Acidic buffered intravenous solution stabilizers for use in methods of treatment

Abstract

Disclosed herein are sterile intravenous solution stabilizers comprising at least one buffer and at least one surfactant, wherein the pH of each sterile intravenous solution stabilizer is in the range of 4.0 to 5.5. Also provided herein are methods for preparing infusion solutions using intravenous solution stabilizers disclosed herein, as well as uses of intravenous solution stabilizers described herein in the treatment of disease. Further, the disclosure provides kits useful in the preparation of infusion solutions.

Description

ACIDIC BUFFERED INTRAVENOUS SOLUTION STABILIZERS FOR USE IN METHODS OF TREATMENTCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 519.691, filed August 15, 2023, the contents of which are herein incorporated by reference in their entirety.FIELD

[0002] Provided herein are intravenous solution stabilizers, kits comprising the intravenous solution stabilizers, and methods for preparing infusion solutions using such kits and intravenous solution stabilizers. Also provided are methods of using infusion solutions prepared using the intravenous solution stabilizers described herein in the treatment of certain disorders, such as cancer, including but not limited to hematological malignancies and solid tumors.BACKGROUND

[0003] Protein-based pharmaceuticals are a fast-growing class of therapeutic agents in (pre)clinical development for a variety of indications. Many protein-based pharmaceuticals are administered to patients intravenously, with some agents requiring extended intravenous (IV) administration periods to facilitate delivery of a specific therapeutic dose while minimizing the risk of adverse events such as cytokine release syndrome. For example, administration during the early phases of clinical trials, before a drug’s safety and pharmacokinetic profdes have been definitively established, can require multiple IV bag dilution steps as well as long IV administration durations of up to 48 hours or more.

[0004] The risk of microbial growth in an infusion solution is an important factor when recommending time for its preparation and administration. Microbial growth is a significant safety concern during IV infusions, particularly for administration durations of several hours to days, and regulatory agencies may request that sponsors generate microbial growth data for infusion solutions that require more than four hours for preparation and administration, regardless of storage temperature.

[0005] While infusion solutions may include a preservative such as benzyl alcohol to inhibit microbial growth, preservatives may reduce protein stability and present a toxicity risk for patients. Accordingly, there remains a need in the art for strategies that reduce or eliminate the use of preservatives while enabling infusion solution preparation and administration periods of several hours to several days.SUMMARY

[0006] The present disclosure addresses this need through the use of acidic, buffered intravenous solution stabilizers that inhibit microbial growth in infusion solutions without requiring the use ofpreservatives or necessitating modifications to a drug product’s shelf-life formulation. Intravenous solution stabilizers (IVSS) may be used in the preparation of infusion solutions to minimize drug product adsorption to IV bags and tubing. Specifically, an IVSS solution may be aseptically transferred to an IV bag containing a diluent such as saline solution prior to the aseptic transfer of liquid drug product to inhibit drug product adsorption.

[0007] Provided herein is a sterile intravenous solution stabilizer comprising at least one buffer and at least one surfactant, wherein the pH of the sterile intravenous solution stabilizer is in the range of 4.0 to5.5.

[0008] In some embodiments, the sterile intravenous solution stabilizer does not contain any of benzyl alcohol, chlorobutanol, meta-cresol, methylparaben, phenoxyethanol, propylparaben, or thimerosal at a concentration effective to inhibit the growth of microbes.

[0009] In some embodiments, the sterile intravenous solution stabilizer is preservative-free.

[0010] In some embodiments, the pH of the sterile intravenous solution stabilizer is in the range of 4.0 to 5.0. In some embodiments, the pH of the sterile intravenous solution stabilizer is in the range of 4.0 to4.5. In some embodiments, the pH of the sterile intravenous solution stabilizer is in the range of 4.5 to 5.0.

[0011] In some embodiments, the pH of the sterile intravenous solution stabilizer is 4.0, 4.1, 4.2, 4.3,4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5. In some embodiments, the pH of the sterile intravenous solution stabilizer is 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0. In some embodiments, the pH of the sterile intravenous solution stabilizer is 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5.

[0012] In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, or 5.4. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 4.1, 4.2, 4.3, 4.4, or 4.5.

[0013] In some embodiments, the at least one buffer is effective to maintain the pH of the sterile intravenous solution stabilizer in the range of 4.0 to 5.5. In some embodiments, the at least one buffer is effective to maintain the pH of the sterile intravenous solution stabilizer in the range of 4.0 to 5.0. In some embodiments, the at least one buffer is effective to maintain the pH of the sterile intravenous solution stabilizer in the range of 4.0 to 4.5. In some embodiments, the at least one buffer is effective to maintain the pH of the sterile intravenous solution stabilizer in the range of 4.5 to 5.0.

[0014] In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around a pH of 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, or5.4. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenoussolution stabilizer around a pH of 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around a pH of 4.1, 4.2, 4.3, 4.4, or 4.5.

[0015] In some embodiments, the at least one buffer is present at a concentration in the range of 0.1 mM to 150 mM. In some embodiments, the at least one buffer is present at a concentration in the range of 0.25 mM to 50 mM. In some embodiments, the at least one buffer is present at a concentration in the range of 5 mM to 50 mM.

[0016] In some embodiments, the at least one buffer is an organic buffer.

[0017] In some embodiments, the at least one buffer is selected from phosphoric acid / phosphate salt, glutamic acid / glutamate salt, acetic acid / acetate salt, citric acid / citrate salt, succinic acid / succinate salt, tartaric acid / tartrate salt, histidine / histidine salt, and combinations of any of the foregoing.

[0018] In some embodiments, the at least one buffer is selected from phosphoric acid / sodium phosphate, glutamic acid / sodium glutamate, acetic acid / sodium acetate, citric acid / sodium citrate, succinic acid / sodium succinate, tartaric acid / sodium tartrate, histidine / histidine HC1, and combinations of any of the foregoing.

[0019] In some embodiments, the at least one buffer comprises citrate.

[0020] In some embodiments, the at least one buffer comprises citrate at a concentration in the range of 0.25 mM to 50 mM. In some embodiments, the at least one buffer comprises citrate at a concentration of 25 mM.

[0021] In some embodiments, the at least one surfactant comprises at least one non-ionic surfactant.

[0022] In some embodiments, the at least one non-ionic surfactant is present at a concentration in the range of 0.001% (w / v) to 1% (w / v). In some embodiments, the at least one non-ionic surfactant is present at a concentration in the range of 0.001% (w / v) to 0.5% (w / v). In some embodiments, the at least one non-ionic surfactant is present at a concentration in the range of 0.004% (w / v) to 0.1% (w / v).

[0023] In some embodiments, the at least one non-ionic surfactant is present at a concentration of 0.005 (w / v)%, 0.006 (w / v)%, 0.007 (w / v)%, 0.008 (w / v)%, 0.009 (w / v)%, 0.01 (w / v)%, 0.02 (w / v)%, 0.03 (w / v)%, 0.04 (w / v)%, 0.05 (w / v)%, 0.06 (w / v)%, 0.07 (w / v)%, 0.08 (w / v)%, 0.09 (w / v)%, 0.1 (w / v)%, 0.2 (w / v)%, 0.3 (w / v)%, 0.4 (w / v)%, 0.5 (w / v)%, 0.6 (w / v)%, 0.7 (w / v)%, 0.8 (w / v)%, 0.9 (w / v)%, or 1 (w / v)%. In some embodiments, the at least one non-ionic surfactant is present at a concentration of 0.1% (w / v).

[0024] In some embodiments, the at least one non-ionic surfactant is selected from cocamides, ethoxylates, and alkoxy lates.

[0025] In some embodiments, the at least one non-ionic surfactant is selected from polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80), alkylaryl polyethers (e.g., oxyethylated alkyl phenol (e.g., Triton™ X-100)), poloxamers (e.g., Pluronics®, e.g., Pluronic® F68), and combinations of any of the foregoing, either within a class of surfactants or among classes of surfactants. In some embodiments, the at least one non-ionic surfactant is selected from polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the at least one non-ionic surfactant is polysorbate 20 or polysorbate 80. In some embodiments, the at least one non-ionic surfactant is polysorbate 20. In some embodiments, the at least one non-ionic surfactant is polysorbate 80.

[0026] In some embodiments, the at least one non-ionic surfactant is polysorbate 80 present at a concentration of 0.1% (w / v).

[0027] In some embodiments, the sterile intravenous solution stabilizer further comprises at least one additional excipient.

[0028] In some embodiments, the at least one additional excipient is selected from amino acids, sugars, polyols, and salts.

[0029] In some embodiments, the at least one additional excipient is a sugar. In some embodiments, the at least one additional excipient is a disaccharide. In some embodiments, the at least one additional excipient is trehalose, sucrose, or a combination thereof.

[0030] In some embodiments, the at least one additional excipient comprises an amino acid. In some embodiments, the at least one additional excipient comprises an amino acid selected from lysine, proline, serine, and alanine. In some embodiments, the at least one additional excipient comprises lysine.

[0031] In some embodiments, the at least one additional excipient is present at a concentration in the range of 0.2 M to 6 M. In some embodiments, the at least one additional excipient is present at a concentration in the range of 0.5 M to 5 M. In some embodiments, the at least one additional excipient is present at a concentration of 1.25 M.

[0032] In some embodiments, the at least one additional excipient comprises L-lysine hydrochloride present at a concentration in the range of 0.2 M to 6 M. In some embodiments, the at least one additional excipient comprises L-lysine hydrochloride present at a concentration in the range of 0.5 M to 5 M. In some embodiments, the at least one additional excipient comprises L-lysine hydrochloride present at a concentration of 1.25 M.

[0033] In some embodiments, the sterile intravenous solution stabilizer consists or consists essentially of the at least one buffer and the at least one surfactant.

[0034] In some embodiments, the sterile intravenous solution stabilizer consists or consists essentially of the at least one buffer, the at least one surfactant, and an additional excipient comprising an amino acid.

[0035] Provided herein is a sterile intravenous solution stabilizer comprising: at least one buffer present at a concentration in the range of 0.1 mM to 150 mM; and at least one non-ionic surfactant present at a concentration in the range of 0.001% (w / v) to 1% (w / v), wherein the pH of the sterile intravenous solution stabilizer is in the range of 4.0 to 5.5.

[0036] In some embodiments, the sterile intravenous solution stabilizer does not contain any of benzyl alcohol, chlorobutanol, meta-cresol, methylparaben, phenoxyethanol, propylparaben, or thimerosal at a concentration effective to inhibit the growth of microbes. In some embodiments, the sterile intravenous solution stabilizer is preservative-free.

[0037] In some embodiments, the sterile intravenous solution stabilizer further comprises at least one additional excipient present at a concentration in the range of 0.2 M to 6 M.

[0038] In some embodiments, the sterile intravenous solution stabilizer consists or consists essentially of the at least one buffer and die at least one non-ionic surfactant.

[0039] In some embodiments, the sterile intravenous solution stabilizer consists or consists essentially of the at least one buffer, the at least one non-ionic surfactant, and an additional excipient comprising an amino acid.

[0040] Provided herein is a sterile intravenous solution stabilizer comprising: at least one buffer selected from phosphoric acid / phosphate salt, glutamic acid / glutamate salt, acetic acid / acetate salt, citric acid / citrate salt, succinic acid / succinate salt, tartaric acid / tartrate salt, histidine / histidine salt, and combinations of any of the foregoing; and at least one non-ionic surfactant selected from polyoxyethylene sorbitan fatty acid esters, alkylaryl polyethers, poloxamers, and combinations of any of the foregoing, wherein the pH of the sterile intravenous solution stabilizer is in the range of 4.0 to 5.5.

[0041] In some embodiments, the at least one buffer is selected from phosphoric acid / sodium phosphate, glutamic acid / sodium glutamate, acetic acid / sodium acetate, citric acid / sodium citrate, succinic acid / sodium succinate, tartaric acid / sodium tartrate, histidine / histidine HC1, and combinations of any of the foregoing.

[0042] In some embodiments, the sterile intravenous solution stabilizer does not contain any of benzyl alcohol, chlorobutanol, meta-cresol, methylparaben, phenoxyethanol, propylparaben, or thimerosal at a concentration effective to inhibit the growth of microbes. In some embodiments, the sterile intravenous solution stabilizer is preservative-free.

[0043] In some embodiments, the at least one non-ionic surfactant is polysorbate 20 or polysorbate 80. In some embodiments, the at least one non-ionic surfactant is polysorbate 20. In some embodiments, the at least one non-ionic surfactant is polysorbate 80.

[0044] In some embodiments, the sterile intravenous solution stabilizer further comprises at least one additional excipient selected from amino acids, sugars, polyols, and salts.

[0045] In some embodiments, the at least one additional excipient is a sugar. In some embodiments, the at least one additional excipient is a disaccharide. In some embodiments, the at least one additional excipient is trehalose, sucrose, or a combination thereof.

[0046] In some embodiments, the at least one additional excipient comprises an amino acid. In some embodiments, the at least one additional excipient comprises an amino acid selected from lysine, proline, serine, and alanine. In some embodiments, the at least one additional excipient comprises lysine.

[0047] In some embodiments, the sterile intravenous solution stabilizer consists or consists essentially of the at least one buffer and die at least one non-ionic surfactant.

[0048] In some embodiments, the sterile intravenous solution stabilizer consists or consists essentially of the at least one buffer, the at least one non-ionic surfactant, and an additional excipient comprising an amino acid.

