N-acetylated and non-acetylated dipeptides containing arginine to reduce the viscosity of viscous compositions of therapeutic polypeptides

#The present application is being filed with a sequence listing in electronic format. The sequence listing provided as a file titled, “A-2142-WO-PCT_sequence listing_ST25.txt,” created Apr. 27, 2018, and is 258 KB in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

#The presented subject matter relates to the field of pharmaceutical compositions of antigen binding polypeptides and methods of reducing viscosity of such compositions. Specifically, disclosed herein are excipients that reduce viscosity of pharmaceutical compositions. Furthermore, the disclosed subject matter presents methods related to making such pharmaceutical compositions.

#Certain therapeutic polypeptides can be difficult to formulate such that an optimal viscosity is attained, whether because of the nature of the therapeutic polypeptide itself, or because of the concentration (high) of the therapeutic polypeptide, or even both. High viscosity formulations are difficult to handle during formulation and packaging. Furthermore, such preparations can be difficult to administer optimally to a patient, and such administration can be uncomfortable for the patient. The need to identify compounds that are useful for reducing viscosity of highly concentrated protein formulations, to develop methods of reducing the viscosity of such formulations, and to provide pharmaceutical formulations with reduced viscosity are well known in the pharmaceutical arts.

#FIG. 1 shows a line graph representation of the viscosity of various pharmaceutical formulations comprising the indicated amounts of a therapeutic antibody (Antibody 1, “Ab1”; concentration is shown as mg/mL) and various excipients at the indicated pH values.

#FIGS. 2A and 2B show a line graph of observed viscosity of pharmaceutical formulations comprising 10 mM glutamic acid buffer pH 5.2 with 4% w/v sucrose vs the concentration of a therapeutic antibody (Antibody 1, “Ab1”)) with and without the indicated excipients in the formulations. FIG. 2A shows the graph so that all values of the samples are shown for each point along the x-axis; and FIG. 2B shows the detail of the viscosity of the formulations wherein the viscosity was observed at 100 cP or less. G52Su, buffer, sucrose and Ab1 (no excipient); G52Su-ArgHCl, 150 mM ArgHCl as excipient; Pro-Arg, 150 mM N-acetyl-Pro-Arg dipeptide as excipient; Ser-Arg, 150 mM N-acetyl-Ser-Arg dipeptide as excipient; Glu-Arg, 25 mM Glu-Arg as excipient; ac-Pro-Arg-NH2, 150 mM N-acetyl-Pro-Arg-NH2 as excipient.

#FIGS. 3A and 3B show a line graph of observed viscosity of pharmaceutical formulations comprising 10 mM glutamic acid buffer pH 5.2 with 4% w/v sucrose vs the concentration of a therapeutic antibody (Antibody 2, “Ab2”)) with and without the indicated excipients in the formulations. FIG. 3A shows the graph so that all values of the samples are shown for each point along the x-axis; and FIG. 3B shows the detail of the viscosity of the formulations wherein the viscosity was observed at 80 cP or less. G52Su, buffer, sucrose and Ab1 (no excipient); G52Su-ArgHCl, 150 mM ArgHCl as excipient; ac-Pro-Arg, 150 mM N-acetyl-Pro-Arg dipeptide as excipient; ac-Ser-Arg, 150 mM N-acetyl-Ser-Arg dipeptide as excipient; Glu-Arg, 25 mM Glu-Arg as excipient; ac-Pro-Arg-NH2, 150 mM N-acetyl-Pro-Arg-NH2 as excipient.

#N-acetyl-serine-arginine, N-acetyl-proline-arginine, N-acetyl-proline-arginine-NH2, and glutamate-arginine dipeptides were found to reduce the viscosity of therapeutic polypeptide formulations, such as those containing antibodies. Surprisingly, while the N-acetyl-dipeptides reduced viscosity to a similar extent as N-acetyl-arginine (NAR), they are significantly more soluble than NAR. Because of their increased solubility, these N-acetyl dipeptides are able to reduce the viscosity of therapeutic proteins even more than NAR because they can be formulated at much higher concentrations.

#Both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. The use of the singular includes the plural unless specifically stated otherwise. The use of “or” means “and/or” unless stated otherwise. The use of the term “including”, as well as other forms, such as “includes” and “included”, is not limiting. Terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit unless specifically stated otherwise. The use of the term “portion” can include part of a moiety or the entire moiety. When a numerical range is mentioned, e.g., 1-5, all intervening values are explicitly included, such as 1, 2, 3, 4, and 5, as well as fractions thereof, such as 1.5, 2.2, 3.4, and 4.1.

#“About” or “˜” mean, when modifying a quantity (e.g., “about” 3 mM), that variation around the modified quantity can occur. These variations can occur by a variety of means, such as typical measuring and handling procedures, inadvertent errors, ingredient purity, and the like.