 or 66, wherein the organic solvent is an alkyl benzoate, an aryl benzoate, an aralkyl benzoate, or any combination thereof. 93. The injectable pharmaceutical composition of clause 92, wherein the organic solvent is benzyl benzoate. 94. The injectable pharmaceutical composition of clause 64 or 65, wherein the organic solvent is a polar aprotic solvent. 95. The injectable pharmaceutical composition of clause 94, wherein the polar aprotic solvent is dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), or a mixture thereof. 96. The injectable pharmaceutical composition of clause 65, wherein the liquid carrier comprises an oil (e.g., a plant-based oil or an animal-based oil). 97. The injectable pharmaceutical composition of clause 96, wherein the oil is coconut oil, cottonseed oil, fish oil, grape seed oil, hazelnut oil, hydrogenated vegetable oils, lime oil, olive oil, palm seed oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, sunflower oil, walnut oil, or any combination thereof. 98. The injectable pharmaceutical composition of clause 97, wherein the oil is sesame oil. 99. The injectable pharmaceutical composition of any one of clauses 1 to 98, wherein the composition comprises a 1:5 to 4:1 weight to weight ratio of the liquid carrier to the particles. 100. The injectable pharmaceutical composition of clause 99, wherein the composition comprises a 1:1 to 2:1 weight to weight ratio of the liquid carrier to the particles. 101. An injectable pharmaceutical composition comprising: particles, the particles comprising: a biopharmaceutical agent; andAttorney Docket No.38821-63329 (008WO) a polyacrylamide-based copolymer comprising: a water-soluble carrier monomer selected from N-(3- methoxypropyl)acrylamide (MPAM), 4-acryloylmorpholine (MORPH), N,N- dimethylacrylamide (DMA), N-hydroxyethyl acrylamide (HEAM), acrylamide (AM), and combinations thereof; and 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-N-diethylacrylamide (DEA), N-tert- butylacrylamide (TBA), N-phenylacrylamide (PHE), and combinations thereof; and a liquid carrier in which the particles are suspended, wherein the liquid carrier is selected from triacylglyceride, diacylglyceride, monoacylglyceride, an acetamide, alkyl alcohol, aryl alcohol, aralkyl alcohol, fatty acid, fatty acid ester, oil, alkane, perfluoroalkane, propylene glycol monoester, propylene glycol diester, butylene glycol monoester, butylene glycol diester, polyethylene glycol diester, and combinations thereof. 102. The injectable pharmaceutical composition of clause 101, wherein the water-soluble carrier monomer is selected from MORPH, MPAM, and combinations thereof. 103. The injectable pharmaceutical composition of any one of clauses 101-102, wherein the functional dopant monomer is selected from AMP, TMA, TBA, PHE, and combinations thereof. 104. The injectable pharmaceutical composition of any one of clauses 101-102, wherein the functional dopant monomer is selected from DEA, PHE, NIP, and combinations thereof. 105. The injectable pharmaceutical composition of clause 104, wherein: the water-soluble carrier monomer is selected from MPAM, MORPH, and combinations thereof; and the functional dopant monomer is selected from NIP, PHE, and combinations thereof. 106. The injectable pharmaceutical composition of clause 104, wherein the water-soluble carrier monomer is MORPH, and the functional dopant monomer is NIP. 107. The injectable pharmaceutical composition of any one of clauses 101-106, wherein the liquid carrier comprises an aralkyl benzoate. 108. The injectable pharmaceutical composition of clause 107, wherein the aralkyl benzoate is benzyl benzoate.Attorney Docket No.38821-63329 (008WO) 109. The injectable pharmaceutical composition of any one of clauses 101-106, wherein the liquid carrier comprises a triacylglyceride. 110. The injectable pharmaceutical composition of clause 109, wherein the triacylglyceride is triacetin. 111. The injectable pharmaceutical composition of any one of clauses 101-106, wherein the liquid carrier comprises N,N-dimethylacetamide (DMAc). 112. The injectable pharmaceutical composition of any one of clauses 101-106, wherein the liquid carrier comprises a fatty acid ester. 113. The injectable pharmaceutical composition of clause 112, wherein the fatty acid ester comprises ethyl oleate. 114. The injectable pharmaceutical composition of any one of clauses 101-106, wherein the liquid carrier comprises a propylene glycol diester and / or a butylene glycol diester. 115. The injectable pharmaceutical composition of clause 114, wherein: the propylene glycol diester is Miglyol 840; and the butylene glycol diester is Miglyol 8810. 116. A syringe, loaded with a composition of any one of clauses 1-115. 117. The syringe of clause 116, configured to dispense the composition at a flow rate of 0.1 mL / min or more in response to a force applied to the syringe of 70 N or less. 118. The syringe of clause 116, configured to dispense the composition at a flow rate of 0.1 mL / min or more in response to a force applied to the syringe of 50 N or less. 119. The syringe of any one of clauses 116 to 118, wherein the syringe comprises a needle having a size of 18 to 32 Gauge (G). 120. The syringe of clause 119, wherein the needle is an 22G needle. 121. The syringe of clause 119, wherein the needle is a 24G needle. 122. The syringe of clause 119, wherein the needle is a 25G needle. 123. The syringe of clause 119, wherein the needle is a 26G needle. 124. The syringe of clause 119, wherein the needle is a 27G needle. 125. The syringe of clause 119, wherein the needle is a 30G needle. 126. The syringe of clause 119, wherein the needle is a 32G needle. 127. The syringe of any one of clauses 119-126, wherein the needle is an ultra-thin walled needle. 128. method of administering a biopharmaceutical to a subject by injection, the method comprising:Attorney Docket No.38821-63329 (008WO) injecting a composition according to any one of clauses 1-115 to administer a therapeutically effective dose of the biopharmaceutical to a subject in need thereof. 129. The method of clause 128, wherein the injecting is performed using a loaded syringe of any one of clauses 116-127. 130. A method of preparing an injectable pharmaceutical composition, the method comprising: a) providing a mixture comprising: a biopharmaceutical agent; a polyacrylamide-based copolymer in water;s and an optional stabilizing agent; b) removing the water from the mixture to obtain particles comprising the biopharmaceutical agent and the polyacrylamide-based copolymer; c) contacting a liquid carrier with the particles to form a suspension of the particles in the liquid carrier. 131. The method of clause 130, wherein in step b) the water is removed via spray drying. 132. The method of clause 130, wherein in step b) the water is removed via electrospray drying. 133. The method of clause 130, wherein in step b) the water is removed via lyophilization. 134. The method of clause 130, wherein the method further comprises a milling step after the lyophilization but prior to step c). 135. The method of any one of clauses 130 to 134, wherein the particles obtained in step b) have a mean diameter of 100 microns or less. 136. The method of any one of clauses 130 to 135, wherein step c) comprises sonicating the particles in the liquid carrier. 137. A solid composition comprising a plurality of particles, the particles comprising 70 wt% or more of a biopharmaceutical agent; and optionally, 5 wt% or less of a polyacrylamide-based copolymer; and optionally, 25 wt% or less of a stabilizing agent. 138. The solid composition of clause 137, wherein the particles comprise 75 wt% or more of the biopharmaceutical agent. 139. The solid composition of clause 137, wherein the particles comprise 80 wt% or more of the biopharmaceutical agent. 140. The solid composition of clause 137, wherein the particles comprise 85 wt% or more of the biopharmaceutical agent.Attorney Docket No.38821-63329 (008WO) 141. The solid composition of clause 137, wherein the particles comprise 90 wt% or more of the biopharmaceutical agent. 142. The solid composition of any one of clauses 137-141, wherein the particles comprise 5 wt% or less of the polyacrylamide-based copolymer. 143. The solid composition of any one of clauses 137-141, wherein the particles comprise 20 wt% or less of the polyacrylamide-based copolymer. 144. The solid composition of any one of clauses 137-141, wherein the particles comprise 15 wt% or less of the polyacrylamide-based copolymer. 145. The solid composition of any one of clauses 137-141, wherein the particles comprise 10 wt% or less of the polyacrylamide-based copolymer. 146. The solid composition of any one of clauses 137-141, wherein the particles comprise 5 wt% or less of the polyacrylamide-based copolymer. 147. The solid composition of any one of clauses 137-146, wherein the particles consist of 90 wt% or more of the biopharmaceutical agent; 5 wt% or less of the polyacrylamide-based copolymer; and 5 wt% or less of an optional aqueous component, wherein the aqueous component optionally includes a buffer. 148. The solid composition of any one of clauses 137-146, wherein the particles comprise 80 to 95 wt% of the biopharmaceutical agent; 0.1 to 5 wt% of the polyacrylamide-based copolymer; and 5 to 15 wt% of the stabilizing agent. 149. The solid composition of clause 147 or 148, wherein the particles comprise 5 wt% or less of an optional aqueous component, wherein the aqueous component optionally includes a buffer. 150. The solid composition of any one of clauses 137-149, wherein the particles are microspheres. 151. The solid composition of any one of clauses 137-149, wherein the particles have a substantially spherical morphology. 152. The solid composition of any one of clauses 137-149, wherein the particles are uniform-sized particles. 153. The solid composition of any one of clauses 137-149, wherein the particles are substantially monodisperse. 154. The injectable composition of any one of clauses 1-115, wherein the stabilizing agent is a carbohydrate. 155. The injectable composition of any one of clauses 1-115, wherein the stabilizing agent is selected from monosaccharide, reduced sugar, disaccharide, cyclodextrin and dextrin.Attorney Docket No.38821-63329 (008WO) 156. The injectable composition of any one of clauses 1-115 and 155, wherein the stabilizing agent is a disaccharide is selected from lactose, sucrose, trehalose, and cellobiose. 157. The injectable composition of any one of clauses 1-115 and 155-156, wherein stabilizing agent is mannitol is selected from glucose, mannose, and mannitol. 158. The injectable composition of any one of clauses 1-115 and 155-157, wherein the particles comprise at least 5 wt% stabilizing agent (e.g., at least 7.5 wt%, at least 10 wt%, at least 12.5 wt%, at least 14 wt%, at least 16.5 wt%, etc.). 159. The injectable composition of any one of clauses 1-115 and 155-158, wherein the particles comprise from 5 to 25 wt% stabilizing agent (e.g., from 5 to 20 wt%, from 5 to 15 wt%, or from 10 to 15 wt%, etc.). 160. The injectable composition of any one of clauses 1-115 and 155-159, wherein the stabilizing agent is an amino acid (e.g., naturally occurring or non-naturally occurring). 161. The injectable composition of clause 160, wherein the amino acid is selected from arginine, histidine, isoleucine, leucine, glutamic acid, glycine, methionine, phenylalanine, proline, tryptophan and tyrosine. 162. The injectable composition of any one of clauses 1-115 and 155-161, wherein the particles comprise at least 5 wt% amino acid stabilizer (e.g., at least 7.5 wt%, at least 10 wt%, at least 12.5 wt%, etc.). 163. The injectable composition of any one of clauses 1-115 and 155-161, wherein the particles comprise from 5 to 25 wt% amino acid stabilizer (e.g., from 5 to 20 wt%, from 5 to 15 wt%, or from 10 to 15 wt%, etc.). 164. The injectable composition of any one of clauses 1-115 and 155-163, wherein the particles further comprise an antioxidant. 165. The injectable composition of clause 164, wherein the antioxidant is selected from methionine, carotenes (e.g., beta carotene), ascorbates (e.g., vitamin C, ascorbic acid), tocopherols (e.g., vitamin E), tocotrienols, ascorbic acid, fumaric acid, maleic acid, sodium edetate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), thiols (e.g., glutathione), polyphenols (e.g., resveratrol), sodium metabisulfite, and citric acid. 166. The injectable composition of any one of clauses 1-115 and 155-165, further comprising one or more of solubilizing agent, permeation enhancer, buffering agent, pH regulator, surfactant, lipid, preservative, filler, bulking agent, or viscosity modifier. 167. The injectable composition of any one of clauses 1-115 and 155-166, further comprising a tonicity agent.Attorney Docket No.38821-63329 (008WO) 168. The injectable composition of clause 167, wherein the tonicity agent is selected from saline, glycerol, and propylene glycol. 169. The injectable composition of any one of clauses 1-115 and 155-168, wherein the biopharmaceutical agent is a peptide, peptide analog or peptide conjugate. 170. The injectable composition of clause 169, wherein the pharmaceutical agent is a peptide conjugate (e.g., a peptide-small molecule conjugate, or a peptide-fatty acid conjugate). 171. The injectable composition of clause 169 or 170, wherein the biopharmaceutical agent comprises a macrocyclic peptide. 172. The injectable composition of clause 169 or 170, wherein the biopharmaceutical agent is a peptide-fatty acid conjugate. 173. The injectable composition of clause 173, the biopharmaceutical agent is an oligonucleotide containing therapeutic agent. 174. The injectable composition of clause 173, wherein the biopharmaceutical agent is an oligonucleotide conjugate (e.g., an oligonucleotide-peptide conjugate, an oligonucleotide- antibody conjugate, or an oligonucleotide-targeting agent conjugate). 175. The injectable composition of clause 173 or 174, wherein the oligonucleotide is selected from antisense oligonucleotide (ASO), aptamer, RNAi, siRNA, shRNA, antagomir, microRNA (miRNA), a pre-miRNA, miR mimic, and splice switching oligonucleotide (SSO). 176. The injectable composition of clause 175, wherein the biopharmaceutical agent an antibody-siRNA conjugate or peptide-siRNA conjugate. 177. An injectable pharmaceutical composition comprising a plurality of particles and a liquid carrier in which the particles are suspended, wherein the particles comprise: 70 wt% (e.g., 75 wt%, 80 wt%, 85 wt%, or 90%) or more of a biopharmaceutical agent; an optional polyacrylamide-based copolymer; an optional stabilizing agent; and the composition comprises at least 500 mg / mL (e.g., at least 510 mg / mL, at least 520 mg / mL, at least 530 mg / mL, at least 540 mg / mL, at least 550 mg / mL, at least 560 mg / mL, at least 570 mg / mL, at least 580 mg / mL, at least 590 mg / mL, at least 600 mg / mL, at least 610 mg / mL, at least 620 mg / mL, at least 630 mg / mL, at least 640 mg / mL, or at least 650 mg / mL) of the biopharmaceutical agent.Attorney Docket No.38821-63329 (008WO) 178. A storage stable solid composition comprising a plurality of particles, the particles comprising: a biopharmaceutical agent (e.g., as described herein); a polyacrylamide-based copolymer (e.g., as described herein); and a stabilizer (e.g., as described herein). 179. The composition of clause 178, wherein the weight ratio of the biopharmaceutical agent to the polyacrylamide-based copolymer to the stabilizer is 15:1:1 or greater (e.g., 16:1:1 or greater, 17:1:1 or greater, 18:1:1 or greater, 19:1:1 or greater, 20:1:1 or greater, 15:1:2 or greater, 16:1:2 or greater, 17:1:2 or greater, 18:1:2 or greater, 19:1:2 or greater, 20:1:2 or greater, 15:1:3 or greater, 16:1:3 or greater, 17:1:3 or greater, 18:1:3 or greater, 19:1:3 or greater, or 20:1:3 or greater). 6. EXAMPLES