[0049] Provided herein is a sterile intravenous solution stabilizer comprising: at least one buffer is selected from phosphoric acid / phosphate salt, glutamic acid / glutamate salt, acetic acid / acetate salt, citric acid / citrate salt, succinic acid / succinate salt, tartaric acid / tartrate salt, histidine / histidine salt, and combinations of any of the foregoing, wherein the at least one buffer is present at a concentration in the range of 0.1 mM to 150 mM; and at least one non-ionic surfactant selected from polyoxyethylene sorbitan fatty acid esters, alkylaryl polyethers, poloxamers, and combinations of any of the foregoing, wherein the at least one non- ionic surfactant is present at a concentration in the range of 0.001% (w / v) to 1% (w / v), wherein the pH of the sterile intravenous solution stabilizer is in the range of 4.0 to 5.5.

[0050] In some embodiments, the sterile intravenous solution stabilizer does not contain any of benzyl alcohol, chlorobutanol, meta-cresol, methylparaben, phenoxyethanol, propylparaben, or thimerosal at a concentration effective to inhibit the growth of microbes. In some embodiments, the sterile intravenous solution stabilizer is preservative-free.

[0051] In some embodiments, the at least one buffer selected from phosphoric acid / sodium phosphate, glutamic acid / sodium glutamate, acetic acid / sodium acetate, citric acid / sodium citrate, succinic acid / sodium succinate, tartaric acid / sodium tartrate, histidine / histidine HC1, and combinations of any of the foregoing.

[0052] In some embodiments, the at least one non-ionic surfactant is polysorbate 20 or polysorbate 80. In some embodiments, the at least one non-ionic surfactant is polysorbate 20. In some embodiments, the at least one non-ionic surfactant is polysorbate 80.

[0053] In some embodiments, the sterile intravenous solution stabilizer further comprises at least one additional excipient selected from amino acids, sugars, polyols, and salts, wherein the at least one additional excipient is present at a concentration in the range of 0.2 M to 6 M.

[0054] In some embodiments, the at least one additional excipient is a sugar. In some embodiments, the at least one additional excipient is a disaccharide. In some embodiments, the at least one additional excipient is trehalose, sucrose, or a combination thereof.

[0055] In some embodiments, the at least one additional excipient comprises an amino acid. In some embodiments, the at least one additional excipient comprises an amino acid selected from lysine, proline, serine, and alanine. In some embodiments, the at least one additional excipient comprises lysine.

[0056] In some embodiments, the sterile intravenous solution stabilizer consists or consists essentially of the at least one buffer and die at least one non-ionic surfactant.

[0057] In some embodiments, the sterile intravenous solution stabilizer consists or consists essentially of the at least one buffer, the at least one non-ionic surfactant, and an additional excipient comprising an amino acid.

[0058] Provided herein is a sterile intravenous solution stabilizer comprising 0.1 mM to 150 mM citric acid / sodium citrate and 0.001% (w / v) to 1% (w / v) polysorbate 80, wherein the pH of the sterile intravenous solution stabilizer is in the range of 4.0 to 5.5.

[0059] In some embodiments, the sterile intravenous solution stabilizer further comprises 0.2 M to 6 M L-lysine hydrochloride. In some embodiments, the sterile intravenous solution stabilizer further comprises 1.25 M L-lysine hydrochloride.

[0060] In some embodiments, the sterile intravenous solution stabilizer comprises 0.1% (w / v) polysorbate 80.

[0061] In some embodiments, the sterile intravenous solution stabilizer further comprises 0.2 M to 6 M L-lysine hydrochloride.

[0062] In some embodiments, the sterile intravenous solution stabilizer consists or consists essentially of 0.1 mM to 150 mM citric acid / sodium citrate; 0.001% (w / v) to 1% (w / v) polysorbate 80; and 0.2 M to 6 M L-lysine hydrochloride, wherein the pH of the sterile intravenous solution stabilizer is in the range of 4.0 to 5.5.

[0063] In some embodiments, the sterile intravenous solution stabilizer comprises 0.1 mM to 150 mM citric acid / sodium citrate, 0.1% (w / v) polysorbate 80, and 1.25 M L-lysine hydrochloride. In some embodiments, the sterile intravenous solution stabilizer consists essentially of 0.1 mM to 150 mM citric acid / sodium citrate, 0.1% (w / v) polysorbate 80, and 1.25 M L-lysine hydrochloride. In someembodiments, the sterile intravenous solution stabilizer consists of 0.1 mM to 150 mM citric acid / sodium citrate, 0.1% (w / v) polysorbate 80, and 1.25 M L-lysine hydrochloride.

[0064] In some embodiments, the sterile intravenous solution stabilizer does not contain any of benzyl alcohol, chlorobutanol, meta-cresol, methylparaben, phenoxyethanol, propylparaben, or thimerosal at a concentration effective to inhibit the growth of microbes. In some embodiments, the sterile intravenous solution stabilizer is preservative-free.

[0065] Provided herein is a method of preparing an infusion solution comprising mixing: a pharmaceutical composition comprising a recombinant protein; at least one diluent; and a sterile intravenous solution stabilizer disclosed herein, wherein the pH of the prepared infusion solution is less than or equal to 6.0.

[0066] In some embodiments, the prepared infusion solution does not contain any of benzy l alcohol, chlorobutanol, meta-cresol, methylparaben, phenoxyethanol, propylparaben, or thimerosal at a concentration effective to inhibit the growth of microbes.

[0067] In some embodiments, the prepared infusion solution is preservative-free.

[0068] In some embodiments, the pH of the prepared infusion solution is less than or equal to 5.5. In some embodiments, the pH of the prepared infusion solution is less than or equal to 5.0. In some embodiments, the pH of the prepared infusion solution is less than or equal to 4.5.

[0069] In some embodiments, the pH of the prepared infusion solution is in the range of 4.0 to 5.5. In some embodiments, the pH of the prepared infusion solution is in the range of 4.0 to 5.0. In some embodiments, the pH of the prepared infusion solution is in the range of 4.0 to 4.5. In some embodiments, the pH of the prepared infusion solution is in the range of 4.5 to 5.0.

[0070] In some embodiments, the pH of the prepared infusion solution is 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5. In some embodiments, the pH of the prepared infusion solution is 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0. In some embodiments, the pH of the prepared infusion solution is 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5.

[0071] In some embodiments, the pharmaceutical composition, the at least one diluent, and the sterile intravenous solution stabilizer are mixed in an intravenous (IV) bag. In some embodiments, the IV bag is an ethylene vinyl acetate (EVA) bag. In some embodiments, the IV bag is a 150 mL EVA IV bag.

[0072] In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 2% to 10% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 2% to 5% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 5% of the IV bag volume.

[0073] In some embodiments, the at least one diluent is selected from saline solutions, dextrose solutions, lactated Ringer’s solution, Ringer’s solution, sterile water, and combinations of any of the foregoing.

[0074] In some embodiments, the at least one diluent comprises saline. In some embodiments, the at least one diluent is an isotonic saline solution. In some embodiments, the at least one diluent comprises 0.9% (w / v) NaCl in water.

[0075] In some embodiments, the at least one diluent comprises dextrose. In some embodiments, the at least one diluent comprises 5% (w / v) dextrose in water.

[0076] In some embodiments, the prepared infusion solution is isotonic.

[0077] In some embodiments, the recombinant protein is stable in the prepared infusion solution for at least 24 hours at room temperature. In some embodiments, the recombinant protein is stable in the prepared infusion solution for at least 48 hours at room temperature. In some embodiments, the recombinant protein is stable in the prepared infusion solution for at least 96 hours at room temperature. In some embodiments, the recombinant protein is stable in the prepared infusion solution for at least 7 days at room temperature.

[0078] In some embodiments, the recombinant protein is stable in the prepared infusion solution for at least 96 hours at a temperature in the range of 2°C to 8°C. In some embodiments, the recombinant protein is stable in the prepared infusion solution for at least 7 days at a temperature in the range of 2°C to 8°C.

[0079] In some embodiments, the level of microbial growth in the prepared infusion solution is less than one half log after 24 hours at room temperature.

[0080] In some embodiments, the level of microbial growth in the prepared infusion solution is less than one half log after 14 days at a temperature in the range of 2°C to 8°C.

[0081] In some embodiments, the recombinant protein is an antigen-binding protein. In some embodiments, the recombinant protein is an antibody.

[0082] Provided herein is a kit for preparing an infusion solution, the kit comprising: a sterile intravenous solution stabilizer disclosed herein; and at least one additional component selected from at least one diluent, a pharmaceutical composition comprising a recombinant protein, an IV bag, and combinations of any of the foregoing.

[0083] Provided herein is a kit for preparing an infusion solution, the kit comprising: at least one diluent; and a sterile intravenous solution stabilizer disclosed herein.

[0084] In some embodiments, the kit further comprises an IV bag. In some embodiments, the IV bag is an ethylene vinyl acetate (EVA) IV bag. In some embodiments, the IV bag is a 150 mL EVA IV bag.

[0085] Provided herein is a kit for preparing an infusion solution, the kit comprising: an IV bag; and a sterile intravenous solution stabilizer disclosed herein.

[0086] In some embodiments, the IV bag is an ethylene vinyl acetate (EVA) IV bag. In some embodiments, the IV bag is a 150 mL EVA IV bag.

[0087] Provided herein is a kit for preparing an infusion solution, the kit comprising: a pharmaceutical composition comprising a recombinant protein; and a sterile intravenous solution stabilizer disclosed herein.

[0088] In some embodiments, the kit further comprises an IV bag. In some embodiments, the IV bag is an ethylene vinyl acetate (EVA) IV bag. In some embodiments, the IV bag is a 150 mL EVA IV bag.

[0089] Provided herein is a kit for preparing an infusion solution, the kit comprising: a pharmaceutical composition comprising a recombinant protein; at least one diluent; and a sterile intravenous solution stabilizer disclosed herein.

[0090] In some embodiments, the kit further comprises an IV bag. In some embodiments, the IV bag is an ethylene vinyl acetate (EVA) IV bag. In some embodiments, the IV bag is a 150 mL EVA IV bag.

[0091] Provided herein is a method of treating a disease or disorder comprising administering an infusion solution prepared according to a method described herein to a subject in need thereof.

[0092] In some embodiments, the infusion solution is stored for at least 4 horns, at least 8 hours, or at least 24 hours prior to administration. In some embodiments, the infusion solution is stored for at least 4 hours, at least 8 hours, or at least 24 hours at room temperature prior to administration.

[0093] In some embodiments, the infusion solution is stored for at least 4 horns, at least 8 hours, or at least 24 hours prior to being administered to the subject for a time in the range of 30 minutes to 2 horns. In some embodiments, the infusion solution is stored for at least 4 hours, at least 8 hours, or at least 24 hours at room temperature prior to being administered to the subject for a time in the range of 30 minutes to 2 hours at room temperature.

[0094] In some embodiments, the infusion solution is administered to the subject for at least 4 horns. In some embodiments, the infusion solution is administered to the subject for at least 8 hours. In some embodiments, the infusion solution is administered to the subject for at least 24 hours.

[0095] In some embodiments, the infusion solution is administered to the subject for at least 4 hours, at least 8 horns, at least 12 hours, or at least 24 hours at room temperature.

[0096] In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is a hematological malignancy, such as, e.g., a leukemia or a lymphoma. In some embodiments, the disease or disorder is a solid tumor.

[0097] Also provided herein is a sterile composition suitable for preparing an infusion solution by one-step mixing with a pharmaceutical composition comprising a recombinant protein, wherein the sterible composition may be present in an IV bag or bottle to which the pharmaceutical composition is added. In some embodiments, the sterile composition has a composition equivalent to that obtained by mixing a sterile intravenous solution stabilizer described herein with at least one diluent selected from saline solutions, dextrose solutions, lactated Ringer’s solution, Ringer’s solution, sterile water, and combinations of any of the foregoing at a ratio in the range of 1 :49 to 1 :9, such as, e.g., 1 :49, 1 : 19, or 1 :9. In some embodiments, such a sterile composition may be used in a method of preparing an infusion solution comprising mixing a pharmaceutical composition comprising a recombinant protein and the sterile composition, wherein the pH of the prepared infusion solution is less than or equal to 6.0. In some embodiments, such a sterile composition may be provided in a kit for preparing an infusion solution, the kit comprising the sterile composition, a pharmaceutical composition comprising a recombinant protein, and optionally an IV bag or an IV bottle.

[0098] As a non-limiting example, the present disclosure provides a sterile composition comprising at least one buffer, at least one surfactant, and at least one salt, wherein the pH of the sterile composition is in the range of 4.0 to 5.5.

[0099] In some embodiments, the sterile composition does not contain any of benzyl alcohol, chlorobutanol, meta-cresol, methylparaben, phenoxyethanol, propylparaben, or thimerosal at a concentration effective to inhibit the growth of microbes.

[0100] In some embodiments, the sterile composition is preservative-free.

[0101] In some embodiments, the pH of the sterile composition is in the range of 4.0 to 5.0. In some embodiments, the pH of the sterile composition is in the range of 4.0 to 4.5. In some embodiments, the pH of the sterile composition is in the range of 4.5 to 5.0.

[0102] In some embodiments, the pH of the sterile composition is 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5. In some embodiments, the pH of the sterile composition is 4.0, 4.1,4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0. In some embodiments, the pH of the sterile composition is 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5.

[0103] In some embodiments, the pH of the sterile composition is centered around a pH of 4.1, 4.2,4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, or 5.4. In some embodiments, the pH of the sterile composition is centered around a pH of 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0. In some embodiments, the pH of the sterile composition is centered around a pH of 4.1, 4.2, 4.3, 4.4, or 4.5.

[0104] In some embodiments, the at least one buffer is effective to maintain the pH of the sterile composition in the range of 4.0 to 5.5. In some embodiments, the at least one buffer is effective to maintain the pH of the sterile composition in the range of 4.0 to 5.0. In some embodiments, the at least one buffer is effective to maintain the pH of the sterile composition in the range of 4.0 to 4.5. In some embodiments, the at least one buffer is effective to maintain the pH of the sterile composition in the range of 4.5 to 5.0.

