Hyaluronidase formulations for high volume administration

Abstract

In one aspect, the disclosure provides a formulation comprising a hyaluronidase and a therapeutically effective amount of an active ingredient. In another aspect, the disclosure provides a method of administering a high volume of formulation in a single administration to treat a disease or condition in a subject.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63,476,830, filed December 22, 2022; U.S. Provisional Application No. 63 / 485,108, filed February 15, 2023; U.S. Provisional Application No. 63 / 507,125, filed June 9, 2023; U.S. Provisional Application No. 63 / 516,732, filed July 31, 2023; U.S. Provisional Application No. 63 / 518,057, filed August 7, 2023; and U.S. Provisional Application No. 63 / 520,524, filed August 18, 2023, each of which is incorporated herein by reference in its entirety.

[0003] sequence list

[0004] This application contains a sequence list, which has been electronically submitted in .XML format and incorporated herein by reference in its entirety. A .XML copy created on December 20, 2023, is named "063995-5088" and is 83KB in size. Technical Field

[0005] This disclosure relates to formulations comprising hyaluronidase and an active ingredient, wherein the formulation can be administered in high volumes to subjects in need while causing minimal side effects. Summary of the Invention

[0006] In one embodiment, this disclosure provides a method of treating a disease or condition in a subject in need, the method comprising administering to the subject via subcutaneous administration of about 3 mL to about 50 mL of a formulation comprising a therapeutically effective amount of an active ingredient selected from small molecules, peptide fragments, biologics, nanoparticles, antibodies, antibody fragments, and small molecule antiviral agents, wherein the subcutaneous administration is performed via a high-volume autoinjector with an initial delivery force of about 3 lbf to about 50 lbf, a final delivery force of about 5 lbf to about 20 lbf, an initial pressure of about 50 psi to about 200 psi, and / or a final pressure of about 20 psi to about 75 psi. In one embodiment, the formulation further comprises hyaluronidase. In one embodiment, the hyaluronidase is recombinant human hyaluronidase. In one embodiment, the hyaluronidase is recombinant human hyaluronidase PH20 enzyme. In one embodiment, the hyaluronidase has an activity of about 150 U / mL to about 150 kU / mL. In one embodiment, the hyaluronidase has an activity of about 500 U / mL to about 5,000 U / mL. In one embodiment, the hyaluronidase has an activity of about 1,500 U / mL to about 10,000 U / mL. In one embodiment, the active ingredient is a small molecule, peptide fragment, biological agent, or nanoparticle. In one embodiment, the active ingredient is an antibody, antibody fragment, or small molecule antiviral agent. In one embodiment, the method includes administering about 10 mL to about 20 mL of the formulation to a subject. In one embodiment, the method includes administering about 3 mL to about 15 mL of the formulation to a subject. In one embodiment, the method includes administering to a subject approximately 3 mL, approximately 3.1 mL, approximately 3.2 mL, approximately 3.4 mL, approximately 3.5 mL, approximately 3.6 mL, approximately 3.7 mL, approximately 3.8 mL, approximately 3.9 mL, approximately 4 mL, approximately 4.1 mL, approximately 4.2 mL, approximately 4.3 mL, approximately 4.4 mL, approximately 4.5 mL, approximately 5 mL, approximately 5.1 mL, approximately 5.2 mL, approximately 5.3 mL, approximately 5.4 mL, approximately 5.5 mL, approximately 5.6 mL, approximately 5.7 mL, approximately 5.8 mL, approximately 5.9 mL, approximately 6 mL, approximately 6.1 mL, approximately 6.2 mL, approximately 6.3 mL, or approximately 6.4 mL. Approximately 6.5 mL, approximately 6.6 mL, approximately 6.7 mL, approximately 6.8 mL, approximately 6.9 mL, approximately 7 mL, approximately 7.1 mL, approximately 7.2 mL, approximately 7.3 mL, approximately 7.4 mL, approximately 7.5 mL, approximately 7.6 mL, approximately 7.7 mL, approximately 7.8 mL, approximately 7.9 mL, approximately 