[0476] 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 routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare the compounds and compositions described herein. General Methods

[0477] All reagent grade materials and solvents were purchased from Sigma Aldrich or Fisher and used as received. Alexa-647-NHS was purchased from Lumiprobe. Slide-A-Lyzer dialysis cassettes (2 kDa MWCO) from Thermo Fisher were used for polymer purification. BSA (A2153-50G, CAS-No:9048-46-8) was purchased as a lyophilized powder from Sigma Aldrich. Human IgG (Cat No: 340-21, Lot: 07J4627) was purchased as a lyophilized powder from Medix Biochemica. HyPure™ Cell Culture Grade Water was purchased from Cytiva. Phosphate Buffered Saline (10010-023) was purchased from Gibco. Syringes used for injection force measurements are Fisherbrand 1mL plastic leur lock syringes (Cat. No: 14955464). Syringes used for formulating protein suspensions with non-solvent were Thermo Scientific 5mL leur slip plastic syringe (Cat. No: S7510-5). Needles used for injection force measurements were BD PrecisionGlide™ needles (26G, ½ in, Ref: 305111). In-vivo proteinAttorney Docket No.38821-63329 (008WO) suspension delivery was performed using BD Insulin Syringes with BD Micro-Fine™ IV Needles (28G, 12.7mm). Statistical analysis

[0478] Injection force data is reported as means with standard deviation. For in vivo experiments, animals were cage blocked, and Mead's Resource Equation was used to identify a sample size above that additional subjects will have little impact on power. Normalized fluorescence intensity and half-life of subcutaneous absorption from in-vivo experiments are reported as means with standard error. Comparison between groups was conducted with the Tukey HSD test in JMP. Results were accepted as significant if p < 0.05. 6.1.1. Example 1 – Synthesis of polyacrylamide-based copolymers General Methods

[0479] Polyacrylamide-based copolymer synthesis: The polyacrylamide-based copolymers may be synthesized using any convenient method. Methods which can be used or adapted for use in preparing copolymers of this disclosure include the exemplary synthetic methods described herein in Example 1.1, and those methods described by Appel et al. in PCT application No. PCT / US2021 / 027693, filed April 16, 2021, and by Mann et al., Sci. Transl. Med. 12, eaba6676 (2020), the disclosures of which are herein incorporated by reference in their entirety.

[0480] Copolymer molecular weight characterization: Mn, Mw, and dispersity for copolymers with HEAM, DMA, MPAM, and MORPH carrier monomers are determined via SEC implementing poly(ethylene glycol) standards (American Polymer Standards Corporation) after passing through two size exclusion chromatography columns.