[0105] In some embodiments, the at least one buffer is effective to center the pH of the sterile composition around a pH of 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, or 5.4. In some embodiments, the at least one buffer is effective to center the pH of the sterile composition around a pH of 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0. In some embodiments, the at least one buffer is effective to center the pH of the sterile composition around a pH of 4.1, 4.2, 4.3, 4.4, or 4.5.

[0106] In some embodiments, the at least one buffer is present at a concentration in the range of 0.1 mM to 150 mM. In some embodiments, the at least one buffer is present at a concentration in the range of 0.25 mM to 50 mM. In some embodiments, the at least one buffer is present at a concentration in the range of 5 mM to 50 mM.

[0107] In some embodiments, the at least one buffer is an organic buffer.

[0108] In some embodiments, the at least one buffer is selected from phosphoric acid / phosphate salt, glutamic acid / glutamate salt, acetic acid / acetate salt, citric acid / citrate salt, succinic acid / succinate salt, tartaric acid / tartrate salt, histidine / histidine salt, and combinations of any of the foregoing.

[0109] In some embodiments, the at least one buffer is selected from phosphoric acid / sodium phosphate, glutamic acid / sodium glutamate, acetic acid / sodium acetate, citric acid / sodium citrate, succinic acid / sodium succinate, tartaric acid / sodium tartrate, histidine / histidine HC1, and combinations of any of the foregoing.

[0110] In some embodiments, the at least one buffer comprises citrate.

[0111] In some embodiments, the at least one buffer comprises citrate at a concentration in the range of 0.25 mM to 50 mM. In some embodiments, the at least one buffer comprises citrate at a concentration of 25 mM.

[0112] In some embodiments, the at least one surfactant comprises at least one non-ionic surfactant.

[0113] In some embodiments, the at least one non-ionic surfactant is present at a concentration in the range of 0.0001% (w / v) to 0.1% (w / v). In some embodiments, the at least one non-ionic surfactant is present at a concentration in the range of 0.0001% (w / v) to 0.05% (w / v). In some embodiments, the at least one non-ionic surfactant is present at a concentration in the range of 0.0004% (w / v) to 0.01% (w / v).

[0114] In some embodiments, the at least one non-ionic surfactant is present at a concentration of 0.0005 (w / v)%, 0.0006 (w / v)%, 0.0007 (w / v)%, 0.0008 (w / v)%, 0.0009 (w / v)%, 0.001 (w / v)%, 0.002 (w / v)%, 0.003 (w / v)%, 0.004 (w / v)%, 0.005 (w / v)%, 0.006 (w / v)%, 0.007 (w / v)%, 0.008 (w / v)%, 0.009 (w / v)%, 0.01 (w / v)%, 0.02 (w / v)%, 0.03 (w / v)%, 0.04 (w / v)%, 0.05 (w / v)%, 0.06 (w / v)%, 0.07 (w / v)%, 0.08 (w / v)%, 0.09 (w / v)%, or 0.1 (w / v)%. In some embodiments, the at least one non-ionic surfactant is present at a concentration of 0.002% (w / v), 0.005% (w / v), or 0.01% (w / v).

[0115] In some embodiments, the at least one non-ionic surfactant is selected from cocamides, ethoxylates, and alkoxy lates.

[0116] In some embodiments, the at least one non-ionic surfactant is selected from polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80), alkylaryl polyethers (e.g., oxyethylated alkyl phenol (e.g., Triton™ X-100)), poloxamers (e.g., Pluronics®, e.g., Phironic® F68), and combinations of any of the foregoing, either within a class of surfactants or among classes of surfactants. In some embodiments, the at least one non-ionic surfactant is selected from polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the at least one non-ionic surfactant is polysorbate 20 or polysorbate 80. In some embodiments, the at least one non-ionic surfactant is polysorbate 20. In some embodiments, the at least one non-ionic surfactant is polysorbate 80.

[0117] In some embodiments, the at least one non-ionic surfactant is polysorbate 80 present at a concentration of 0.002% (w / v), 0.005% (w / v), or 0.01% (w / v).

[0118] In some embodiments, the at least one salt is sodium chloride.

[0119] In some embodiments, the at least one salt is present at a concentration in the range of 0.8% (w / v) to 0.9% (w / v).

[0120] In some embodiments, the at least one salt is sodium chloride present at a concentration in the range of 0.8% (w / v) to 0.9% (w / v).

[0121] In some embodiments, the sterile composition further comprises at least one additional excipient.

[0122] In some embodiments, the at least one additional excipient is selected from amino acids, sugars, and polyols.

[0123] In some embodiments, the at least one additional excipient is a sugar. In some embodiments, the at least one additional excipient is a disaccharide. In some embodiments, the at least one additional excipient is trehalose, sucrose, or a combination thereof.

[0124] In some embodiments, the at least one additional excipient comprises an amino acid. In some embodiments, the at least one additional excipient comprises an amino acid selected from lysine, proline, serine, and alanine. In some embodiments, the at least one additional excipient comprises lysine.

[0125] In some embodiments, the at least one additional excipient is present at a concentration in the range of 0.2 M to 6 M. In some embodiments, the at least one additional excipient is present at a concentration in the range of 0.5 M to 5 M. In some embodiments, the at least one additional excipient is present at a concentration of 1.25 M.

[0126] In some embodiments, the at least one additional excipient comprises L-lysine hydrochloride present at a concentration in the range of 0.2 M to 6 M. In some embodiments, the at least one additional excipient comprises L-lysine hydrochloride present at a concentration in the range of 0.5 M to 5 M. In some embodiments, the at least one additional excipient comprises L-lysine hydrochloride present at a concentration of 1.25 M.

[0127] In some embodiments, the sterile composition consists or consists essentially of the at least one buffer, the at least one surfactant, and the at least one salt.

[0128] In some embodiments, the sterile composition consists or consists essentially of the at least one buffer, the at least one surfactant, the at least one salt, and an additional excipient comprising an amino acid.

[0129] The present disclosure also provides a sterile composition comprising: at least one buffer is selected from phosphoric acid / phosphate salt, glutamic acid / glutamate salt, acetic acid / acetate salt, citric acid / citrate salt, succinic acid / succinate salt, tartaric acid / tartrate salt, histidine / histidine salt, and combinations of any of the foregoing, wherein the at least one buffer is present at a concentration in the range of 0.01 mM to 15 mM; at least one non-ionic surfactant selected from polyoxyethylene sorbitan fatty acid esters, alkylaryl polyethers, poloxamers, and combinations of any of the foregoing, wherein the at least one nonionic surfactant is present at a concentration in the range of 0.0001% (w / v) to 0.1% (w / v); and at least one salt present at a concentration in the range of 0.8% (w / v) to 0.9% (w / v), wherein the pH of the sterile intravenous solution stabilizer is in the range of 4.0 to 5.5.

[0130] In some embodiments, the at least one buffer selected from phosphoric acid / sodium phosphate, glutamic acid / sodium glutamate, acetic acid / sodium acetate, citric acid / sodium citrate, succinic acid / sodium succinate, tartaric acid / sodium tartrate, histidine / histidine HC1, and combinations of any of the foregoing.

[0131] The present disclosure also provides a sterile composition comprising 0.01 mM to 15 mM citric acid / sodium citrate, 0.0001% (w / v) to 0.1% (w / v) polysorbate 80, and 0.8% (w / v) to 0.9% (w / v) sodium chloride, wherein the pH of the sterile intravenous solution stabilizer is in the range of 4.0 to 5.5.

[0132] In some embodiments, the sterile composition further comprises 0.02 M to 0.6 M L-lysine hydrochloride.BRIEF DESCRIPTION OF THE DRAWINGS

[0133] FIG. 1 depicts the log change in Enterobacter cloacae levels in infusion solutions comprising one of four recombinant proteins (RP1, RP2, RP3, RP4) or dextrose over 24 hours at 25°C.

[0134] FIG. 2 depicts the log change in Enterobacter cloacae levels in infusion solutions comprising one of two recombinant proteins (RP2 or RP8) over 48 hours at 25°C, where each infusion solution has a pH of 4.5, 5.0, or 5.5.DETAILED DESCRIPTIONDEFINITIONS

[0135] Where a range of values is provided herein, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0136] As used herein, the terms “a” and “an” mean “one or more” unless specifically indicated otherwise. Additionally, “one or more” and “at least one” are used interchangeably herein. Furthermore, unless otherwise required by context, singular terms include pluralities and plural terms include the singular.

[0137] Throughout this specification and the claims which follow, unless the context requires otherwise, the term “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. When used herein, the term “comprising” can be substituted with the term “containing” or “including” or sometimes when used herein with the term “having”.

[0138] As used herein, “consisting of’ excludes any element, step, or ingredient not specified in the embodiment feature or claim element. As used herein, “consisting essentially of’ does not exclude materials or steps that do not materially affect the basic and novel characteristics of the embodiment feature or claim element.

[0139] In each instance herein, any of the terms “comprising,” “consisting essentially of,” “consisting of,” and their variations may be replaced with any of the other two terms or their variations.

[0140] As used herein, the term “antibody” generally refers to a tetrameric immunoglobulin protein comprising two light chain polypeptides (about 25 kDa each) and two heavy chain polypeptides (about 50-70 kDa each). The term “light chain” or “immunoglobulin light chain” refers to a polypeptide comprising, from amino terminus to carboxyl terminus, a single immunoglobulin light chain variable region (VL) and a single immunoglobulin light chain constant domain (CL). The immunoglobulin light chain constant domain (CL) can be a human kappa (K) or human lambda (Z) constant domain. The term “heavy chain” or “immunoglobulin heavy chain” refers to a polypeptide comprising, from amino terminus to carboxyl terminus, a single immunoglobulin heavy chain variable region (VH), an immunoglobulin heavy chain constant domain 1 (CHI), an immunoglobulin hinge region, an immunoglobulin heavy chain constant domain 2 (CH2), an immunoglobulin heavy chain constant domain 3 (CH3), and optionally an immunoglobulin heavy chain constant domain 4 (CH4). Heavy chains are classified as mu (p), delta (A), gamma (y), alpha (a), and epsilon (e), and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. The IgG-class and IgA-class antibodies are further divided into subclasses, namely, IgGl, IgG2, IgG3, and IgG4, and IgAl and IgA2, respectively. The heavy chains in IgG, IgA, and IgD antibodies have three constant domains (CHI, CH2, and CH3), whereas the heavy chains in IgM and IgE antibodies have four constant domains (CHI, CH2, CH3, and CH4). The immunoglobulin heavy chain constant domains can be from any immunoglobulin isotype, including subty pes. The antibody chains are linked together via inter-polypeptide disulfide bonds between the CL domain and the CHI domain (i.e., between the light and heavy chain) and between the hinge regions of the two antibody heavy chains.

[0141] Variable regions of immunoglobulin chains generally exhibit the same overall structure, comprising relatively conserved framework regions (FR) joined by three hypervariable regions, more often called “complementarity determining regions” or CDRs. The CDRs from the two chains of each heavy chain and light chain pair typically are aligned by the framework regions to form a structure that binds specifically to a specific epitope on the target protein. From N-terminus to C-terminus, naturally- occurring light and heavy chain variable regions both typically conform with the following order of these elements: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. A numbering system has been devised for assigning numbers to amino acids that occupy positions in each of these domains. This numbering system is defined in Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, MD), or Chothia & Lesk, 1987, J. Mol. Biol. 196:901-917; Chothia et al., 1989, Nature 342:878-883. The CDRs and FRs of a given antibody may be identified using this system. Other numbering systems for the amino acids in immunoglobulin chains include IMGT® (the international ImMunoGeneTics information system; Lefranc et al., Dev. Comp. Immunol. 29:185-203; 2005) and AHo (Honegger and Pluckthun, J. Mol. Biol. 309(3):657-670; 2001).

[0142] As used in the context of this disclosure, an “antigen-binding fragment,” used interchangeably herein with “binding fragment” or “fragment,” is a portion of an antibody that lacks at least some of theamino acids present in a full-length heavy chain and / or light chain, but which is still capable of specifically binding to an antigen. An antigen-binding fragment includes, but is not limited to, a singlechain variable fragment (scFv), a nanobody (e.g., VH domain of heavy chain only antibodies (e.g., camelid heavy chain antibodies); VHH fragment, see Cortez-Retamozo et al., Cancer Research, Vol. 64:2853-57, 2004), a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fv fragment, a Fd fragment, and a CDR fragment, and can be derived from any mammalian source, such as human, mouse, rat, rabbit, or camelid. Antigen-binding fragments may compete for binding of a target antigen with an intact antibody, and the fragments may be produced by the modification of intact antibodies (e.g., enzymatic or chemical cleavage) or synthesized de novo using recombinant DNA technologies or peptide synthesis. In some embodiments, the antigen-binding fragment comprises at least one CDR from an antibody that binds to the antigen, for example, the heavy chain CDR3 from an antibody that binds to the antigen. In other embodiments, the antigen-binding fragment comprises all three CDRs from the heavy chain of an antibody that binds to the antigen or all three CDRs from the light chain of an antibody that binds to the antigen. In still other embodiments, the antigen-binding fragment comprises all six CDRs from an antibody that binds to the antigen (three from the heavy chain and three from the light chain).

[0143] Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual “Fc” fragment which contains all but the first domain of the immunoglobulin heavy chain constant region. The Fab fragment contains the variable domains from the light and heavy chains, as well as the constant domain of the light chain and the first constant domain (CHI) of the heavy chain. Thus, a “Fab fragment” is comprised of one immunoglobulin light chain (light chain variable region (VL) and constant region (CL)) and the CHI domain and variable region (VH) of one immunoglobulin heavy chain. The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule. The “Fd fragment” comprises the VH and CHI domains from an immunoglobulin heavy chain. The Fd fragment represents the heavy chain component of the Fab fragment.