8 mL, approximately 8.1 mL, approximately 8.2 mL, approximately 8.3 mL, approximately 8.4 mL, approximately 8.5 mL, approximately 8.6 mL, approximately 8.7 mL, approximately 8.8 mL, approximately 8.9 mL, approximately 9 mL, approximately 9.1 mL, approximately 9.2 mL, approximately 9.3 mL, approximately 9.4 mL, approximately 9.5 mL, approximately 9.6 mL, approximately 9.7mL, approximately 9.8mL, approximately 9.9mL, approximately 10mL, approximately 10.1mL, approximately 10.2mL, approximately 10.3mL, approximately 10.4mL, approximately 10.5mL, approximately 10.6mL, approximately 10.7mL, approximately 10.8mL, approximately 10.9mL, approximately 11mL, approximately 11.1mL, approximately 11.2mL, approximately 11.3mL, approximately 11.4mL, approximately 11.5mL, approximately 11.6mL, approximately 11.7mL, approximately 11.8mL, approximately 11.9mL, approximately 12mL, approximately 12.1mL, approximately 12.2mL, approximately 12.3mL, approximately 12.4mL, approximately 12.5mL, approximately 12.6mL, approximately 12.7mL, approximately 12.8mL, approximately 12.9mL mL, approximately 13 mL, approximately 13.1 mL, approximately 13.2 mL, approximately 13.3 mL, approximately 13.4 mL, approximately 13.5 mL, approximately 13.6 mL, approximately 13.7 mL, approximately 13.8 mL, approximately 13.9 mL, approximately 14 mL, approximately 14.1 mL, approximately 14.2 mL, approximately 14.3 mL, approximately 14.4 mL, approximately 14.5 mL, approximately 14.6 mL, approximately 14.7 mL, approximately 14.8 mL, approximately 14.9 mL, approximately 15 mL, approximately 15.1 mL, approximately 15.2 mL, approximately 15.3 mL, approximately 15.4 mL, approximately 15.5 mL, approximately 15.6 mL, approximately 15.7 mL, approximately 15.8 mL, approximately 15.9 mL, approximately 16 mL, approximately 16.1 mL L, approximately 16.2 mL, approximately 16.3 mL, approximately 16.4 mL, approximately 16.5 mL, approximately 16.6 mL, approximately 16.7 mL, approximately 16.8 mL, approximately 16.9 mL, approximately 17 mL, approximately 17.1 mL, approximately 17.2 mL, approximately 17.3 mL, approximately 17.4 mL, approximately 17.5 mL, approximately 17.6 mL, approximately 17.7 mL, approximately 17.8 mL, approximately 17.9 mL, approximately 18 mL, approximately 18.1 mL, approximately 18.2 mL, approximately 18.3 mL, approximately 18.4 mL, approximately 18.5 mL, approximately 18.6 mL, approximately 18.7 mL, approximately 18.8 mL, approximately 18.9 mL, approximately 19 mL, approximately 19.1 mL, approximately 19.2 mL, approximately 19.3 mL mL, approximately 19.4 mL, approximately 19.5 mL, approximately 19.6 mL, approximately 19.7 mL, approximately 19.8 mL, approximately 19.9 mL, approximately 20 mL, approximately 20.1 mL, approximately 20.2 mL, approximately 20.3 mL, approximately 20.4 mL, approximately 20.5 mL, approximately 20.6 mL, approximately 20.7 mL, approximately 20.8 mL, approximately 20.9 mL, approximately 21 mL, approximately 21.1 mL, approximately 21.2 mL, approximately 21.3 mL, approximately 21.4 mL, approximately 21.5 mL, approximately 21.6 mL, approximately 21.7 mL, approximately 21.8 mL, approximately 21.9 mL, approximately 22 mL, approximately 22.1 mL, approximately 22.2 mL, approximately 22.3 mL, approximately 22.4 mL, approximately 22.The dosages are approximately 5 mL, 22.6 mL, 22.7 mL, 22.8 mL, 22.9 mL, 23 mL, 23.1 mL, 23.2 mL, 23.3 mL, 23.4 mL, 23.5 mL, 23.6 mL, 23.7 mL, 23.8 mL, 23.9 mL, 24 mL, 24.1 mL, 24.2 mL, 24.3 mL, 24.4 mL, 24.5 mL, 24.6 mL, 24.7 mL, 24.8 mL, 24.9 mL, or 25 mL. In one embodiment, the method includes administering the formulation using a high-volume autoinjector. In one embodiment, the method includes administering the formulation using a high-volume autoinjector with an initial delivery force of approximately 3 lbf to approximately 50 lbf. In one embodiment, the method includes administering the formulation using a high-volume autoinjector with a final delivery force of approximately 5 lbf to approximately 20 lbf. In one embodiment, the method includes administering the formulation using a high-volume autoinjector at an initial pressure of about 50 psi to about 200 psi. In one embodiment, the method includes administering the