[0481] 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. Example 1.1 – Synthesis of MoNiAttorney Docket No.38821-63329 (008WO)

[0482] The amphiphilic acrylamide copolymer excipient 4-acryloylmorpholine77%-N- isopropylacrylamide23% (MoNi 77:23, also referred to herein as “MoNi”) was prepared according to methods described by Mann et al., Sci. Transl. Med. 12, eaba6676 (2020). Briefly, MORPH (645 mg, 4.57 mmol, 41.5 eq.), NIP (105 mg, 0.93 mmol, 8.5 eq.), RAFT CTA 2-cyano-2-propyl dodecyl trithiocarbonate (2-CPDT) (38 mg, 0.11 mmol, 1 eq.), and initiator 2,2-azobis(2-methyl-propionitrile) AIBN (3.6 mg, 0.02 mmol, 0.2 eq.) were combined and diluted with N,N-dimethylformamide (DMF) to a total volume of 2.25 mL (33.3 (w / v) vinyl monomer concentration) in an 8-mL scintillation vial equipped with a PTFE septa. The reaction mixture was sparged with nitrogen gas for 10 min and then heated for 12 hours at 65°C. To remove the CTA Z terminus of the resulting polymer, AIBN (360 mg, 2.2 mmol, 20 eq.) and lauroyl peroxide (LPO) (88 mg, 0.22 mmol, 2 eq.) were added to the reaction mixture, which was then sparged with nitrogen gas for 10 min and heated for 12 hours at 90°C. CTA Z group removal was confirmed by the ratio of the refractive index to ultraviolet (310 nm) intensity in size exclusion chromatography (SEC) analysis. Resulting polymers were precipitated three times from ether and dried under vacuum overnight. Resulting composition and molecular weights were determined via1H NMR spectroscopy (e.g., in d6-DMSO) and SEC with PEG standards. Example 1.2 - Copolymer molecular weight characterization by SEC

[0483] Mn, Mw, and Ð for MoNi was determined via SEC implementing PEG standards (American Polymer Standards Corporation) after passing through two SEC columns [inner diameter, 7.8 mm; Mw range, 200 to 600,000 g mol-1; Resolve Mixed Bed Low divinylbenzene (DVB) (Jordi Labs)] in a mobile phase of DMF with 0.1 M LiBr at 35°C anda flow rate of 1.0 mL min 1 [Dionex UltiMate 3000 pump, degasser, and autosampler(Thermo Fisher Scientific)].

[0484] MoNi polymer was also characterized by determining the molecular weight (Mn SEC) and dispersity using an RI detector and polymethylmethacrylate standards. The running solvent was N,N-dimethylformamide (DMF) with 1 g / L LiBr (flow rate: 1mL / min) heated to 50 °C and samples were prepared at 5 mg / mL. Separation was done through two Jordi Labs Resolve Mixed Bed Low Divinylbenzene (DVB) columns in series and data was collected by a Dionex Ultimate 3000 Variable Wavelength detector and RefractoMax521 RI detector. The RI traces were normalized and areas under the curves for the 310 nm absorbance signals were calculated with Prism 10.Attorney Docket No.38821-63329 (008WO)

[0485] FIG. 1, panels a to c illustrate characterization of MoNi. Panel a depicts a SEC trace of MoNi. Panel b depicts a1H NMR of MoNi. Panel c depicts a DSC of MoNi at a temperature ramp and cooling rate of 10 °C / min showing a glass transition temperature between 130 and 140 °C (top line = cooling; lower line = heating). 6.1.2. Example 2 – Preparation of particles and particle suspensions

[0486] Particles and particle suspensions including a subject polyacrylamide-based copolymer and a protein agent were prepared by one of the following methods. Example 2.1 - General Method A - Lyophilization and ball milling

[0487] The protein agent in water is optionally combined with a subject polyacrylamide- based copolymer and a buffer. The water is then removed by lyophilization, and the resulting mixture is milled to provide particles. A liquid carrier (e.g., as described herein) is then added to the particles with mixing to provide a suspension of the particles in the liquid carrier. Example 2.2 - General Method B – Spray drying

[0488] The protein agent in water, or an aqueous-organic solvent mixture, is optionally combined with a subject polyacrylamide-based copolymer. The water, or an aqueous-organic mixture, is then removed by spray drying to provide particles. A liquid carrier (e.g., as described herein) is then added to the particles with mixing to provide a suspension of the particles in the liquid carrier.

[0489] FIG. 2 illustrates a schematic of the spray drying process and formulation of example particle suspensions.

[0490] Method B1- Spray drying BSA particles: BSA feed solutions were prepared by dissolving lyophilized BSA in cell grade water at 2 wt% (20 mg / mL). BSA solutions filter. After sterile filtering, 7kDa MoNi was added to the feed solution at a concentration of 0.1wt% (1 mg / mL). Feed solutions were stored on ice prior to spray drying.

[0491] Samples were spray dried using a Buchi B-290 Mini Spray Dryer equipped with a high-performance cyclone. Samples were spray dried using an inlet temperature of 150 °CAttorney Docket No.38821-63329 (008WO) (outlet ~67 °C), aspirator pressure of 40 mm, and a pump rate of 20% (6 mL / min). Collected particles was transferred to a 50mL falcon tube and stored at 4 °C with desiccant.

[0492] Method B2- Spray drying BSA particles with polysorbate 80 (Tween 80): BSA feed solutions were prepared by dissolving lyophilized BSA in cell grade water at 2 wt% (20 mg / mL). BSA solutions dissolved at room temperature for one hour prior to sterile filtering 80 was added to the feed solution at a concentration of 0.0176 wt% (0.176 mg / mL). Polysorbate 80 concentration was chosen to add equal moles of MoNi and polysorbate 80 to the spray drying feed solution. Feed solutions were stored on ice prior to spray drying.

[0493] Samples were spray dried using a Buchi B-290 Mini Spray Dryer equipped with a high-performance cyclone. Samples were spray dried using an inlet temperature of 150 °C (outlet ~67 °C), aspirator pressure of 40 mm, and a pump rate of 20% (6 mL / min). Collected particles was transferred to a 50mL falcon tube and stored at 4 °C with desiccant.

[0494] Method B3- Spray drying human immunoglobulin G (hIgG) particles: hIgG feed solutions were prepared by dissolving lyophilized hIgG in cell grade water at 10 wt% (100 mg / mL). hIgG solutions dissolved at 4 °C for four hours prior to sterile filtering using a 0.2 minimized by filtering 2 wt% BSA through the sterile filter followed by five water rinses. Nanodrop was used to confirm BSA was not detectable in the filtrate. After sterile filtering the hIgG, 7kDa MoNi was added to the feed solution at a concentration of 0.5 wt% (5 mg / mL). Feed solutions were stored on ice prior to spray drying.

[0495] Samples were spray dried using a Buchi B-290 Mini Spray Dryer equipped with a high-performance cyclone. Samples were spray dried using an inlet temperature of 130 °C (outlet ~77 °C), aspirator pressure of 40 mm, and a pump rate of 5% (2 mL / min). Collected particles was transferred to a 50mL falcon tube and stored at 4 °C with desiccant.

[0496] Particle characterization: Particle morphology was characterized by scanning electron microscopy (SEM). Samples were grounded to an aluminum pin stub using double-sided conductive copper tape. A 5.0 nm thick layer of pure gold was deposited onto the samples using a Leica ACE600 Vacuum system. SEM analysis was performed using the FEI Magellan 400 XHR Scanning Electron Microscope at 5.00 kV and high vacuum in field-free mode.Attorney Docket No.38821-63329 (008WO)

[0497] Particle density was measured using an AccuPyc 1330. A known sample mass of spray dried particles between 200 and 300 mg was measured into a small sample cell with a volume of 1 cm3. Particle volume was measured over 999 cycles. The known mass, as measured by analytical balance, and the average sample volume was used to calculate particle density.

[0498] Formulating suspensions: Suspensions were formulated by combining a known mass of spray dried particles with a known volume of non-solvent. Protein concentration in mg / mL was determined by assuming total volume encompassed non-solvent volume as well as spray dried particle volume. Unless otherwise specified, protein particles were assumed to have a density of 1 g / cm3.

[0499] To minimize non-solvent evaporation when preparing suspensions, spray dried particles were added to the barrel of a 6mL luer slip syringe. The mass of spray dried particles was measured using an analytical balance. The desired volume of non-solvent or non-solvent combination was added to the syringe barrel through the syringe tip using a p200 pipette. After the syringe was capped, and the protein suspension was mixed inside the syringe using a vortex for 5 minutes or until all powder was fully dispersed. Protein suspensions were transferred from 6mL luer slip syringes to the alternative desired syringe (1 mL luer lock syringes or insulin syringes) by back loading for force of injection experiments or animal experiments respectively. Example 2.3 - Characterizing flow properties of particle suspensions

[0500] The flow properties of particle suspensions were characterized through rheology and injection force measurements.