[0144] The “Fc fragment” or “Fc domain” of an immunoglobulin generally comprises two constant domains, a CH2 domain and a CH3 domain, and optionally comprises a CH4 domain. The Fc domain may be an Fc domain from an IgGl, IgG2, IgG3, or IgG4 immunoglobulin. In some embodiments, the Fc domain comprises CH2 and CH3 domains from a human IgGl or human IgG2 immunoglobulin. The Fc domain may retain effector function, such as Clq binding, complement dependent cytotoxicity (CDC), Fc receptor binding, antibody -dependent cell-mediated cytotoxicity (ADCC), and phagocytosis. In other embodiments, the Fc domain may be modified to reduce or eliminate effector function.

[0145] A “Fab1fragment” is a Fab fragment having at the C-terminus of the CHI domain one or more cysteine residues from the antibody hinge region.

[0146] A “F(ab')2 fragment” is a bivalent fragment including two Fab' fragments linked by a disulfide bridge between the heavy chains at the hinge region.

[0147] The “Fv” fragment is the minimum fragment that contains a complete antigen recognition and binding site from an antibody. This fragment consists of a dimer of one immunoglobulin heavy chain variable region (VH) and one immunoglobulin light chain variable region (VL) in tight, non-covalent association. It is in this configuration that the three CDRs of each variable region interact to define an antigen binding site on the surface of the VH-VL dimer. A single light chain or heavy chain variable region (or half of an Fv fragment comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site comprising both VH and VL.

[0148] A “single-chain variable fragment” or “scFv fragment” comprises the VH and VL regions of an antibody, wherein these regions are present in a single polypeptide chain, and optionally comprising a peptide linker between the VH and VL regions that enables the Fv to form the desired structure for antigen binding (see e.g., Bird et al., Science, Vol. 242:423-426, 1988; and Huston et al., Proc. Natl. Acad. Sci. USA, Vol. 85:5879-5883, 1988).

[0149] A “nanobody” is the heavy chain variable region of a heavy -chain antibody. Such variable domains are the smallest fully functional antigen-binding fragment of such heavy -chain antibodies, with a molecular mass of only 15 kDa. See Cortez-Retamozo et al., Cancer Research 64:2853-57, 2004. Functional heav -chain antibodies devoid of light chains are naturally occurring in certain species of animals, such as nurse sharks, wobbegong sharks, and Camelidae, such as camels, dromedaries, alpacas and llamas. The antigen-binding site is reduced to a single domain, the VHH domain, in these animals. These antibodies form antigen-binding regions using only heavy chain variable region, i.e., these functional antibodies are homodimers of heavy chains only (referred to as "heavy -chain antibodies” or “HCAbs”). Camelized VHH reportedly recombines with IgG2 and IgG3 constant regions that contain hinge, CH2, and CH3 domains and lack a CHI domain. Camelized VHH domains have been found to bind to antigen with high affinity (Desmyter et al., J. Biol. Chem., Vol. 276:26285-90, 2001) and possess high stability in solution (Ewert et al., Biochemistry, Vol. 41:3628-36, 2002). Methods for generating antibodies having camelized heavy chains are described in, for example, U.S. Patent Publication Nos. 2005 / 0136049 and 2005 / 0037421. Alternative scaffolds can be made from human variable-like domains that more closely match the shark V-NAR scaffold and may provide a framework for a long penetrating loop structure. Human heavy -chain antibodies can be produced by transgenic animals expressing human immunoglobulin genes, such as UniAb™ antibodies produced by UniRat™ transgenic rats.

[0150] As used herein, a “buffer” refers to a buffered solution that resists changes in pH by the action of its acid-base conjugate components.

[0151] As used herein, a “diluent” refers to a liquid solution intended for use in diluting another substance.

[0152] As used herein, a “kit” refers to a collection of items used together for a given purpose or purposes.

[0153] As used herein, a “pharmaceutical composition” refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such compositions are sterile. “Pharmaceutically acceptable” excipients (e.g., vehicles, additives) are those which can reasonably be administered to a subject mammal to provide an effective dose of the active ingredient employed.

[0154] As used herein, a “preservative” refers to a compound which can be included in a composition to reduce bacterial action therein. Examples of preservatives include, but are not limited to, octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride (a mixture of alkylbenzyldimethylammonium chlorides in which the alkyl groups are long-chain compounds), and benzethonium chloride. Other types of preservatives include, but are not limited to, aromatic alcohols such as phenol, butyl, and benzyl alcohol, alkyl parabens such as methyl and propyl paraben, catechol, resorcinol, cyclohexanol, 3 -pentanol, and m-cresol.

[0155] As used herein, a “recombinant protein” refers to a heterologous protein produced by a host cell transfected with a nucleic acid encoding the protein when the host cell is cultivated in cell culture.

[0156] As used herein, a “stable” composition is one in which the protein therein essentially retains its physical stability and / or chemical stability and / or biological activity upon storage. In some embodiments, the composition essentially retains its physical and chemical stability, as well as its biological activity upon storage. The storage period is generally selected based on the intended shelf-life of the composition. Various analytical techniques for measuring protein stability are available in the art and are reviewed in Peptide and Protein Drug Delivery, 247-301. Vincent Lee Ed., Marcel Dekker, Inc., New York, N.Y., Pubs. (1991) and Jones. A. Adv. Drug Delivery Rev. 10: 29-90) (1993), for example. Stability can be measured at a selected temperature for a selected time period. Stability can be evaluated qualitatively and / or quantitatively in a variety of different ways, including evaluation of aggregate formation (for example, using size exclusion chromatography, by measuring turbidity', and / or by visual inspection); by assessing charge heterogeneity using cation exchange chromatography, image capillary isoelectric focusing (icIEF) or capillary zone electrophoresis; amino-terminal or carboxy-terminal sequence analysis; mass spectrometric analysis; SDS-PAGE analysis to compare reduced and intact antibody; peptide map (for example tryptic or LYS-C) analysis; evaluating biological activity or antigen binding function of the antibody; etc. Instability may involve any one or more of: aggregation, deamidation (e.g., Asn deamidation), oxidation (e.g., Met oxidation), isomerization (e.g., Asp isomerization),clipping / hydrolysis / fragmentation (e.g., hinge region fragmentation), succinimide formation, unpaired cysteine(s), N-terminal extension, C-terminal processing, glycosylation differences, etc.

[0157] As used herein, a “sterile” composition is aseptic or free or essentially free from all living microorganisms and their spores. In some embodiments of this disclosure, references to “sterile intravenous solution stabilizers(s)” may be replaced with references to “sterile composition(s).”

[0158] As used herein, a “subject” is a mammal being assessed for treatment and / or being treated. Subjects may be human, but also include other mammals, particularly those mammals useful as laboratory models for human disease, e.g., mouse, rat, etc. In some embodiments, the subject is a human.STERILE INTRAVENOUS SOLUTION STABILIZER PH

[0159] Sterile intravenous solution stabilizers of the present disclosure may be produced using well-known, routine methods for making formulations. To reduce microbial growth during product shelf life and / or when used in the preparation of an infusion solution, sterile intravenous solution stabilizers of the present disclosure are prepared such that they maintain an acidic pH value in the range of 4.0 to 5.5 during product shelf life. pH adjusting agents suitable for preparing a sterile intravenous solution stabilizer with a pH in the range of 4.0 to 5.5 are known in the art.

[0160] In some embodiments, the pH of the sterile intravenous solution stabilizer is in the range of 4.0 to 5.0. In some embodiments, the pH of the sterile intravenous solution stabilizer is in the range of 4.0 to 4.5. In some embodiments, the pH of the sterile intravenous solution stabilizer is in the range of 4.5 to 5.0. In some embodiments, the pH of the sterile intravenous solution stabilizer is in the range of 4.0 to5.4, or 4.0 to 5.3, or 4.0 to 5.2, or 4.0 to 5.2, or 4.0 to 5.1, or 4.0 to 5.0, or 4.0 to 4.9, or 4.0 to 4.8, or 4.0 to 4.7, or 4.0 to 4.6, or 4.0 to 4.5, or 4.0 to 4.4, or 4.0 to 4.3, or 4.0 to 4.2. In some embodiments, the pH of the sterile intravenous solution stabilizer is in the range of 4.1 to 5.5, or 4.2 to 5.5, or 4.3 to 5.5, or 4.4 to 5.5, or 4.5 to 5.5, or 4.6 to 5.5, or 4.7 or 5.5, or 4.8 to 5.5, or 4.9 to 5.5, or 5.0 to 5.5, or 5.1 to 5.5, or 5.2 to 5.5, or 5.3 to 5.5.

[0161] In some embodiments, the pH of the sterile intravenous solution stabilizer is 4.0, 4.1, 4.2, 4.3,4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5. In some embodiments, the pH of the sterile intravenous solution stabilizer is 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0. In some embodiments, the pH of the sterile intravenous solution stabilizer is 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5.

[0162] In some embodiments, the pH of the sterile intravenous solution stabilizer is 4.0. In some embodiments, the pH of the sterile intravenous solution stabilizer is 4.1. In some embodiments, the pH of the sterile intravenous solution stabilizer is 4.2. In some embodiments, the pH of the sterile intravenous solution stabilizer is 4.3. In some embodiments, the pH of the sterile intravenous solution stabilizer is 4.4. In some embodiments, the pH of the sterile intravenous solution stabilizer is 4.5. In some embodiments, the pH of the sterile intravenous solution stabilizer is 4.6. In some embodiments, the pH of the sterileintravenous solution stabilizer is 4.7. In some embodiments, the pH of the sterile intravenous solution stabilizer is 4.8. In some embodiments, the pH of the sterile intravenous solution stabilizer is 4.9. In some embodiments, the pH of the sterile intravenous solution stabilizer is 5.0. In some embodiments, the pH of the sterile intravenous solution stabilizer is 5.1. In some embodiments, the pH of the sterile intravenous solution stabilizer is 5.2. In some embodiments, the pH of the sterile intravenous solution stabilizer is 5.3. In some embodiments, the pH of the sterile intravenous solution stabilizer is 5.4. In some embodiments, the pH of the sterile intravenous solution stabilizer is 5.5.

[0163] In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, or 5.4. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5.

[0164] In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 4.0. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 4.1. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 4.2. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 4.3. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 4.4. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 4.5. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 4.6. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 4.7. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 4.8. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 4.9. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 5.0. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 5.1. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 5.2. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 5.3. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 5.4. In some embodiments, the pH of the sterile intravenous solution stabilizer is centered around a pH of 5.5.BUFFERS

[0165] A buffer is a solution with acid / base conjugate components that enable the solution to resist changes in pH. Independently from the buffer(s) used in a sterile intravenous solution stabilizer of the present disclosure, the pH of the sterile intravenous solution stabilizer is adjusted to a value in the range of 4.0 to 5.5, such as, e.g., by adjustment with an acid or base known in the art. Sterile intravenous solution stabilizers described herein are buffered to maintain an acidic pH in the range of 4.0 to 5.5 atstorage conditions for the product shelf life, such as, e.g., 36 months at a temperature in the range of 2°C to 8°C, optionally followed by 1 month at room temperature, or 3 years at 4°C, or 1 month at 25 °C, or 2 weeks at 25 °C, or 7 days at 25 °C. Various buffers are known to persons skilled in the art and include, but are not limited to, organic buffers (such as, e.g., histidine buffers, citrate buffers, gluconate buffers, succinate buffers, acetate buffers, glycylglycine and other organic acid buffers, and phosphate buffers).

[0166] In some embodiments of the present disclosure, the at least one buffer is effective to maintain the pH of the sterile intravenous solution stabilizer in the range of 4.0 to 5.5. In some embodiments, the at least one buffer is effective to maintain the pH of the sterile intravenous solution stabilizer in the range of 4.0 to 5.0. In some embodiments, the at least one buffer is effective to maintain the pH of the sterile intravenous solution stabilizer in the range of 4.0 to 4.5. In some embodiments, die at least one buffer is effective to maintain the pH of the sterile intravenous solution stabilizer in the range of 4.5 to 5.0.

[0167] In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around a value of 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around 4.0. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around 4.1. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around 4.2. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around 4.3. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around 4.4. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around 4.5. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around 4.6. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around 4.7. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around 4.8. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around 4.9. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around 5.0. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around 5.1. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around 5.2. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around 5.3. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around 5.4. In some embodiments, the at least one buffer is effective to center the pH of the sterile intravenous solution stabilizer around 5.5.

[0168] In some embodiments, the at least one buffer is centered, at 25°C, in a pH range of 4.0 to 5.5, or 4.5 to 5.5, or 4.0 to 4.5, or 4.5 to 5.0. In some embodiments, the at least one buffer has a pKa within one pH unit of pH 4.8-5.0 at 25°C.

[0169] In some embodiments, the at least one buffer comprises acetic acid / acetate, having a pKa of 4.75 at 25°C. In some embodiments, the at least one buffer comprises glutamic acid / glutamate, having a pKa of 4.27 at 25°C. Non-limiting alternative buffers contemplated for sterile intravenous solution stabilizers of the present disclosure include succinate (pKa of 4.21 at 25 °C), propionate (pKa of 4.87 at 25 °C), malate (pKa of 5.13 at 25 °C), pyridine (pKa of 5.23 at 25 °C), and piperazine (pKa of 5.33 at 25 °C). In some embodiments, the buffer can be provided as a sodium salt (or a disodium salt, as appropriate), or in the alternative, as a potassium, magnesium, or ammonium salt.

[0170] In some embodiments, the at least one buffer comprises a salt selected from phosphate, acetate, citrate, succinate, and tartrate. In some embodiments, the at least one buffer comprises citrate.

[0171] In some embodiments, the at least one buffer selected from phosphoric acid / sodium phosphate, glutamic acid / sodium glutamate, acetic acid / sodium acetate, citric acid / sodium citrate, succinic acid / sodium succinate, tartaric acid / sodium tartrate, histidine / histidine HC1, and combinations of any of the foregoing.

[0172] In some embodiments, the at least one buffer is selected from phosphoric acid / sodium phosphate, glutamic acid / sodium glutamate, acetic acid / sodium acetate, citric acid / sodium citrate, succinic acid / sodium succinate, tartaric acid / sodium tartrate, histidine / histidine HC1, and combinations of any of the foregoing. In some embodiments, the at least one buffer is selected from phosphoric acid / sodium phosphate, citric acid / sodium citrate, succinic acid, histidine, glutamate, acetate, and combinations of any of the foregoing.

[0173] The skilled person will be readily able to adjust the buffer concentration to maintain the pH of the sterile intravenous solution stabilizer in a desired pH range at storage conditions for the product shelf life, such as, e.g., 3 years at 4°C, or 1 month at 25°C, or 2 weeks at 25°C, or 7 days at 25°C. Suitable buffer concentrations include, but are not limited to, concentrations of 200 mM or less, such as, e.g., 200 mM, 190 mM, 180 mM, 170 mM, 160 mM, 150 mM, 140 mM, 130 mM, 120 mM, 110 mM, 100 mM, 95 mM, 90 mM, 85 mM, 80 mM, 75 mM, 70 mM, 65 mM, 60 mM, 55 mM, 50 mM, 45 mM, 40 mM, 35 mM, 30 mM, 25 mM, 20 mM, 15 mM, 10 mM, or 5 mM.

[0174] In some embodiments, the at least one buffer is present at a concentration in the range of 0.1 mM to 200 mM or 0.1 mM to 150 mM. In some embodiments, the at least one buffer is present at a concentration in the range of 5 mM to 200 mM. In some embodiments, the at least one buffer is present at a concentration in the range of 10 mM to 50 mM or 10 mM to 30 mM. In some embodiments, the at least one buffer is present at a concentration in the range of 2 mM to 40 mM, or 5 mM to 20 mM, or 10 mM to 25 mM, or 15 mM to 25 mM.

[0175] In some embodiments, the at least one buffer comprises citrate at a concentration in the range of 0.25 mM to 50 mM. In some embodiments, the at least one buffer comprises citrate at a concentration in the range of 10 mM to 50 mM or 10 mM to 30 mM. In some embodiments, the at least one buffer comprises citrate at a concentration of 25 mM.SURFACTANTS

[0176] Surfactants are surface-active agents that typically possess a polar head and a hydrophobic tail. Surfactants preferentially accumulate at interfaces and reduce interfacial tension. Surfactants are commonly used in pharmaceutical compositions to reduce surface adsorption, particularly surface adsorption of proteins. Additionally, surfactants can mitigate aggregate formation, including agitation-induced aggregation, and control protein conformational stability.

[0177] Non-limiting examples of surfactants that can be used in a sterile intravenous solution stabilizer of the present disclosure include: polyoxyethylene-sorbitan fatty acid esters (Tween™); polyethylene-polypropylene glycols; polyoxyethylene-stearates; polyoxyethylene alkyl ethers (e.g., polyoxyethylene monolauryl ether); alkylphenylpolyoxy-ethylene ethers (Triton™-X); polyethyl glycol; polypropyl glycol; polyoxyethylene-polyoxypropylene copolymer (Poloxamer®, Pluronic®); sodium dodecyl sulfate (SDS); sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropy-, or isostearamidopropyl-betaine (e.g., lauroamidopropyl); myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl-, or disodium methyl oleyl-taurate; and the MONAQUA™ series (Mona Industries, Inc., Paterson, N.J.). Non-limiting examples of polyoxy ethylenesorbitan-fatty acid esters include polysorbate 20 (sold under the trademark Tween 20™) and polysorbate 80 (sold under the trademark Tween 80™)- Non-limiting examples of polyethylenepolypropylene copolymers include Pluronic® F68 or Poloxamer 188™. Non-limiting examples of polyoxyethylene-stearates include products sold under the trademark Myrj™. Non-limiting examples of polyoxy -ethylene alkyl ethers include products sold under the trademark Brij™. Non-limiting examples of alkylphenolpoly -oxyethylenes include products sold under the trade name Triton™-X.

[0178] In some embodiments, the at least one surfactant comprises at least one non-ionic surfactant. In some embodiments, the at least one non-ionic surfactant is selected from cocamides, ethoxylates, and alkoxy lates. In some embodiments, the at least one non-ionic surfactant is selected from polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80), alkylaryl polyethers (e.g., oxyethylated alkyl phenol (e.g., Triton™ X-100)), poloxamers (e.g., Pluronics®, e.g., Pluronic® F68), and combinations of any of the foregoing, either within a class of surfactants or among classes of surfactants. In some embodiments, the at least one non-ionic surfactant is selected from polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the at least one non-ionic surfactant ispolysorbate 20 or polysorbate 80. In some embodiments, the at least one non-ionic surfactant is polysorbate 20. In some embodiments, the at least one non-ionic surfactant is polysorbate 80.

[0179] A sterile intravenous solution stabilizer of the present disclosure includes at least one surfactant in an amount sufficient to reduce interfacial tension and / or surface adsorption in the sterile intravenous solution stabilizer at storage conditions for the product shelf life, such as, e.g., 3 years at 4°C, or 1 month at 25°C, or 2 weeks at 25°C, or 7 days at 25°C. In some embodiments, the at least one non-ionic surfactant is present at a concentration in the range of 0.001% (w / v) to 1% (w / v). In some embodiments, the at least one non-ionic surfactant is present at a concentration in the range of 0.001% (w / v) to 0.5% (w / v), or 0.004% (w / v) to 0.25% (w / v), or 0.005% (w / v) to 0.2% (w / v), or 0.004% (w / v) to 0.1% (w / v).

[0180] In some embodiments, the at least one non-ionic surfactant is present at a concentration of 0.005 (w / v)%, 0.006 (w / v)%, 0.007 (w / v)%, 0.008 (w / v)%, 0.009 (w / v)%, 0.01 (w / v)%, 0.02 (w / v)%, 0.03 (w / v)%, 0.04 (w / v)%, 0.05 (w / v)%, 0.06 (w / v)%, 0.07 (w / v)%, 0.08 (w / v)%, 0.09 (w / v)%, 0.1 (w / v)%, 0.2 (w / v)%, 0.3 (w / v)%, 0.4 (w / v)%, 0.5 (w / v)%, 0.6 (w / v)%, 0.7 (w / v)%, 0.8 (w / v)%, 0.9 (w / v)%, or 1 (w / v)%.

[0181] In some embodiments, the at least one non-ionic surfactant is present at a concentration of 0.1% (w / v). In some embodiments, the at least one non-ionic surfactant is polysorbate 20 present at a concentration of 0.1% (w / v). In some embodiments, the at least one non-ionic surfactant is polysorbate 80 present at a concentration of 0.1% (w / v).ADDITIONAL EXCIPIENTS

[0182] Tonicity agents and stabilizing excipients such as amino acids, sugars, polyols, and salts can help mitigate inter- and intra-molecular interactions between proteins and / or excipients. Additional excipients that may be used in a sterile intravenous solution stabilizer of the present disclosure include, but are not limited to, tonicity agents capable of adjusting or maintaining the tonicity of a liquid composition, as well as solubility enhancers and excipients that enhance stability against thermal denaturation. For example, tonicity agents and / or stabilizing excipients included in sterile intravenous solution stabilizers can be used to provide isotonicity, hypotonicity, or hypertonicity to a sterile intravenous solution stabilizer such that it is suitable for administration to a subject. These excipients also can be used, for example, to facilitate maintenance of a protein’s structure and / or to minimize electrostatic, solution protein-protein interactions.

[0183] In some embodiments, a sterile intravenous solution stabilizer of the present disclosure comprises at least one additional excipient. In some embodiments, the at least one additional excipient is selected from amino acids (e.g., glycine, methionine, proline, lysine, arginine, histidine, or glutamic acid), sugars (e.g., fructose, glucose, glyceraldehyde, lactose, arabinose, mannose, xylose, ribose, rhamnose, galactose maltose, sucrose, trehalose, sorbose, sucralose, melezitose, and raffinose), polyols (e.g.,sorbitol, glycerol, mannitol, xylitol, maltitol, lactitol, erythritol, and threitol), salts, and combinations of any of the foregoing, within a class of excipients or among classes of excipients.

[0184] In some embodiments, the at least one additional excipient is selected from sugars and polyols (such as, e.g., sorbitol, mannitol, glycerol, erythritol, caprylate, tryptophanate, sarcoside, and glycine).

[0185] In some embodiments, the at least one additional excipient is a sugar, such as, e.g., a disaccharide, such as, e.g., trehalose, sucrose, or a combination thereof.

[0186] In some embodiments, the at least one additional excipient comprises an amino acid. In some embodiments, the at least one additional excipient comprises an amino acid selected from lysine, proline, serine, and alanine. In some embodiments, the at least one additional excipient comprises lysine. In some embodiments, the at least one additional excipient comprises proline. In some embodiments, the at least one additional excipient comprises serine. In some embodiments, the at least one additional excipient comprises alanine. In some embodiments, the at least one additional excipient comprises two or more amino acids, such as, e.g., two or more of lysine, proline, serine, and alanine.

[0187] An amino acid excipient of the present disclosure can be provided as a salt, such as, e.g., a hydrochloride salt, a potassium salt, or a sodium salt.

[0188] In some embodiments, the at least one additional excipient is present at a concentration in the range of 0.2 M to 6 M, or 0.2 M to 5.5 M, or 0.2 M to 5 M, or 0.2 M to 4.5 M, or 0.2 M to 4 M, or 0.2 M to 3.5 M, or 0.2 M to 3 M, or 0.2 M to 2.5 M, or 0.2 M to 2 M, or 0.2 M to 1.5 M. In some embodiments, the at least one additional excipient is present at a concentration in the range of 0.5 M to 5 M, or 0.5 M to 4.5 M, or 0.5 M to 4 M, or 0.5 M to 3.5 M, or 0.5 M to 3 M, or 0.5 M to 2.5 M, or 0.5 M to 2 M, or 0.5 M to 1.5 M. In some embodiments, the at least one additional excipient is present at a concentration of 0.25 M, 0.5 M, 0.75 M, 1 M, 1.25 M, 1.5 M, 1.75 M, 2 M, 2.25 M, 2.5 M, 2.75 M, 3 M, 3.25 M, 3.5 M, 3.75 M, 4 M, 4.25 M, 4.5 M, 4.75 M, 5 M, 5.25 M, 5.5 M, 5.75 M, or 6 M. In some embodiments, the at least one additional excipient is present at a concentration of 0.75 M, 1 M, 1.25 M, 1.5 M, or 1.75 M. In some embodiments, the at least one additional excipient is present at a concentration of 1 M, 1.25 M, or 1.5 M. In some embodiments, the at least one additional excipient is present at a concentration of 1.25 M.

[0189] In some embodiments, the at least one additional excipient comprises an amino acid present at a concentration of 0.75 M, 1 M, 1.25 M, 1.5 M, or 1.75 M. In some embodiments, the at least one additional excipient comprises an amino acid present at a concentration of 1 M, 1.25 M, or 1.5 M. In some embodiments, the at least one additional excipient comprises an amino acid present at a concentration of 1.25 M.

[0190] In some embodiments, the at least one additional excipient comprises L-lysine hydrochloride present at a concentration of 0.75 M, 1 M, 1.25 M, 1.5 M, or 1.75 M. In some embodiments, the at least one additional excipient comprises L-lysine hydrochloride present at a concentration of 1 M, 1.25 M, or1.5 M. In some embodiments, the at least one additional excipient comprises L-lysine hydrochloride present at a concentration of 1.25 M.INFUSION SOLUTION PREPARATION METHODS

[0191] Sterile intravenous solution stabilizers of the present disclosure may be used in the preparation of intravenous infusion solutions. For example, some embodiments of the present disclosure relate to a method of preparing an infusion solution, the method comprising mixing a sterile intravenous solution stabilizer of the present disclosure, a pharmaceutical composition comprising a recombinant protein, and optionally at least one diluent to obtain an infusion solution with a pH less or equal to 6.0. In some embodiments, the prepared infusion solution does not contain any of benz l alcohol, chlorobutanol, meta-cresol, methylparaben, phenoxyethanol, propylparaben, or thimerosal at a concentration effective to inhibit the growth of microbes. In some embodiments, the prepared infusion solution is preservative-free.

[0192] The pharmaceutical composition, the sterile intravenous solution stabilizer, and the optional at least one diluent may be added to a vessel (e.g., an IV bag or bottle) and mixed in any order. For example, in some embodiments, the pharmaceutical composition and the sterile intravenous solution stabilizer may be added to the vessel sequentially (in either order) or simultaneously and mixed to produce a homogenous solution prior to adding at least one diluent to reduce the concentration of the homogenous solution. Alternatively, in some embodiments, the pharmaceutical composition and the at least one diluent may be added to the vessel sequentially (in either order) or simultaneously and mixed to produce a homogenous solution prior to adding the sterile intravenous solution stabilizer. In other embodiments, the pharmaceutical composition, the at least one diluent, and the sterile intravenous solution stabilizer and added to the vessel sequentially (in any order) or simultaneously and mixed to obtain the infusion solution.

[0193] In some embodiments, the sterile intravenous solution stabilizer is added to the vessel before the pharmaceutical composition. Adding the sterile intravenous solution stabilizer to the vessel prior to the addition of the pharmaceutical composition may reduce adsorption of the recombinant protein to the vessel.