[0501] Rheological characterization: Rheological testing was performed using a stress- controlled TA Instruments DHR-2 rheometer. Rheology of solid-like formulations (BSA without MoNi) was performed at 25 °C using a 20 mm diameter serrated parallel plate at a 500 μm gap. Rheology of liquid-like formulations (BSA with MoNi) was performed at 25 °C using a 40 mm cone geometry with a 50 μm gap. Frequency sweeps were performed at a strain of 1% within the linear viscoelastic regime. Flow sweeps were performed from high to low shear rates with steady state sensing.Attorney Docket No.38821-63329 (008WO)

[0502] Injection force measurements: Force of injection was quantified by measuring the force required to inject a protein particle suspension through a known needle gauge at a known flow rate using a syringe of known barrel dimensions. A force sensor was built that encompassed a load cell (FUTEK LLB30050 lb Subminiture Load Button (Model #: LLB300, Item #: FSH03954, Serial #: 705242) attached to a syringe pump (KD Scientific Syringe Pump (Model #: LEGATO 100, Catalog #: 788100, Serial #: D103954)). An Omega Engineering Platinum Series Meter (Model #: DP8PT, Serial #: 18110196) was used to translate load cell resistance measurements to force values in Kg. The load cell was calibrated prior to measuring injection force. A lab view program records the forces measured throughout the duration of an injection experiment and displays a graph of injection force over time.

[0503] Injection force experiments were performed as follows. A 1mL Thermo Fisher luer lock syringe with the desired needle gauge was loaded into the syringe pump. The syringe pump height was adjusted so that the load button of the force sensor was in contact with the end of the syringe plunger. The initial force was at or very close to 0 Kg. The appropriate syringe barrel dimensions as well as desired flow rate and injection volume were then selected. The syringe pump moved at the programmed rate injecting protein suspension through the attached needle. The force sensor coupled with the Omega unit measured the force required to inject the protein suspension at the desired flow rate. A lab view program recorded the forces measured throughout the duration of an injection experiment and displayed a graph of injection force over time. Force of injection was quantified by subtracting the average initial force (background) from the average plateau injection force. Injection force in Kg was converted to injection force in Newtons by multiplying by 9.81.

[0504] Exemplary Formulations: Tables 1 and 2 below provide formulations obtained by General Method A and General Method B respectively.

[0505] Table 1: Bovine serum albumin (BSA) injectable formulations prepared by General Method A:Attorney Docket No.38821-63329 (008WO) Table 1: BSA Formulations – Prepared by General Method A

[0506] Formulations 2, 4, 5 and 7 include the polyacrylamide-based copolymer MoNi. Formulations 1, 3 and 6 and comparative injectable formulations that do not include a subject polyacrylamide-based copolymer.Attorney Docket No.38821-63329 (008WO)

[0507] With reference to formulations 6 and 7, as seen in Table 1 formulation 7 which includes the subject copolymer MoNi as a polymer additive in the particles and a total solids content of 460 mg / mL is injectable through both a 21G and a 26G needle, whereas formulation 6 which has a lower total solids content and does not include any polymer additive is injectable through a 21G needle, but not a ...

Claims

Attorney Docket No.38821-63329 (008WO) WHAT IS CLAIMED IS:

1. A solid composition comprising a plurality of particles, the particles comprising: a biopharmaceutical agent; a polyacrylamide-based copolymer; and optionally, a stabilizing agent.

2. The solid composition of claim 1, wherein the particles comprising a weight ratio of a biopharmaceutical agent to a polyacrylamide-based copolymer of 10:1 or greater.

3. The composition of claim 2, wherein the weight ratio of the biopharmaceutical agent to the polyacrylamide-based copolymer is 11:1 or greater (e.g., 12:1 or greater, 13:1 or greater, 14:1 or greater, 15:1 or greater, 16:1 or greater, 17:1 or greater, 18:1 or greater, 19:1 or greater, 20:1 or greater, 21:1 or greater, 22:1 or greater, 23:1 or greater, 24:1 or greater, or 25:1 or greater).

4. The composition of any one of claims 1 to 3, wherein the particles comprise 50 wt% or more of the biopharmaceutical agent (e.g., 60 wt% or more, 70 wt% or more, 80 wt% or more, or more, or 90 wt% or more) of the biopharmaceutical agent.

5. The composition of any one of claims 1 to 4, wherein the particles comprise 5 wt% or less of the polyacrylamide-based copolymer (e.g., 0.1 to 5 wt%, 1 to 5 wt%, etc.).

6. The composition of any one of claims 1 to 5, wherein the particles comprise 50 wt% or less of a stabilizing agent (e.g., 15 wt% or less, 15 wt% or less, 15 wt% or less, 15 wt% or less, 10 wt%, 5 wt% or less, etc.).

7. The composition of any one of claims 1 to 6, wherein the particles comprise: 70 wt% or more of a biopharmaceutical agent; optionally, 5 wt% or less of a polyacrylamide-based copolymer; and optionally, 25 wt% or less of a stabilizing agent.

8. The composition of claim 6, wherein the particles consist of: 90 wt% or more of the biopharmaceutical agent;Attorney Docket No.38821-63329 (008WO) 5 wt% or less of the polyacrylamide-based copolymer; and 5 wt% or less of an optional aqueous component, wherein the aqueous component optionally includes a buffer.

9. The composition of claim 7 or 8, wherein the biopharmaceutical agent is 91 wt% or more (e.g., 92 wt% or more, 93 wt% or more, 94 wt% or more, 95 wt% or more, 96 wt% or more, 97 wt% or more, 98 wt% or more, or 99 wt% or more) of the particles, particularly 95 wt% or more of the particles.

10. The composition of any one of claims 7 to 9, wherein the polyacrylamide-based copolymer is 4.5 wt% or less (e.g., 4 wt% or less, 3.5 wt% or less, 3 wt% or less, 2.5 wt% or less, 2 wt% or less, 1.5 wt% or less, or 1 wt% or less) of the particles.

11. The composition of any one of claims 7 to 10, wherein the ratio of the polyacrylamide-based copolymer to the biopharmaceutical agent in the particles is 5:95 or less (e.g., 4:96 or less, 3:97 or less, 2:98 or less, or 1:99 or less).

12. The composition of any one of claims 7 to 11, wherein the particles comprise 5 wt% or less of an aqueous component consisting of a buffer (e.g., 4 wt% or less, 3 wt% or less, 2 wt% or less, or 1 wt% or less).

13. The composition of any one of claims 1 to 12, wherein the particles have a mean diameter of 50 microns or less (e.g., 40 microns or less, 30 microns or less, 25 microns or less, 20 microns or less, 15 microns or less, 10 microns or less, 9 microns or less, 8 microns or less, 7 microns or less, 6 microns or less, or 5 microns or less).

14. The composition of claim 13, wherein the particles have a mean diameter of from 0.2 to 10 microns (e.g., from 0.2 to 9 microns, from 0.2 to 8 microns, from 0.2 to 7 microns, from 0.2 to 6 microns, or from 0.2 to 5 microns), such as from 1 to 10 microns (e.g., from 1 to 9 microns, from 1 to 8 microns, from 1 to 7 microns, from 1 to 6 microns, or from 1 to 5 microns).Attorney Docket No.38821-63329 (008WO) 15. The composition of claim 13, wherein the particles have a mean diameter of from 5 to 50 microns (e.g., from 5 to 40 microns, from 5 to 30 microns, from 5 to 25 microns, from 5 to 20 microns, from 5 to 15 microns, or from 5 to 10 microns).

16. The composition of any one of claims 1 to 15, wherein the particles have a volume median diameter (VMD) of between 1 and 10 microns (e.g., between 1 and 5 microns, or between 2 and 3 microns).

17. The composition of any one of claims 1 to 16, wherein the particles have a particle size distribution characterized by at least 90% of the particles having a diameter (D90) of 50 microns or less (e.g., 40 microns or less, 30 microns or less, 25 microns or less, 20 microns or less, 15 microns or less, 10 microns or less, 9 microns or less, 8 microns or less, 7 microns or less, 6 microns or less, or 5 microns or less).

18. The composition of any one of claims 1 to 17, wherein the particles are polydisperse.

19. The composition of any one of claims 1 to 18, wherein the particles have a particle size distribution width (i.e., (D90-D10) / D50) of 1.1 or more (e.g., 1.1 or more, 1.2 or more, 1.3 or more, 1.4 or more, 1.5 or more, 1.6 or more, 1.7 or more, 1.8 or more, 1.9 or more, 2.0 or more, 2.1 or more, 2.2 or more, 2.3 or more, 2.4 or more, 2.5 or more, or 3.0 or more).

20. The composition of any one of claims 1 to 19, wherein the particles have a substantially spherical morphology (e.g., the particles are microspheres).

21. The composition of any one of claims 1 to 20, wherein the particles have a density from 1 g / cm3to 1.5 g / cm3(e.g., from 1.1 g / cm3to 1.5 g / cm3, from 1.2 g / cm3to 1.5 g / cm3, from 1.3 g / cm3to 1.5 g / cm3, from 1.4 g / cm3to 1.5 g / cm3, from 1 g / cm3to 1.4 g / cm3, from 1 g / cm3to 1.3 g / cm3, from 1.1 g / cm3to 1.4 g / cm3, from 1.2 g / cm3to 1.4 g / cm3, or from 1.25 g / cm3to 1.35 g / cm3).

22. The composition of claim 21, wherein the particles have a density of 1.2 g / cm3to 1.4 g / cm3, such as 1.25 g / cm3to 1.35 g / cm3(e.g., 1.25 g / cm3, 1.26 g / cm3, 1.27 g / cm3, 1.28 g / cm3, 1.29 g / cm3, 1.3 g / cm3, 1.31 g / cm3, 1.32 g / cm3, 1.33 g / cm3, 1.34 g / cm3, or 1.35 g / cm3).Attorney Docket No.38821-63329 (008WO) 23. The composition of any one of claims 1 to 22, wherein the composition is storage stable.

24. An injectable pharmaceutical composition comprising: a solid composition of any one of claims 1 to 23; and a liquid carrier in which the particles are suspended.

25. The injectable pharmaceutical composition of claim 24, wherein the composition comprises at least 500 mg / mL of the biopharmaceutical agent (e.g., at least 510 mg / mL, at least 520 mg / mL, at least 530 mg / mL, at least 540 mg / mL, at least 550 mg / mL, at least 560 mg / mL, at least 570 mg / mL, at least 580 mg / mL, at least 590 mg / mL, or at least 600 mg / mL).

26. The injectable pharmaceutical composition of claim 24, wherein the composition comprises 400 to 800 mg / mL of the biopharmaceutical agent (e.g., 425 to 800 mg / mL, 450 to 800 mg / mL, 475 to 800 mg / mL, 500 to 800 mg / mL, 525 to 800 mg / mL, 550 to 800 mg / mL, 575 to 800 mg / mL, 600 to 800 mg / mL, 625 to 800 mg / mL, 650 to 800 mg / mL, 675 to 800 mg / mL, 700 to 800 mg / mL, 750 to 800 mg / mL, 425 to 800 mg / mL, 775 to 800 mg / mL, 425 to 750 mg / mL, 450 to 750 mg / mL, 475 to 750 mg / mL, 500 to 750 mg / mL, 525 to 750 mg / mL, 550 to 750 mg / mL, 575 to 750 mg / mL, 600 to 750 mg / mL, 625 to 750 mg / mL, 650 to 750 mg / mL, 675 to 750 mg / mL, 700 to 750 mg / mL, 725 to 750 mg / mL, 425 to 700 mg / mL, 450 to 700 mg / mL, 475 to 700 mg / mL, 500 to 700 mg / mL, 525 to 700 mg / mL, 550 to 700 mg / mL, 575 to 700 mg / mL, 600 to 700 mg / mL, 625 to 700 mg / mL, 650 to 700 mg / mL, 675 to 700 mg / mL, 425 to 650 mg / mL, 450 to 650 mg / mL, 475 to 650 mg / mL, 500 to 650 mg / mL, 525 to 650 mg / mL, 550 to 650 mg / mL, 575 to 650 mg / mL, 600 to 650 mg / mL, 625 to 650 mg / mL, 400 to 600 mg / mL, 425 to 600 mg / mL, 450 to 600 mg / mL, 475 to 600 mg / mL, 500 to 600 mg / mL, 525 to 600 mg / mL, 550 to 600 mg / mL, 575 to 600 mg / mL, 400 to 550 mg / mL, 425 to 550 mg / mL, 450 to 550 mg / mL, 475 to 550 mg / mL, 500 to 550 mg / mL, 525 to 550 mg / mL, 400 to 500 mg / mL, 425 to 500 mg / mL, 450 to 500 mg / mL, 475 to 500 mg / mL, 400 to 450 mg / mL, or 425 to 450 mg / mL).

27. The injectable pharmaceutical composition of claim 24 or 25, wherein the solid composition is a spray dried solid composition.Attorney Docket No.38821-63329 (008WO) 28. The injectable pharmaceutical composition of any one of claims 24 to 27, wherein the liquid carrier comprises one or more liquids selected from triacylglyceride, acetamide, fatty acid ester, aryl acid ester, and combinations thereof.

29. The injectable pharmaceutical composition of claim 28, wherein the liquid carrier comprises an aralkyl benzoate (e.g., benzyl benzoate).

30. The injectable pharmaceutical composition of claim 28, wherein the liquid carrier comprises a triacylglyceride that is triacetin.

31. The injectable pharmaceutical composition of claim 28, wherein the liquid carrier comprises N,N-dimethylacetamide (DMAc).

32. The injectable pharmaceutical composition of claim 28, wherein the liquid carrier comprises a fatty acid ester (e.g., ethyl oleate).

33. The injectable pharmaceutical composition of any one of claims 24 to 32, wherein the injectable pharmaceutical composition is injectable with a glide force of 500 to 8000 g (e.g., 1000 to 8000 g, 1500 to 8000 g, 2000 to 8000 g, 2500 to 8000 g, 3000 to 8000 g, 3500 to 8000 g, 4000 to 8000 g, 4500 to 8000 g, 5000 to 8000 g, 5500 to 8000 g, 6000 to 8000 g, 6500 to 8000 g, 7000 to 8000 g, 7500 to 8000 g, 1000 to 7500 g, 1500 to 7500 g, 2000 to 7500 g, 2500 to 7500 g, 3000 to 7500 g, 3500 to 7500 g, 4000 to 7500 g, 4500 to 7500 g, 5000 to 7500 g, 5500 to 7500 g, 6000 to 7500 g, 6500 to 7500 g, 7000 to 7500 g, 1000 to 7000 g, 1500 to 7000 g, 2000 to 7000 g, 2500 to 7000 g, 3000 to 7000 g, 3500 to 7000 g, 4000 to 7000 g, 4500 to 7000 g, 5000 to 7000 g, 5500 to 7000 g, 6000 to 7000 g, 6500 to 7000 g, 1000 to 6500 g, 1500 to 6500 g, 2000 to 6500 g, 2500 to 6500 g, 3000 to 6500 g, 3500 to 6500 g, 4000 to 6500 g, 4500 to 6500 g, 5000 to 6500 g, 5500 to 6500 g, 6000 to 6500 g, 1000 to 6000 g, 1500 to 6000 g, 2000 to 6000 g, 2500 to 6000 g, 3000 to 6000 g, 3500 to 6000 g, 4000 to 6000 g, 4500 to 6000 g, 5000 to 6000 g, 5500 to 6000 g, 1000 to 5500 g, 1500 to 5500 g, 2000 to 5500 g, 2500 to 5500 g, 3000 to 5500 g, 3500 to 5500 g, 4000 to 5500 g, 4500 to 5500 g, 5000 to 5500 g, 1000 to 5000 g, 1500 to 5000 g, 2000 to 5000 g, 2500 to 5000 g, 3000 to 5000 g, 3500 to 5000 g, 4000 to 5000 g, 4500 to 5000 g, 1000 to 4500 g, 1500 to 4500 g, 2000 to 4500 g, 2500 to 4500 g, 3000 to 4500 g, 3500 to 4500 g, 4000 to 4500 g, 1000 to 4000 g, 1500 to 4000 g, 2000 to 4000 g, 2500 to 4000 g,Attorney Docket No.38821-63329 (008WO) 3000 to 4000 g, 3500 to 4000 g, 1000 to 3500 g, 1500 to 3500 g, 2000 to 3500 g, 2500 to 3500 g, 3000 to 3500 g, 1000 to 3000 g, 1500 to 3000 g, 2000 to 3000 g, 2500 to 3000 g, 1000 to 2500 g, 1500 to 2500 g, 2000 to 2500 g, 1000 to 2000 g, 1500 to 2000 g, or 1000 to 1500 g).

34. An injectable pharmaceutical composition comprising: particles, the particles comprising: a biopharmaceutical agent; and a polyacrylamide-based copolymer; and a liquid carrier in which the particles are suspended, wherein: the injectable pharmaceutical composition comprises at least 500 mg / mL of the biopharmaceutical agent; and the liquid carrier is ethyl oleate.

35. An injectable pharmaceutical composition comprising: particles, the particles comprising: a biopharmaceutical agent; and a polyacrylamide-based copolymer; and a liquid carrier in which the particles are suspended, wherein: the injectable pharmaceutical composition comprises at least 500 mg / mL of the biopharmaceutical agent; and the liquid carrier is triacetin, or a mixture comprising at least 50% v / v triacetin (e.g., at least 75% v / v, or at least 90% v / v) and dimethylacetamide (DMAC).

36. An injectable pharmaceutical composition comprising: particles, the particles comprising: a biopharmaceutical agent; and a polyacrylamide-based copolymer; and a liquid carrier in which the particles are suspended, wherein: the injectable pharmaceutical composition comprises at least 500 mg / mL of the biopharmaceutical agent; andAttorney Docket No.38821-63329 (008WO) the liquid carrier is benzyl benzoate, or a mixture comprising at least 50% v / v benzyl benzoate (e.g., at least 75% v / v, or at least 90% v / v) and dimethylacetamide (DMAC).