[0194] In some embodiments, the at least one diluent is added to the vessel, followed by the sterile intravenous solution stabilizer, followed by the pharmaceutical composition.

[0195] In some embodiments, the pharmaceutical composition, the at least one diluent, and the sterile intravenous solution stabilizer are mixed in an IV bag.

[0196] In some embodiments, the IV bag is a 50 mL, 100 mL, 150 mL, 200 mL, 250 mL, 500 mL, or 1,000 mL bag. In some embodiments, the IV bag is a 50 mL bag. In some embodiments, the IV bag is a 100 mL bag. In some embodiments, the IV bag is a 150 mL bag. In some embodiments, the IV bag is a200 mL bag. In some embodiments, the IV bag is a 250 mL bag. In some embodiments, the IV bag is a 500 mL bag. In some embodiments, the IV bag is a 1,000 mL bag.

[0197] In some embodiments, the IV bag is a polyvinyl chloride (PVC) bag. In some embodiments, the IV bag is a 50 mL, 100 mL, 150 mL, 200 mL, 250 mL, 500 mL, or 1,000 mL PVC bag.

[0198] In some embodiments, the IV bag comprises polypropylene. In some embodiments, the IV bag is a 50 mL, 100 mL, 150 mL, 200 mL, 250 mL, 500 mL, or 1,000 mL IV bag comprising polypropylene.

[0199] In some embodiments, the IV bag is an ethylene vinyl acetate (EVA) bag. In some embodiments, the IV bag is a 50 mL, 100 mL, 150 mL, 200 mL, 250 mL, 500 mL, or 1,000 mL EVA bag.

[0200] In some embodiments, the IV bag comprises polyolefin. In some embodiments, the IV bag is a 50 mL, 100 mL, 150 mL, 200 mL, 250 mL, 00 mL, or 1,000 mL IV bag comprising polyolefin.

[0201] In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 2% to 10% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 2% to 5% of the IV bag volume.

[0202] In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% of the IV bag volume.

[0203] In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 2% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 2.5% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 3% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 3.5% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 4% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 4.5% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 5% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 5.5% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 6% of the IV bag volume. In some embodiments, the method comprises mixing an amountof the sterile intravenous solution stabilizer equivalent to 6.5% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 7% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 7.5% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 8% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 8.5% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 9% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 9.5% of the IV bag volume. In some embodiments, the method comprises mixing an amount of the sterile intravenous solution stabilizer equivalent to 10% of the IV bag volume.DILUENTS

[0204] Diluents are substances used to dilute other substances, for example, to reduce potency, viscosity, or concentration. Prior to an IV infusion procedure, a therapeutic agent in a concentrated liquid formulation can be diluted into a liquid diluent in an IV bag or bottle. Commonly used diluents for IV infusions include, but are not limited to, saline solutions (e.g., isotonic saline solutions, e.g., 0.9% (w / v) NaCl in water; half normal saline solution), dextrose solutions (e.g., 5% (w / v) dextrose in water), lactated Ringer’s solution, Ringer’s solution, sterile water, and combinations of any of the foregoing.

[0205] Diluents used in the disclosed infusion solution preparation methods may be selected for compatibility with the recombinant protein to be administered. Additionally, the amount of diluent used in the preparation of an infusion solution may be selected to obtain a desired concentration of recombinant protein for infusion, accounting for the volumes of the pharmaceutical composition and the sterile intravenous solution stabilizer used to prepare the infusion solution.

[0206] In some embodiments of the present disclosure, the at least one diluent comprises saline. In some embodiments, the at least one diluent is an isotonic saline solution. In some embodiments, the at least one diluent comprises 0.9% (w / v) NaCl in water.

[0207] In some embodiments of the present disclosure, the at least one diluent comprises dextrose. In some embodiments, the at least one diluent comprises 5% (w / v) dextrose in water.

[0208] In some embodiments of the present disclosure, the at least one diluent is Ringer’s solution.

[0209] In some embodiments of the present disclosure, the at least one diluent is lactated Ringer’s solution.

[0210] In some embodiments of the present disclosure, the at least one diluent is sterile water.

[0211] In some embodiments of the present disclosure, the at least one isotonic.PHARMACEUTICAL COMPOSITIONS COMPRISING RECOMBINANT PROTEINS

[0212] IV solution stabilizers of the present disclosure may be used to reduce adsorption of a recombinant protein to an IV bag and / or IV tubing, and, in some embodiments, may limit microbial growth during IV administration without requiring the use of preservatives.

[0213] Any type of recombinant protein, including proteins containing single polypeptide chains or multiple polypeptide chains, may be used with an IV solution stabilizer of the present disclosure. Illustratively, recombinant proteins that may be used with IV solution stabilizers disclosed herein include, but are not limited to, secreted proteins, non-secreted proteins, intracellular proteins, and membrane-bound proteins. Alternatively, recombinant proteins that may be used with IV solution stabilizers disclosed herein include, but are not limited to, cytokines, growth factors, hormones, muteins, fusion proteins, antibodies, antibody fragments, peptibodies, T-cell engaging molecules, and multi-specific antigen binding proteins.

[0214] In some embodiments, the recombinant protein is an antigen-binding protein. Antigen-binding proteins include, but are not limited to, antibodies, peptibodies, antibody derivatives, antibody analogs, fusion proteins (including, e.g., single chain variable fragments (scFvs), double-chain (divalent) scFvs, and IgGscFv (see, e.g., Orcutt et al., 2010, Protein Eng Des Sei 23:221-228)), hetero-IgGs (see, e.g., Liu et al., 2015, J Biol Chem 290:7535-7562), muteins, and XmAb® (Xencor, Inc., Monrovia, CA). Additional antigen-binding proteins include, but are not limited to, bispecific T cell engagers (BiTE® molecules), bispecific T-cell engagers having extensions, such as, e.g., half-life extensions (HLE), such as, e.g., HLE BiTE molecules, Heterolg BITE molecules, and others, chimeric antigen receptors (CARs, CAR Ts), and T cell receptors (TCRs).

[0215] In some embodiments, the antigen-binding protein binds to one of more of the following, alone or in any combination: CD proteins including, but not limited to, CD3, CD4, CD5, CD7, CD8, CD19, CD20, CD22, CD25, CD30, CD33, CD34, CD38, CD40, CD70, CD123, CD133, CD138, CD171, and CD 174, HER receptor family proteins, including, for instance, HER2, HER3, HER4, and the EGF receptor, EGFRvIH, cell adhesion molecules, for example, LFA-1, Mol, pl 50,95, VLA-4, ICAM-1, VCAM, and alpha v / beta 3 integrin, growth factors, including but not limited to, for example, vascular endothelial growth factor (“VEGF”); VEGFR2, growth hormone, thyroid stimulating hormone, follicle stimulating hormone, luteinizing hormone, growth hormone releasing factor, parathyroid hormone, mullerian-inhibiting substance, human macrophage inflammatory protein (MIP-1 -alpha), erythropoietin (EPO), nerve growth factor, such as, e.g., NGF-beta, platelet-derived growth factor (PDGF), fibroblast growth factors, including, for instance, aFGF and bFGF, epidermal growth factor (EGF), Cripto, transforming growth factors (TGF), including, among others, TGF-a and TGF-P, including TGF-pi, TGF-p2, TGF-p3, TGF-p4, or TGF-p5, insulin-like growth factors-I and -II (IGF-I and IGF-II), des(l-3)- IGF-I (brain IGF-I), and osteoinductive factors, insulins and insulin-related proteins, including, but notlimited to, insulin, insulin A chain, insulin B-chain, proinsulin, and insulin-like growth factor binding proteins; coagulation and coagulation-related proteins, such as, among others, factor VIII, tissue factor, von Willebrand factor, protein C, alpha- 1 -antitrypsin, plasminogen activators, such as urokinase and tissue plasminogen activator (“t-PA”), bombazine, thrombin, thrombopoietin, and thrombopoietin receptor, colony stimulating factors (CSFs), including the following, among others, M-CSF, GM-CSF, and G-CSF, other blood and serum proteins, including but not limited to albumin, IgE, and blood group antigens, receptors and receptor-associated proteins, including, for example, flk2 / flt3 receptor, obesity (OB) receptor, growth hormone receptors, and T-cell receptors; neurotrophic factors, including but not limited to, bone-derived neurotrophic factor (BDNF) and neurotrophin-3, -4, -5, or -6 (NT-3, NT-4, NT-5, or NT-6); relaxin A-chain, relaxin B-chain, and prorelaxin, interferons, including for example, interferonalpha, -beta, and -gamma, interleukins (ILs), e.g., IL-1 to IL-10, IL-12, IL-15, IL-17, IL-23, IL-12 / IL-23, IL-2Ra, IL1-R1, IL-6 receptor, IL-4 receptor and / or IL-13 to the receptor, IL-13RA2, or IL-17 receptor, IL-1RAP; viral antigens, including but not limited to, an AIDS envelope viral antigen, lipoproteins, calcitonin, glucagon, atrial natriuretic factor, lung surfactant, tumor necrosis factor-alpha and -beta, enkephalinase, BCM A, IgKappa, ROR-1, ERBB2, mesothelin, RANTES (regulated on activation normally T-cell expressed and secreted), mouse gonadotropin-associated peptide, DNase, FR-alpha, inhibin, and activin, integrin, protein A or D, rheumatoid factors, immunotoxins, bone morphogenetic protein (BMP), superoxide dismutase, surface membrane proteins, decay accelerating factor (DAF), AIDS envelope, transport proteins, homing receptors, MIC (MIC-a, MIC-B), ULBP 1-6, EPCAM, addressins, regulatory proteins, immunoadhesins, antigen-binding proteins, somatropin, CTGF, CTLA4, eotaxin-1, MUC1, CEA, c-MET, Claudin-18, GPC-3, EPHA2, FPA, LMP1, MG7, NY-ESO-1, PSCA, ganglioside GD2, ganglioside GM2, BAFF, OPGL (RANKL), myostatin, Dickkopf-1 (DKK-1), Ang2, NGF, IGF-1 receptor, hepatocyte growth factor (HGF), TRAIL-R2, c-Kit, B7RP-1, PSMA, NKG2D-1, programmed cell death protein 1 and ligand, PD1 and PDL1, mannose receptor / hCGP, hepatitis-C virus, mesothelin dsFv[PE38] conjugate, Legionella pneumophila (lly), IFN gamma, interferon gamma induced protein 10 (IP 10), IFNAR, TALL-1, thymic stromal lymphopoietin (TSLP), proprotein convertase subtilisin / Kexin Type 9 (PCSK9), stem cell factors, Flt-3, calcitonin gene-related peptide (CGRP), OX40L, a4 7, platelet specific (platelet glycoprotein Ilb / IIIb (PAC-1), transforming growth factor beta (TFGP), Zona pellucida sperm-binding protein 3 (ZP-3), TWEAK, platelet derived growth factor receptor alpha (PDGFRa), sclerostin, and biologically active fragments or variants of any of the foregoing.

[0216] In other embodiments, the recombinant protein is an antibody. In some embodiments, the antibody is a human antibody. In some embodiments, the antibody is an IgGl antibody. In some embodiments, the antibody is a human IgGl antibody. In some embodiments, the antibody is an IgG4 antibody. In some embodiments, the antibody is a human IgG4 antibody. In some embodiments, the antibody is an IgG2 antibody. In some embodiments, the antibody is a human IgG2 antibody.

[0217] Recombinant proteins administered in combination with the IV solution stabilizers disclosed herein may be mixed with IV solution stabilizer in the form of a pharmaceutical composition. The pharmaceutical composition may be prepared and stored as a liquid formulation or may be prepared and stored as a lyophilized formulation that is reconstituted shortly before use. Pharmaceutical compositions comprising recombinant proteins that are used in infusion solution preparation methods of the present disclosure may be prepared for storage by mixing therapeutic agents having the desired degree of purity with optional pharmaceutically acceptable carriers or excipients. “Pharmaceutically acceptable” refers to molecules, compounds, and compositions that are non-toxic to human recipients at the dosages and concentrations employed and / or do not produce allergic or adverse reactions when administered to humans. In certain embodiments, the pharmaceutical composition may contain formulation materials for modifying, maintaining, or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. In such embodiments, suitable formulation materials include, but are not limited to, amino acids (such as, e.g., glycine, glutamine, asparagine, arginine, or lysine); antioxidants (such as, e.g., ascorbic acid, sodium sulfite, or sodium hydrogen-sulfite); buffers (such as, e.g., borate, bicarbonate, Tris-HCl, citrates, phosphates, or other organic acids); bulking agents (such as, e g., mannitol or glycine); chelating agents (such as, e.g., ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as, e.g., caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxy propyl-beta-cyclodextrin); fillers; coatings; monosaccharides; disaccharides; and other carbohydrates (such as, e.g., glucose, mannose, or dextrins); proteins (such as, e.g., serum albumin, gelatin, or immunoglobulins); emulsifying agents; hydrophilic polymers (such as, e.g., polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as, e.g., sodium, potassium, magnesium, calcium, acetate, hydrochloride, phosphate, and the like); solvents (such as, e.g., glycerin, propylene glycol, or polyethylene glycol); sugar alcohols (such as, e.g., mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as, e.g., poloxamers, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate 80, triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancing agents (such as, e.g., sucrose or sorbitol); tonicity enhancing agents (such as, e.g., alkali metal halides, e.g., sodium or potassium chloride, mannitol, or sorbitol); delivery' vehicles; diluents; excipients, and / or pharmaceutical adjuvants. Methods and suitable materials for formulating molecules for therapeutic use are known in the pharmaceutical arts, and are described, for example, in REMINGTON’S PHARMACEUTICAL SCIENCES, 18th Edition, (A.R. Genrmo, ed.), 1990, Mack Publishing Company.PREPARED INFUSION SOLUTION PH AND STERILITY

[0218] To limit microbial growth during IV administration, particularly during extended administration periods of several hours to days, infusion solutions prepared according to methods of the present disclosure have a pH less than or equal to 5.5. In some embodiments, the pH of the preparedinfusion solution is less than or equal to 5.0. In some embodiments, the pH of the prepared infusion solution is less than or equal to 4.5.