37. The injectable pharmaceutical composition of any one of claims 34 to 36, wherein the injectable pharmaceutical composition comprises at least 510 mg / mL (e.g., at least 520 mg / mL, at least 530 mg / mL, at least 540 mg / mL, at least 550 mg / mL, at least 560 mg / mL, at least 570 mg / mL, at least 580 mg / mL, at least 590 mg / mL, at least 600 mg / mL, at least 610 mg / mL, at least 620 mg / mL, at least 630 mg / mL, at least 640 mg / mL, or at least 650 mg / mL) of the biopharmaceutical agent.

38. The injectable pharmaceutical composition of any one of claims 34 to 36, wherein: the injectable pharmaceutical composition comprises 400 to 800 mg / mL of the biopharmaceutical agent (e.g., 425 to 800 mg / mL, 450 to 800 mg / mL, 475 to 800 mg / mL, 500 to 800 mg / mL, 525 to 800 mg / mL, 550 to 800 mg / mL, 575 to 800 mg / mL, 600 to 800 mg / mL, 625 to 800 mg / mL, 650 to 800 mg / mL, 675 to 800 mg / mL, 700 to 800 mg / mL, 750 to 800 mg / mL, 425 to 800 mg / mL, 775 to 800 mg / mL, 425 to 750 mg / mL, 450 to 750 mg / mL, 475 to 750 mg / mL, 500 to 750 mg / mL, 525 to 750 mg / mL, 550 to 750 mg / mL, 575 to 750 mg / mL, 600 to 750 mg / mL, 625 to 750 mg / mL, 650 to 750 mg / mL, 675 to 750 mg / mL, 700 to 750 mg / mL, 725 to 750 mg / mL, 425 to 700 mg / mL, 450 to 700 mg / mL, 475 to 700 mg / mL, 500 to 700 mg / mL, 525 to 700 mg / mL, 550 to 700 mg / mL, 575 to 700 mg / mL, 600 to 700 mg / mL, 625 to 700 mg / mL, 650 to 700 mg / mL, 675 to 700 mg / mL, 425 to 650 mg / mL, 450 to 650 mg / mL, 475 to 650 mg / mL, 500 to 650 mg / mL, 525 to 650 mg / mL, 550 to 650 mg / mL, 575 to 650 mg / mL, 600 to 650 mg / mL, 625 to 650 mg / mL, 400 to 600 mg / mL, 425 to 600 mg / mL, 450 to 600 mg / mL, 475 to 600 mg / mL, 500 to 600 mg / mL, 525 to 600 mg / mL, 550 to 600 mg / mL, 575 to 600 mg / mL, 400 to 550 mg / mL, 425 to 550 mg / mL, 450 to 550 mg / mL, 475 to 550 mg / mL, 500 to 550 mg / mL, 525 to 550 mg / mL, 400 to 500 mg / mL, 425 to 500 mg / mL, 450 to 500 mg / mL, 475 to 500 mg / mL, 400 to 450 mg / mL, or 425 to 450 mg / mL); and the injectable pharmaceutical composition is injectable with a glide force of 500 to 8000 g (e.g., 1000 to 8000 g, 1500 to 8000 g, 2000 to 8000 g, 2500 to 8000 g, 3000 to 8000 g, 3500 to 8000 g, 4000 to 8000 g, 4500 to 8000 g, 5000 to 8000 g, 5500 to 8000 g, 6000 to 8000 g, 6500 to 8000 g, 7000 to 8000 g, 7500 to 8000 g, 1000 to 7500 g, 1500 to 7500 g, 2000 to 7500 g, 2500 to 7500 g, 3000 to 7500 g, 3500 to 7500 g, 4000 to 7500 g, 4500 to 7500 g, 5000 to 7500 g, 5500 to 7500 g, 6000 to 7500 g, 6500 to 7500 g, 7000 to 7500 g,Attorney Docket No.38821-63329 (008WO) 1000 to 7000 g, 1500 to 7000 g, 2000 to 7000 g, 2500 to 7000 g, 3000 to 7000 g, 3500 to 7000 g, 4000 to 7000 g, 4500 to 7000 g, 5000 to 7000 g, 5500 to 7000 g, 6000 to 7000 g, 6500 to 7000 g, 1000 to 6500 g, 1500 to 6500 g, 2000 to 6500 g, 2500 to 6500 g, 3000 to 6500 g, 3500 to 6500 g, 4000 to 6500 g, 4500 to 6500 g, 5000 to 6500 g, 5500 to 6500 g, 6000 to 6500 g, 1000 to 6000 g, 1500 to 6000 g, 2000 to 6000 g, 2500 to 6000 g, 3000 to 6000 g, 3500 to 6000 g, 4000 to 6000 g, 4500 to 6000 g, 5000 to 6000 g, 5500 to 6000 g, 1000 to 5500 g, 1500 to 5500 g, 2000 to 5500 g, 2500 to 5500 g, 3000 to 5500 g, 3500 to 5500 g, 4000 to 5500 g, 4500 to 5500 g, 5000 to 5500 g, 1000 to 5000 g, 1500 to 5000 g, 2000 to 5000 g, 2500 to 5000 g, 3000 to 5000 g, 3500 to 5000 g, 4000 to 5000 g, 4500 to 5000 g, 1000 to 4500 g, 1500 to 4500 g, 2000 to 4500 g, 2500 to 4500 g, 3000 to 4500 g, 3500 to 4500 g, 4000 to 4500 g, 1000 to 4000 g, 1500 to 4000 g, 2000 to 4000 g, 2500 to 4000 g, 3000 to 4000 g, 3500 to 4000 g, 1000 to 3500 g, 1500 to 3500 g, 2000 to 3500 g, 2500 to 3500 g, 3000 to 3500 g, 1000 to 3000 g, 1500 to 3000 g, 2000 to 3000 g, 2500 to 3000 g, 1000 to 2500 g, 1500 to 2500 g, 2000 to 2500 g, 1000 to 2000 g, 1500 to 2000 g, or 1000 to 1500 g).

39. The injectable pharmaceutical composition of claim 38, wherein the injectable pharmaceutical composition comprises 500 to 750 mg / mL of the biopharmaceutical agent, wherein the composition is injectable with a glide force of 1000 to 4500 g.

40. The injectable pharmaceutical composition of any one of claims 34-39, wherein the composition is capable of being injected at a rate of 6 mL / min through a glass syringe with a staked, 27 G ultra thin-walled, ½'' needle with an injection force of 50 N or less.

41. The injectable pharmaceutical composition of claim 39 or 40, wherein the composition comprises a 3:1 to 1:3 weight to weight ratio of the liquid carrier to the particles (e.g., 2:1, 1:1, or 1:2).

42. The injectable pharmaceutical composition of any one of claims 39-41, further comprising one or more of a stabilizing agent, preservative, filler, bulking agent, sugar, polysaccharide, or viscosity modifier.

43. The injectable pharmaceutical composition of claim 42, further comprising a stabilizing agent.Attorney Docket No.38821-63329 (008WO) 44. The injectable pharmaceutical composition of claim 43, wherein the stabilizing agent is selected from surfactants, poloxamers, povidones, polyvinylpyrrolidone (PVP) polymer, polyvinyl alcohol (PVA) polymer, carbohydrates, polysaccharides (e.g., dextrans, alginates), cellulosics (e.g., hydroxypropyl methyl cellulose (HPMC), sugars, reduced sugars, methyl cellulose (MC)), amphoteric compounds, salts, amino acids, and combinations thereof.

45. The injectable pharmaceutical composition of claim 44, wherein the stabilizing agent is a carbohydrate.

46. The injectable pharmaceutical composition of claim 44 or 45, wherein the stabilizing agent is selected from monosaccharide, reduced sugar, disaccharide, cyclodextrin and dextrin.

47. The injectable pharmaceutical composition of claim 46, wherein the stabilizing agent is a disaccharide is selected from lactose, sucrose, trehalose, and cellobiose.

48. The injectable pharmaceutical composition of claim 47, wherein the disaccharide is trehalose.

49. The injectable pharmaceutical composition of claim 46, wherein the stabilizing agent is a monosaccharide or reduced sugar.

50. The injectable pharmaceutical composition of claim 44, wherein the stabilizing agent is selected from glucose, mannose, and mannitol.

51. The injectable pharmaceutical composition of any one of claims 44-50, wherein the particles comprise at least 5 wt% stabilizing agent (e.g., at least 7.5 wt%, at least 10 wt%, at least 12.5 wt%, at least 14 wt%, at least 16.5 wt%, etc.).

52. The injectable pharmaceutical composition of claim 51, wherein the particles comprise from 5 to 25 wt% stabilizing agent (e.g., from 5 to 20 wt%, from 5 to 15 wt%, or from 10 to 15 wt%, etc.).Attorney Docket No.38821-63329 (008WO) 53. The injectable pharmaceutical composition of claim 44, wherein the stabilizing agent is an amino acid (e.g., naturally occurring or non-naturally occurring).

54. The injectable pharmaceutical composition of claim 53, wherein the amino acid is selected from arginine, histidine, isoleucine, leucine, glutamic acid, glycine, methionine, phenylalanine, proline, tryptophan and tyrosine.

55. The injectable pharmaceutical composition of claim 54, wherein the amino acid is arginine.

56. The injectable pharmaceutical composition of claim 54, wherein the amino acid is glycine, histidine, or proline.

57. The injectable pharmaceutical composition of any one of claims 53-56, wherein the particles comprise at least 5 wt% amino acid stabilizer (e.g., at least 7.5 wt%, at least 10 wt%, at least 12.5 wt%, etc.).

58. The injectable pharmaceutical composition of any one of claims 53-56, wherein the particles comprise at least 1 wt% amino acid stabilizer (e.g., at least 2wt%, at least 3 wt%, at least 5 wt%, at least 7.5 wt%, at least 10 wt%, etc.).

59. The injectable pharmaceutical composition of any one of claims 1-58, wherein the particles further comprise an antioxidant.

60. The injectable pharmaceutical composition of claim 59, wherein the antioxidant is selected from methionine, carotenes (e.g., beta carotene), ascorbates (e.g., vitamin C, ascorbic acid), tocopherols (e.g., vitamin E), tocotrienols, ascorbic acid, fumaric acid, maleic acid, sodium edetate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), thiols (e.g., glutathione), polyphenols (e.g., resveratrol), sodium metabisulfite, and citric acid.

61. The injectable pharmaceutical composition of claim 60, further comprising one or more of solubilizing agent, permeation enhancer, buffering agent, pH regulator, surfactant, lipid, preservative, filler, bulking agent, or viscosity modifier.Attorney Docket No.38821-63329 (008WO) 62. The injectable pharmaceutical composition of any one of claims 1-61, further comprising a tonicity agent.

63. The injectable pharmaceutical composition of claim 62, wherein the tonicity agent is selected from saline, glycerol, and propylene glycol.

64. The injectable pharmaceutical composition of any one of claims 24-63, wherein the biopharmaceutical agent comprises a polypeptide (e.g., peptide or protein).

65. The injectable pharmaceutical composition of claim 64, wherein the polypeptide is susceptible to aggregation in an aqueous medium.

66. The injectable pharmaceutical composition of claim 63 or 64, wherein the polypeptide is selected from antibodies and fragments thereof, cytokines, chemokines, hormones, vaccine antigens, cancer antigens, adjuvants, and conjugates thereof.

67. The injectable pharmaceutical composition of any one of claims 64-66, wherein the polypeptide is a protein, or a conjugate thereof.

68. The injectable pharmaceutical composition of claim 67, wherein the protein is an antibody or a fragment thereof, or a conjugate thereof.

69. The injectable pharmaceutical composition of claim 68, wherein the protein is a monoclonal antibody, a polyclonal antibody, an immunoglobulin G (IgG) antibody, an IgA antibody, an IgM antibody, a Fc fusion protein, or a fragment thereof, or a conjugate thereof.

70. The injectable pharmaceutical composition of any one of claims 67-69, wherein the biopharmaceutical agent (e.g., nucleic acid, peptide, protein or antibody) is conjugated to a heterologous agent (e.g., small molecule) via an optional linker.

71. The injectable pharmaceutical composition of claim 69, wherein the conjugated heterologous agent (e.g., small molecule) is selected from drug, cytotoxic agent, chemotherapeutic agent, cytostatic agent, steroid, degrader, molecular glue, imaging agent,Attorney Docket No.38821-63329 (008WO) therapeutic radionuclide, and cell surface receptor binding moiety (e.g., ASGPR or M6PR binding moiety).

72. The injectable pharmaceutical composition of any one of claims 64-66, wherein the polypeptide is a hormone or analog thereof.

73. The injectable pharmaceutical composition of claim 72, wherein the polypeptide is insulin or an analog thereof.

74. The injectable pharmaceutical composition of claim 72, wherein the polypeptide is selected from glucagon, GLP-1 receptor agonist, amylin, and analogs thereof.

75. The injectable pharmaceutical composition of claim 74, wherein the biopharmaceutical agent is insulin or an analog thereof.

76. The injectable pharmaceutical composition any one of claims 24-63, wherein the biopharmaceutical agent is a peptide, peptide analog or peptide conjugate.

77. The injectable pharmaceutical composition of claim 76, wherein the pharmaceutical agent is a peptide conjugate (e.g., a peptide-small molecule conjugate, or a peptide-fatty acid conjugate).

78. The injectable pharmaceutical composition of claim 76 or 77, wherein the biopharmaceutical agent comprises a macrocyclic peptide.

79. The injectable pharmaceutical composition of claim 76 or 77, wherein the biopharmaceutical agent is a peptide-fatty acid conjugate.

80. The injectable pharmaceutical composition of any one of claims 24-63, wherein the biopharmaceutical agent is an oligonucleotide containing therapeutic agent.

81. The injectable pharmaceutical composition of any one of claims 24-63, wherein the biopharmaceutical agent is an oligonucleotide conjugate (e.g., an oligonucleotide-peptideAttorney Docket No.38821-63329 (008WO) conjugate, an oligonucleotide-antibody conjugate, or an oligonucleotide-targeting agent conjugate).

82. The injectable pharmaceutical composition of claim 80 or 81, wherein the oligonucleotide is selected from antisense oligonucleotide (ASO), aptamer, RNAi, siRNA, shRNA, antagomir, microRNA (miRNA), a pre-miRNA, miR mimic, and splice switching oligonucleotide (SSO).

83. The injectable pharmaceutical composition of claim 81, wherein the biopharmaceutical agent an antibody-siRNA conjugate or peptide-siRNA conjugate.

84. An injectable pharmaceutical composition comprising a plurality of particles and a liquid carrier in which the particles are suspended, wherein the particles comprise: 95 wt% (e.g., 96 wt%, 97 wt%, 98 wt%, or 99%) or more of a biopharmaceutical agent; and an optional polyacrylamide-based copolymer; and the composition comprises at least 500 mg / mL (e.g., at least 510 mg / mL, at least 520 mg / mL, at least 530 mg / mL, at least 540 mg / mL, at least 550 mg / mL, at least 560 mg / mL, at least 570 mg / mL, at least 580 mg / mL, at least 590 mg / mL, at least 600 mg / mL, at least 610 mg / mL, at least 620 mg / mL, at least 630 mg / mL, at least 640 mg / mL, or at least 650 mg / mL) of the biopharmaceutical agent.

85. An injectable pharmaceutical composition comprising a plurality of particles and a liquid carrier in which the particles are suspended, wherein the particles comprise: 70 wt% (e.g., 75 wt%, 80 wt%, 85 wt%, or 90%) or more of a biopharmaceutical agent; an optional polyacrylamide-based copolymer; an optional stabilizing agent; and the composition comprises at least 500 mg / mL (e.g., at least 510 mg / mL, at least 520 mg / mL, at least 530 mg / mL, at least 540 mg / mL, at least 550 mg / mL, at least 560 mg / mL, at least 570 mg / mL, at least 580 mg / mL, at least 590 mg / mL, at least 600 mg / mL, at least 610 mg / mL, atAttorney Docket No.38821-63329 (008WO) least 620 mg / mL, at least 630 mg / mL, at least 640 mg / mL, or at least 650 mg / mL) of the biopharmaceutical agent.

86. The injectable pharmaceutical composition of any one of claims 84-85, wherein the composition is capable of being injected at a rate of 6 mL / min through a glass syringe with a staked, 27 G ultra thin-walled, ½'' needle with an injection force of 50 N or less.

87. The injectable pharmaceutical composition of claim 83 or 84, wherein the particles comprise the polyacrylamide-based copolymer.

88. The injectable pharmaceutical composition of claim 86, wherein the polyacrylamide- based copolymer comprises 5 wt% or less (e.g., 4.5 wt% or less, 4 wt% or less, 3.5 wt% or less, 3 wt% or less, 2.5 wt% or less, 2 wt% or less, 1.5 wt% or less, or 1 wt% or less) of the particles.

89. The composition of any one of claims 1 to 88, wherein the polyacrylamide-based copolymer comprises: a water-soluble carrier monomer selected from N-(3-methoxypropyl)acrylamide (MPAM), 4-acryloylmorpholine (MORPH), N,N-dimethylacrylamide (DMA), N- hydroxyethyl acrylamide (HEAM), acrylamide (AM), and combinations thereof; and 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-N- diethylacrylamide (DEA), N-tert-butylacrylamide (TBA), N-phenylacrylamide (PHE), and combinations thereof.

90. The composition of claim 89, wherein the water-soluble carrier monomer is selected from MORPH, MPAM, and combinations thereof.