[0219] In some embodiments, the pH of the prepared infusion solution is in the range of 4.0 to 5.5. In some embodiments, the pH of the prepared infusion solution is in the range of 4.0 to 5.0. In some embodiments, the pH of the prepared infusion solution is in the range of 4.0 to 4.5. In some embodiments, the pH of the prepared infusion solution is in the range of 4.5 to 5.0.

[0220] In some embodiments, the pH of the prepared infusion solution is 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5. In some embodiments, the pH of the prepared infusion solution is 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0. In some embodiments, the pH of the prepared infusion solution is 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5.

[0221] In some embodiments, the pH of the prepared infusion solution is 4.0. In some embodiments, the pH of the prepared infusion solution is 4.1. In some embodiments, the pH of the prepared infusion solution is 4.2. In some embodiments, the pH of the prepared infusion solution is 4.3. In some embodiments, the pH of the prepared infusion solution is 4.4. In some embodiments, the pH of the prepared infusion solution is 4.5. In some embodiments, the pH of the prepared infusion solution is 4.6. In some embodiments, the pH of the prepared infusion solution is 4.7. In some embodiments, the pH of the prepared infusion solution is 4.8. In some embodiments, the pH of the prepared infusion solution is 4.9. In some embodiments, the pH of the prepared infusion solution is 5.0. In some embodiments, the pH of the prepared infusion solution is 5.1. In some embodiments, the pH of the prepared infusion solution is 5.2. In some embodiments, the pH of the prepared infusion solution is 5.3. In some embodiments, the pH of the prepared infusion solution is 5.4. In some embodiments, the pH of the prepared infusion solution is 5.5.

[0222] In some embodiments, the pH of the prepared infusion solution is centered around a pH of 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5. In some embodiments, the pH of the prepared infusion solution is centered around a pH of 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0. In some embodiments, the pH of the prepared infusion solution is centered around a pH of 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5.

[0223] In some embodiments, the pH of the prepared infusion solution is centered around a pH of 4.0. In some embodiments, the pH of the prepared infusion solution is centered around a pH of 4.1. In some embodiments, the pH of the prepared infusion solution is centered around a pH of 4.2. In some embodiments, the pH of the prepared infusion solution is centered around a pH of 4.3. In some embodiments, the pH of the prepared infusion solution is centered around a pH of 4.4. In some embodiments, the pH of the prepared infusion solution is centered around a pH of 4.5. In some embodiments, the pH of the prepared infusion solution is centered around a pH of 4.6. In some embodiments, the pH of the prepared infusion solution is centered around a pH of 4.7. In some embodiments, the pH of the prepared infusion solution is centered around a pH of 4.8. In someembodiments, the pH of the prepared infusion solution is centered around a pH of 4.9. In some embodiments, the pH of the prepared infusion solution is centered around a pH of 5.0. In some embodiments, the pH of the prepared infusion solution is centered around a pH of 5.1. In some embodiments, the pH of the prepared infusion solution is centered around a pH of 5.2. In some embodiments, the pH of the prepared infusion solution is centered around a pH of 5.3. In some embodiments, the pH of the prepared infusion solution is centered around a pH of 5.4. In some embodiments, the pH of the prepared infusion solution is centered around a pH of 5.5.

[0224] Preservatives are often included in infusion solutions to limit microbial growth during IV administration, particularly during extended IV administration. However, infusion solutions prepared according to methods described herein may be free of one or more preservatives (e g., may be preservative free) because their acidic pH is sufficient to reduce bacterial action over the administration period. For example, in some embodiments, the prepared infusion solution does not contain any of benzyl alcohol, chlorobutanol, meta-cresol, methylparaben, phenoxyethanol, propylparaben, or thimerosal at a concentration effective to inhibit the growth of microbes. In some embodiments, the prepared infusion solution is preservative-free.

[0225] In some embodiments, the level of microbial growth in the prepared infusion solution is less than one half log after 24 hours, or after 48 hours, or after 72 hours, or after 96 hours, or after 7 days at room temperature. In some embodiments, the level of growth of Escherichia coli in the prepared infusion solution is less than one half log after 24 hours, or after 48 hours, or after 72 hours, or after 96 hours, or after 7 days at room temperature. In some embodiments, the level of growth of Pseudomonas aeruginosa in the prepared infusion solution is less than one half log after 24 hours, or after 48 hours, or after 72 hours, or after 96 hours, or after 7 days at room temperature. In some embodiments, the level of growth of Enterobacter cloacae in the prepared infusion solution is less than one half log after 24 hours, or after 48 hours, or after 72 hours, or after 96 hours, or after 7 days at room temperature. In some embodiments, the level of growth of Staphylococcus aureus in the prepared infusion solution is less than one half log after 24 hours, or after 48 hours, or after 72 hours, or after 96 hours, or after 7 days at room temperature. In some embodiments, the level of growth of Micrococcus luteus in the prepared infusion solution is less than one half log after 24 hours, or after 48 hours, or after 72 hours, or after 96 hours, or after 7 days at room temperature. In some embodiments, the level of growth of Candida albicans in the prepared infusion solution is less than one half log after 24 hours, or after 48 hours, or after 72 hours, or after 96 hours, or after 7 days at room temperature.

[0226] In some embodiments, the level of growth of Enterobacter cloacae in the prepared infusion solution is less than one half log after 24 hours at room temperature. In some embodiments, the level of growth of Enterobacter cloacae in the prepared infusion solution is less than one half log after 48 hours at room temperature. In some embodiments, the level of growth of Enterobacter cloacae in the prepared infusion solution is less than one half log after 72 hours at room temperature. In some embodiments, thelevel of growth of Enierobacter cloacae in the prepared infusion solution is less than one half log after 96 hours at room temperature. In some embodiments, the level of growth of Enterobacter cloacae in the prepared infusion solution is less than one half log after 7 days at room temperature.

[0227] In some embodiments, the level of microbial growth in the prepared infusion solution is less than one half log after 14 days at a temperature in the range of 2°C to 8°C. In some embodiments, the level of growth of Escherichia coli in the prepared infusion solution is less than one half log after 14 days at a temperature in the range of 2°C to 8°C. In some embodiments, the level of growth of Pseudomonas aeruginosa in the prepared infusion solution is less than one half log after 14 days at a temperature in the range of 2°C to 8°C. In some embodiments, the level of growth of Enterobacter cloacae in the prepared infusion solution is less than one half log after 14 days at a temperature in the range of 2°C to 8°C. In some embodiments, the level of growth of Staphylococcus aureus in the prepared infusion solution is less than one half log after 14 days at a temperature in the range of 2°C to 8°C. In some embodiments, the level of growth of Micrococcus luteus in the prepared infusion solution is less than one half log after 14 days at a temperature in the range of 2°C to 8°C. In some embodiments, the level of growth of Candida albicans in the prepared infusion solution is less than one half log after 14 days at a temperature in the range of 2°C to 8°C.KITS

[0228] The present disclosure also provides kits comprising sterile intravenous solution stabilizers disclosed herein, including kits comprising a sterile intravenous solution stabilizer disclosed herein and instructions for use. Such kits may be useful in preparing an infusion solution and / or treating a subject suffering from a disease or disorder (e.g., cancer). For example, the present disclosure provides a kit for preparing an infusion solution, the kit comprising a sterile intravenous solution stabilizer disclosed herein; at least one additional component selected from at least one diluent, a pharmaceutical composition comprising a recombinant protein, an IV bag, and combinations of any of the foregoing; and optionally instructions for use.

[0229] In some embodiments, the kit comprises at least one diluent and a sterile intravenous solution stabilizer disclosed herein.

[0230] In some embodiments, the kit comprises an IV bag and a sterile intravenous solution stabilizer disclosed herein.

[0231] In some embodiments, the kit comprises at least one diluent, an IV bag, and a sterile intravenous solution stabilizer disclosed herein.

[0232] In some embodiments, the kit comprises a pharmaceutical composition comprising a recombinant protein; and a sterile intravenous solution stabilizer disclosed herein.

[0233] In some embodiments, the kit comprises a pharmaceutical composition comprising a recombinant protein; an IV bag; and a sterile intravenous solution stabilizer disclosed herein.

[0234] In some embodiments, the kit comprises a pharmaceutical composition comprising a recombinant protein; at least one diluent; and a sterile intravenous solution stabilizer disclosed herein.

[0235] In some embodiments, the kit comprises a pharmaceutical composition comprising a recombinant protein; at least one diluent; an IV bag; and a sterile intravenous solution stabilizer disclosed herein.

[0236] Non-limiting examples of IV bags that may be included in kits of the present disclosure include 50 mL, 100 mL, 150 mL, 200 mL, 250 mL, 500 mL, and 1,000 mL IV bags. In some embodiments, the IV bag is a 50 mL bag. In some embodiments, the IV bag is a 100 mL bag. In some embodiments, the IV bag is a 150 mL bag. In some embodiments, the IV bag is a 200 mL bag. In some embodiments, the IV bag is a 250 mL bag. In some embodiments, the IV bag is a 500 mL bag. In some embodiments, the IV bag is a 1,000 mL bag.

[0237] Additionally, IV bags included in kits of the present disclosure may be made from a variety of materials, including, but not limited to polyvinyl chloride (PVC), polypropylene, polyolefin, and / or ethylene vinyl acetate (EVA).

[0238] In some embodiments, the IV bag is a PVC bag. In some embodiments, the IV bag is a 50 mL, 100 mL, 150 mL, 200 mL, 250 mL, 500 mL, or 1,000 mL PVC bag.

[0239] In some embodiments, the IV bag comprises polypropylene. In some embodiments, the IV bag is a 50 mL, 100 mL, 150 mL, 200 mL, 250 mL, 500 mL, or 1,000 mL IV bag comprising polypropylene.

[0240] In some embodiments, the IV bag comprises polyolefin. In some embodiments, the IV bag is a 50 mL, 100 mL, 150 mL, 200 mL, 250 mL, 500 mL, or 1,000 mL IV bag comprising polyolefin.

[0241] In some embodiments, the IV bag is an EVA bag. In some embodiments, the IV bag is a 50 mL, 100 mL, 150 mL, 200 mL, 250 mL, 500 mL, or 1,000 mL EVA bag.

[0242] Kits of the present disclosure may include one or more containers of the sterile intravenous solution stabilizer and / or one or more containers of the at least one diluent and / or one or more containers of a pharmaceutical composition comprising a recombinant protein. Additionally, the disclosed kits may contain one or more separate documents containing information pertaining to the contents of the kit and / or the use of its contents, e.g., for preparing an infusion solution and / or administering the same to a subject in need thereof.

[0243] The following examples are provided for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present disclosure in any fashion. One skilled in the art willreadily appreciate that the present disclosure is well-adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those objects, ends, and advantages inherent herein. Changes therein and other uses which are encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art.EXAMPLESEXAMPLE 1: Infusion Solution pH and Microbial Growth

[0244] This study was set up with the intent to monitor microbial growth in IV infusion solutions containing clinically relevant protein concentrations and excipient levels for multiple protein therapeutics. Specifically, microbial growth in the infusion solutions was monitored for up to 24 hours at room temperature and up to 14 days at 2°C to 8°C. The rate of microbial growth as a function of excipient concentration was examined in infusion composed of drug product (or dextrose as a control), IV Solution Stabilizer (IVSS: 25 mM citric acid monohydrate, 1.25 M L-lysine hydrochloride, and 0.1% (w / v) polysorbate 80 (PS80), pH 7), and saline (0.9% NaCl). All drug product samples contained 10 mM acetate or glutamate, 9% sucrose, and 0.01% PS80 (Table 1).TABLE 1. IV Solution Formulation Components

[0245] A 1500 mL volume of each formulation was sterile filtered through a 0.22 pm filter in a biosafety cabinet. 100 mL of filtered formulation was then transferred into each of 14 empty IV bags. 150 mL IV bags composed of ethyl vinyl acetate (EVA) were employed in this study. A syringe was used to remove excess air from each bag after adding the infusion solution. One IV bag was prepared for each formulation for each of the six challenge microorganisms (Escherichia coli', Pseudomonas aeruginosa', Enterobacter cloacae', Staphylococcus aureus', Micrococcus luteus', Candida albicans) and one additionalIV bag for an un-inoculated negative control for both 2-8°C and room temperature storage conditions (14 bags per formulation).

[0246] The challenge microorganisms were grown under the following conditions outlined in Table 2. Cultures were harvested with PHSS or an equivalent diluent. The harvested cultures were washed four times by centrifuging the cells at 10,000 rpm for 2 minutes, decanting the supernatant, adding PHSS to the culture, and vortexing. The challenge microorganisms were then diluted to achieve approximately less than 104CFU / mL.TABLE 2. Challenge Microorganism Growth and Recovery Conditions

[0247] One IV bag per challenge microorganism was inoculated in a Biological Safety Cabinet (BSC). Specifically, each bag was inoculated through a disinfected port with an inoculum consisting of <104CFU / mL and approximately 1% of the sample volume. The target final concentration of challenge microorganism in the sample was <100 CFU / mL. Post-inoculation, the injection port was disinfected with a sterile wipe soaked in isopropyl alcohol (IP A) and allowed to dry before gently mixing.

[0248] The inoculated IV bags were assayed for surviving microorganisms at the following time points during storage at 2°C to 8°C: 0; 4 days; 8 days; 12 days; and 14 days. The inoculated IV bags were assayed for surviving microorganisms at the following time points during storage at 25°C: 0, 6 hours; 8 hours; 10 hours; 12 hours; 14 horns; and 24 hours. The 0-hour assay served as inoculum verification to determine the inoculum level in each IV bag. To assay for surviving microorganisms, the injection port of each IV bag was wiped with a sterile wipe soaked with IPA and allowed to dry. The IV bag was gently mixed before approximately 3 mL of solution from the IV bag was withdrawn and dispensed into alabeled sterile test tube. The injection port was then disinfected with a sterile wipe soaked in IPA and allowed to dry.

[0249] Each solution was membrane filtered in a BSC. Approximately 20 mL of 0.1% peptone water (PEPW) was added to each funnel. The assayed solution was vortexed, and 1 mL was added to each funnel. Each IV bag was assayed in duplicate. Where necessary, additional dilutions were performed (e.g., 10'1, 10'2, etc.) in order to obtain plates in the countable range (<300 CFU / plate).

[0250] Each filter membrane was washed with three approximately 100 mL aliquots of PEPW. The membrane filters were aseptically removed and placed on agar media (Tryptic Soy Agar (TSA) or Sabouraud Dextrose Agar (SABDEX)) and incubated using the recovery conditions described in Table 2. If two consecutive time points yielded no recovery counts for any organism, testing of the subsequent time points could be skipped, with testing of only the last time point (192-196 horns) performed. Each IV bag was placed in a new sterile plastic bag after each subsequent assay.

[0251] A diluent negative control was prepared by membrane filtering three approximately 100 mL aliquots of PEPW. A 1 mL aliquot of PHSS was also membrane filtered at each time point where PHSS was used to dilute a sample aliquot to achieve counts in the countable range (<300 CFU / plate). The membrane filters were placed on Tryptic Soy Agar (TSA). Average CFU / mL were calculated as follows:1(Plate 1 Count) -(Plate 2 Count) . - - X Dilution1= Average CFU / mL.

[0252] In Tables 3-14, the log change is calculated as logio(Average CFU / mL at time point / Average CFU mL at time 0). According to USP <51>, the level of microbial growth is only considered to be a concern if it surpasses one half log compared to time zero. The results from the microbial growth study at 2°C to 8°C did not show concerning growth in any of the microbes tested out to fourteen days (Tables 9-14). Moreover, the only microbe that grew and remained at a concerning level during the 24 hour incubation at room temperature, including at the 24 hour time point, was Enterobacter cloacae (Tables 3-8; FIG. 1). As shown in FIG. 1, the one half log of growth limit for Enterobacter cloacae was only surpassed by RP4 at 24 hours.

[0253] RP2, RP3, and RP4 are all of similar molecule type with similar levels of buffer and excipients in the formulations tested. Upon further evaluation of the buffer compositions, a difference in pH was identified for these formulations. Specifically, both RP3 and RP4 IV bag solutions had pH measurements above 6.0, while the solution pH for RP2 IV bag solutions was below 6.0. The difference in IV solution pH is a result of the ratio of drug product formulation volume (buffered at pH 4.2) added to the infusion solution versus the volume of I VS S (buffered at pH 7.0).TABLE 3. Initial CFU / mL (tO) and Log Change (t6, t8, tlO, tl2, tl4, and t24) in Escherichia coli Levels at Room TemperatureTABLE 4. Initial CFU / mL (tO) and Log Change (t6, t8, tlO, tl2, tl4, and t24) in Pseudomonas aeruginosa Levels at Room TemperatureTABLE 5. Initial CFU / mL (tO) and Log Change (t6, t8, tlO, tl2, tl4, and t24) in Staphylococcus aureus Levels at Room TemperatureTABLE 6. Initial CFU / mL (tO) and Log Change (t6, t8, tlO, tl2, tl4, and t24) inMicrococcus luteus Levels at Room TemperatureTABLE 7. Initial CFU / mL (tO) and Log Change (t6, t8, tlO, tl2, tl4, and t24) in Enter obacter cloacae Levels at Room TemperatureTABLE 8. Initial CFU / mL (tO) and Log Change (t6, t8, tlO, t!2, t!4, and t24) in Candida albicans Levels at Room TemperatureTABLE 9. Initial CFU / mL (tO) and Log Change (t4, t8, 112, tl 4) in Escherichia coli Levels at 2°C to 8°CTABLE 10. Initial CFU / mL (tO) and Log Change (t4, t8, 112, 114) in Pseudomonas aeruginosa Levels at 2°C to 8°CTABLE 11. Initial CFU / mL (tO) and Log Change (t4, t8, tl2, tl4) in Staphylococcus aureus Levels at 2°C to 8°CTABLE 12. Initial CFU / mL (tO) and Log Change (t4, t8, tl2, tl4) in Micrococcus luteus Levels at 2°C to 8°CTABLE 13. Initial CFU / mL (tO) and Log Change (t4, t8, 112, 114) in Enterobacter cloacae Levels at 2°C to 8°CTABLE 14. Initial CFU / mL (tO) and Log Change (t4, t8, tl2, tl4) in Candida albicans Levels at 2°C to 8°CEXAMPLE 2: Microbial Growth in Low pH Infusion Solutions

[0254] To further investigate the impact of solution pH on microbial growth in infusion solutions comprising saline, IVSS, and drug product, two drug product formulations comprising therapeuticproteins (RP2, RP8) were diluted into 0.9% saline with 5% IVSS (25 mM citric acid monohydrate, 1.25 M L-lysine hydrochloride, and 0.1% (w / v) polysorbate 80, pH 7) and titrated to pH 4.5, 5.0, or 5.5. The titrated solutions were inoculated with Enterobacter cloacae (target final concentration: <100 CFU / mL) in 50 mL plastic conical tubes. As shown in FIG. 2, E. cloacae growth was well-controlled at 25°C up to 48 hours in the infusion solution at pH 4.5.EXAMPLE 3: Therapeutic Protein Stability and Solution pH

[0255] Therapeutic protein stability as a function of solution pH (5.0, 5.5, 6.0, 7.0) in EVA IV bags was assessed for four therapeutic proteins (RP2, RP5, RP6, and RP7) at concentrations of 1 pg / mL and 100 pg / mL for up to 14 days. Samples were analyzed by recombinant protein (RP) titer, size exclusion chromatography (SEC), high accuracy liquid particle counter (HIAC), and visual inspection at 0, 2, 5, 7, and 14 days. For protein recovery / RP titer, fluorescence peaks were used to assess peak area. While slight fluctuations were observed, protein recovery concentration was generally within ± 5% across molecules, concentrations, and pH conditions. Additionally, HIAC results were within specifications for all molecules and conditions tested. Finally, the percentage of high molecular weight aggregates (% HMW) exhibited only slight fluctuations across pH conditions, with molecule specific changes in % HMW observed over the course of 14 days.

[0256] All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference. What is described in an embodiment of the disclosure can be combined with one or more other embodiments of the disclosure unless context clearly indicates otherwise.

[0257] The disclosed subject matter is not intended to be limited in scope by the specific embodiments described herein, which are instead intended as non-limiting illustrations of individual aspects of the disclosure. Functionally equivalent methods and components are within the scope of the disclosure. Indeed, various modifications of the disclosed subject matter, in addition to those shown and described herein, will be apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the disclosed subject matter.

[0258] The descriptions of the various embodiments and / or examples of the disclosed subject matter have been presented for purposes of illustration, but are not intended to be exhaustive or limiting in any way. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The terminology' used herein was chosen to best explain the principles of the embodiments, the practical application, or technicalimprovement over technologies found in the marketplace, and / or to enable others of ordinary skill in the art to understand the disclosed subject matter.

Claims

What is claimed is:

1. A sterile intravenous solution stabilizer comprising: at least one buffer; and at least one surfactant, wherein the pH of the sterile intravenous solution stabilizer is in the range of 4.0 to 5.5; and further wherein the sterile intravenous solution stabilizer does not contain any of benzyl alcohol, chlorobutanol, meta-cresol, methylparaben, phenoxyethanol, propylparaben, or thimerosal at a concentration effective to inhibit the growth of microbes.

2. The sterile intravenous solution stabilizer of claim 1, wherein the at least one buffer is present at a concentration in the range of 0.1 mM to 150 mM.

3. The sterile intravenous solution stabilizer of claim 1 or claim 2, wherein the at least one buffer is present at a concentration in the range of 0.25 mM to 50 mM.

4. The sterile intravenous solution stabilizer of any one of claims 1 to 3, wherein the at least one buffer is selected from phosphoric acid / phosphate salt, glutamic acid / glutamate salt, acetic acid / acetate salt, citric acid / citrate salt, succinic acid / succinate salt, tartaric acid / tartrate salt, histidine / histidine salt, and combinations of any of the foregoing.

5. The sterile intravenous solution stabilizer of any one of claims 1 to 4, wherein the at least one buffer comprises citrate at a concentration in the range of 0.25 mM to 50 mM.

6. The sterile intravenous solution stabilizer of any one of claims 1 to 5, wherein the at least one buffer is effective to maintain the pH of the sterile intravenous solution stabilizer in the range of 4.0 to 5.5.

7. The sterile intravenous solution stabilizer of any one of claims 1 to 6, further comprising at least one additional excipient.

8. The sterile intravenous solution stabilizer of claim 7, wherein the at least one additional excipient is selected from amino acids, sugars, polyols, and salts.

9. The sterile intravenous solution stabilizer of claim 7 or claim 8, wherein the at least one additional excipient is present at a concentration in the range of 0.2 M to 6 M.

10. The sterile intravenous solution stabilizer of any one of claims 7 to 9, wherein the at least one additional excipient comprises an amino acid.

11. The sterile intravenous solution stabilizer of any one of claims 7 to 10, wherein the at least one additional excipient comprises an amino acid selected from lysine, proline, serine, and alanine.

12. The sterile intravenous solution stabilizer of any one of claims 7 to 11, wherein the at least one additional excipient comprises lysine.

13. The sterile intravenous solution stabilizer of any one of claims 1 to 12, wherein the at least one surfactant comprises at least one non-ionic surfactant.

14. The sterile intravenous solution stabilizer of claim 13, wherein the at least one non-ionic surfactant is present at a concentration in the range of 0.001% (w / v) to 1% (w / v).

15. The sterile intravenous solution stabilizer of claim 13 or claim 14, wherein the at least one non- ionic surfactant is present at a concentration in the range of 0.001% (w / v) to 0.5% (w / v).

16. The sterile intravenous solution stabilizer of any one of claims 13 to 15, wherein the at least one non-ionic surfactant is present at a concentration of 0.1% (w / v).

17. The sterile intravenous solution stabilizer of any one of claims 13 to 16, wherein the at least one non-ionic surfactant is selected from cocamides, ethoxylates, and alkoxylates.

18. The sterile intravenous solution stabilizer of any one of claims 13 to 16, wherein the at least one non-ionic surfactant is selected from sorbitan fatty acid esters and polyethylene glycol sorbitan fatty acid esters.

19. The sterile intravenous solution stabilizer of any one of claims 13 to 16, wherein the at least one non-ionic surfactant is selected from polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

20. The sterile intravenous solution stabilizer of any one of claims 1 to 19, wherein the pH of the sterile intravenous solution stabilizer is in the range of 4.0 to 5.0.

21. The sterile intravenous solution stabilizer of any one of claims 1 to 20, wherein the sterile intravenous solution stabilizer is preservative-free.

22. A method of preparing an infusion solution comprising mixing: a pharmaceutical composition comprising a recombinant protein; at least one diluent; and the sterile intravenous solution stabilizer of any one of claims 1 to 21; wherein the pH of the prepared infusion solution is less than or equal to 6.0; and further wherein the prepared infusion solution does not contain any of benzyl alcohol, chlorobutanol, meta-cresol, methylparaben, phenoxyethanol, propylparaben, or thimerosal at a concentration effective to inhibit the growth of microbes.

23. The method of claim 22, wherein the prepared infusion solution is isotonic.

24. The method of claim 22 or claim 23, wherein the at least one diluent is selected from saline solutions, dextrose solutions, lactated Ringer’s solution, Ringer’s solution, sterile water, and combinations of any of the foregoing.

25. The method of claim 22 or claim 23, wherein the at least one diluent comprises saline.

26. The method of any one of claims 22 to 25, wherein the pH of the prepared infusion solution is in the range of 4.0 to 5.5.

27. The method of any one of claims 22 to 25, wherein the pH of the prepared infusion solution is in the range of 4.5 to 5.0.

28. The method of any one of claims 22 to 27, wherein the prepared infusion solution is preservative- free.

29. The method of any one of claims 22 to 28, wherein the recombinant protein is stable in the prepared infusion solution for at least 24 hours at room temperature.

30. The method of any one of claims 22 to 29, wherein the recombinant protein is stable in the prepared infusion solution for at least 96 hours at a temperature in the range of 2°C to 8°C.

31. The method of any one of claims 22 to 30, wherein the level of microbial growth in the prepared infusion solution is less than one half log after 24 hours at room temperature.

32. The method of any one of claims 22 to 31, wherein the level of microbial growth in the prepared infusion solution is less than one half log after 14 days at a temperature in the range of 2°C to 8°C.

33. The method of any one of claims 22 to 32, wherein the pharmaceutical composition, the at least one diluent, and the sterile intravenous solution stabilizer are mixed in an intravenous (IV) bag.

34. The method of claim 33, comprising mixing an amount of the sterile intravenous solution stabilizer equivalent to 2% to 10% of the IV bag volume.

35. A kit for preparing an infusion solution, comprising: a pharmaceutical composition comprising a recombinant protein; at least one diluent; and a sterile intravenous solution stabilizer of any one of claims 1 to 21.

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