91. The composition of claim 90, wherein the water-soluble carrier monomer comprises MORPH.

92. The composition of claim 90, wherein the water-soluble carrier monomer comprises MPAM.Attorney Docket No.38821-63329 (008WO) 93. The composition of any one of claims 89-92, wherein the functional dopant monomer is selected from AMP, TMA, TBA, PHE, and combinations thereof.

94. The composition of any one of claims 89-92, wherein the functional dopant monomer is selected from DEA, PHE, NIP, and combinations thereof.

95. The composition of any one of claims 89-92, wherein the functional dopant monomer comprises TRI.

96. The composition of any one of claims 89-92, wherein the functional dopant monomer comprises PHE.

97. The composition of any one of claims 89-92, wherein the functional dopant monomer comprises NIP.

98. The composition of any one of claims 89-92, wherein the functional dopant monomer comprises DEA.

99. The composition of claim 89, wherein: the water-soluble carrier monomer is selected from MPAM, MORPH, and combinations thereof; and the functional dopant monomer is selected from NIP, PHE, and combinations thereof.

100. The composition of claim 89, wherein: the water-soluble carrier monomer is selected from MPAM, MORPH, and combinations thereof; and the functional dopant monomer is selected from AMP, TMA, TBA, PHE, and combinations thereof.

101. The composition of claim 89, wherein the water-soluble carrier monomer is MPAM, and the functional dopant monomer is PHE.Attorney Docket No.38821-63329 (008WO) 102. The composition of claim 89, wherein the water-soluble carrier monomer is MORPH, and the functional dopant monomer is PHE.

103. The composition of claim 89, wherein the water-soluble carrier monomer is MORPH, and the functional dopant monomer is NIP.

104. The composition of any one of claims 89-103, wherein the polyacrylamide-based copolymer comprises: 70 wt% to 98 wt% of the water-soluble carrier monomer; and 2 wt% to 30 wt% of the functional dopant monomer.

105. The composition of any one of claims 89-104, wherein the polyacrylamide-based copolymer comprises: 80 wt% to 95 wt% of the water-soluble carrier monomer; and 5 wt% to 20 wt% of the functional dopant monomer.

106. The composition of any one of claims 89-105, wherein the polyacrylamide-based copolymer comprises: 83 wt% to 98 wt% of the water-soluble carrier monomer; and 2 wt% to 17 wt% of the functional dopant monomer.

107. The composition of claim 89, wherein the polyacrylamide-based copolymer comprises a random copolymer consisting of: a water-soluble carrier monomer selected from N-(3-methoxypropyl)acrylamide (MPAM) and 4-acryloylmorpholine (MORPH); and a functional dopant monomer that is N-isopropylacrylamide (NIP), wherein the random copolymer comprises from 10% to 28% by weight of NIP.

108. The composition of claim 107, wherein the water-soluble carrier monomer is MORPH.

109. The composition of claim 89, wherein the polyacrylamide-based copolymer comprises: 70 wt% to 85 wt% of MORPH; andAttorney Docket No.38821-63329 (008WO) 15 wt% to 30 wt% of NIP.

110. The composition of claim 89, wherein the polyacrylamide-based copolymer comprises: 74 wt% to 80 wt% of MORPH; and 20 wt% to 26 wt% of NIP.

111. The composition of claim 89, wherein the copolymer comprises: 74% to 80% by weight of MORPH; and 20% to 26% by weight of NIP; the average molecular weight (Mn) of the copolymer is from 1,000 g / mol to 5,000 g / mol; and the degree of polymerization of the copolymer is 10 to 50.

112. The composition of claim 89, wherein the polyacrylamide-based copolymer comprises: 77 wt% of MORPH; and 23 wt% of NIP.

113. The composition of claim 112, wherein the composition further comprises hyaluronidase.

114. The composition of claim 89, wherein the polyacrylamide-based copolymer comprises: 77 wt% of MORPH; and 23 wt% of NIP; and wherein the biopharmaceutical agent is hyaluronidase.

115. The composition of any one of claims 89-114, wherein the degree of polymerization of the polyacrylamide-based copolymer is 10 to 500.

116. The composition of claim 115, wherein the degree of polymerization of the polyacrylamide-based copolymer is 20 to 200.Attorney Docket No.38821-63329 (008WO) 117. The composition of claim 116, wherein the degree of polymerization of the polyacrylamide-based copolymer is 50.

118. The composition of any one of claims 89-117, wherein a number-average molecular weight of the polyacrylamide-based copolymer is 1,000 g / mol to 40,000 g / mol.

119. The composition of any one of claims 89-117, wherein a number-average molecular weight of the polyacrylamide-based copolymer is 1,000 g / mol to 20,000 g / mol.

120. The composition of any one of claims 89-117, wherein a number-average molecular weight of the polyacrylamide-based copolymer is 1,000 g / mol to 15,000 g / mol.

121. The composition of any one of claims 89-117, wherein a number-average molecular weight of the polyacrylamide-based copolymer is 3,000 g / mol to 12,000 g / mol.

122. The composition of 121, wherein a number-average molecular weight of the polyacrylamide-based copolymer is 2,000 g / mol to 10,000 g / mol.

123. The composition of 122, wherein a number-average molecular weight of the polyacrylamide-based copolymer is 4,000 g / mol to 8,000 g / mol.

124. The composition of 122, wherein a number-average molecular weight of the polyacrylamide-based copolymer is 4,000 g / mol to 6,000 g / mol.

125. The composition of any one of claims 24 to 124, wherein the pharmaceutical composition is storage stable.

126. The composition of claim 125, wherein the pharmaceutical composition demonstrates less than 10 mol % (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) degradation of the bioactivity of the biopharmaceutical agent after storage at 2-8oC for 4 weeks or longer (e.g., 3, 6, or 12 months).Attorney Docket No.38821-63329 (008WO) 127. A storage stable solid composition comprising a plurality of particles, the particles comprising: a biopharmaceutical agent (e.g., as described herein); a polyacrylamide-based copolymer (e.g., as described herein); and a stabilizer (e.g., as described herein).

128. The composition of claim 127, wherein the weight ratio of the biopharmaceutical agent to the polyacrylamide-based copolymer to the stabilizer is 15:1:1 or greater (e.g., 16:1:1 or greater, 17:1:1 or greater, 18:1:1 or greater, 19:1:1 or greater, 20:1:1 or greater, 15:1:2 or greater, 16:1:2 or greater, 17:1:2 or greater, 18:1:2 or greater, 19:1:2 or greater, 20:1:2 or greater, 15:1:3 or greater, 16:1:3 or greater, 17:1:3 or greater, 18:1:3 or greater, 19:1:3 or greater, or 20:1:3 or greater).

129. A syringe, loaded with a composition of any one of claims 1-128.

130. The syringe of claim 129, configured to dispense the composition at a flow rate of 0.1 mL / min or more in response to a force applied to the syringe of 70 N or less.

131. The syringe of claim 129, configured to dispense the composition at a flow rate of 0.1 mL / min or more in response to a force applied to the syringe of 50 N or less.

132. The syringe of any one of claims 129-131, wherein the syringe comprises a needle having a size of 18 to 32 Gauge (G) (e.g., a 22G needle, a 24G needle, a 25G needle, a 26G needle, a 27G needle, a 30G needle, or a 32G needle).

133. The syringe of claim 132, wherein the needle is an ultra-thin walled needle.

134. A method of administering a biopharmaceutical agent to a subject in need thereof, the method comprising: injecting a therapeutically effective amount of a composition according to any one of claims 1-128 to administer the biopharmaceutical agent to the subject.

135. The method of claim 134, wherein the injecting is performed using a loaded syringe of any one of claims 127-138.Attorney Docket No.38821-63329 (008WO) 136. A method of preparing an injectable pharmaceutical composition, the method comprising: a) providing a mixture comprising: a biopharmaceutical agent; a polyacrylamide-based copolymer in aqueous solution; and an optional stabilizing agent, wherein the ratio of the polyacrylamide-based copolymer to the biopharmaceutical agent in the mixture is 5:95 or less (e.g., 4:96 or less, 3:97 or less, 2:98 or less, or 1:99 or less); b) spray drying the mixture to obtain particles comprising the biopharmaceutical agent and the polyacrylamide-based copolymer; contacting a liquid carrier with the particles to form a suspension of the particles in the liquid carrier.

137. The method of claim 136, wherein the particles obtained in step b) have a mean diameter of 10 microns or less.

138. The method of claim 136 or 137, wherein the particles have a particle size distribution of at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, or at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of the particles having a diameter of less than 10 microns, preferably wherein the particles have a particle size distribution of at least 96% of the particles having a diameter of less than 10 microns, more preferably wherein the particles have a particle size distribution of at least 98% of the particles having a diameter of less than 10 microns.

139. The method of any one of claims 136-138, wherein the particles are vacuum dried before step c), preferably wherein the particles are vacuum dried until the water content of the particles is less than 5%wt (e.g., less than 4%, less than 3%, less than 2%, or less than 1%).

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