formulation using a high-volume autoinjector at a final pressure of about 20 psi to about 75 psi. In one embodiment, the formulation is in a pre-filled syringe. In one embodiment, the pre-filled syringe contains approximately 3 mL, approximately 3.1 mL, approximately 3.2 mL, approximately 3.4 mL, approximately 3.5 mL, approximately 3.6 mL, approximately 3.7 mL, approximately 3.8 mL, approximately 3.9 mL, approximately 4 mL, approximately 4.1 mL, approximately 4.2 mL, approximately 4.3 mL, approximately 4.4 mL, approximately 4.5 mL, approximately 5 mL, approximately 5.1 mL, approximately 5.2 mL, approximately 5.3 mL, approximately 5.4 mL, approximately 5.5 mL, approximately 5.6 mL, approximately 5.7 mL, approximately 5.8 mL, approximately 5.9 mL, approximately 6 mL, approximately 6.1 mL, approximately 6.2 mL, approximately 6.3 mL, approximately 6.4 mL, approximately 6.5 mL, approximately 6.6 mL, approximately 6.7 mL, approximately 6.8 mL, approximately 6.9 mL, approximately 7 mL, approximately 7.1 mL, approximately 7.2 mL, and approximately 7 mL. 3mL, approximately 7.4mL, approximately 7.5mL, approximately 7.6mL, approximately 7.7mL, approximately 7.8mL, approximately 7.9mL, approximately 8mL, approximately 8.1mL, approximately 8.2mL, approximately 8.3mL, approximately 8.4mL, approximately 8.5mL, approximately 8.6mL, approximately 8.7mL, approximately 8.8mL, approximately 8.9mL, approximately 9mL, approximately 9.1mL, approximately 9.2mL, approximately 9.3mL, approximately 9.4mL, approximately 9.5mL, approximately 9.6mL, approximately 9.7mL, approximately 9.8mL, approximately 9.9mL, approximately 10mL, approximately 10.1mL, approximately 10.2mL, approximately 10.3mL, approximately 10.4mL, approximately 10.5mL, approximately 10.6mL, approximately 10.7mL, approximately 10.8mL, approximately 10.9mL, approximately 11mL, approximately 11.1mL, approximately 11.2mL, approximately 11.3mL, approximately 11.4mL, approximately 11.5mL, approximately 11.6mL, approximately 11.7mL, approximately 11.8mL, approximately 11.9mL, approximately 12mL, approximately 12.1mL, approximately 12.2mL, approximately 12.3mL, approximately 12.4mL, approximately 12.5mL, approximately 12.6mL, approximately 12.7mL, approximately 12.8mL, approximately 12.9mL, approximately 13mL, approximately 13.1mL, approximately 13.2mL, approximately 13.3mL, approximately 13.4mL, approximately 13.5mL, approximately 13.6mL, approximately 13.7mL, approximately 13.8mL, approximately 13.9mL, approximately 14mL, approximately 14.1mL, approximately 14.2mL, approximately 14.3mL, approximately 1 4.4mL, approximately 14.5mL, approximately 14.6mL, approximately 14.7mL, approximately 14.8mL, approximately 14.9mL, approximately 15mL, approximately 15.1mL, approximately 15.2mL, approximately 15.3mL, approximately 15.4mL, approximately 15.5mL, approximately 15.6mL, approximately 15.7mL, approximately 15.8mL, approximately 15.9mL, approximately 16mL, approximately 16.1mL, approximately 16.2mL, approximately 16.3mL, approximately 16.4mL, approximately 16.5mL, approximately 16.6mL, approximately 16.7mL, approximately 16.8mL, approximately 16.9mL, approximately 17mL, approximately 17.1mL, approximately 17.2mL, approximately 17.3mL, approximately 17.4mL, approximately 17.5mL Approximately 17.6 mL, approximately 17.7 mL, approximately 17.8 mL, approximately 17.9 mL, approximately 18 mL, approximately 18.1 mL, approximately 18.2 mL, approximately 18.3 mL, approximately 18.4 mL, approximately 18.5 mL, approximately 18.6 mL, approximately 18.7 mL, approximately 18.8 mL, approximately 18.9 mL, approximately 19 mL, approximately 19.1 mL, approximately 19.2 mL, approximately 19.3 mL, approximately 19.4 mL, approximately 19.5 mL, approximately 19.6 mL, approximately 19.7 mL, approximately 19.8 mL, approximately 19.9 mL, approximately 20 mL, approximately 20.1 mL, approximately 20.2 mL, approximately 20.3 mL, approximately 20.4 mL, approximately 20.5 mL, approximately 20.6 mL, approximately 20.7 mL L, approximately 20.8 mL, approximately 20.9 mL, approximately 21 mL, approximately 21.1 mL, approximately 21.2 mL, approximately 21.3 mL, approximately 21.4 mL, approximately 21.5 mL, approximately 21.6 mL, approximately 21.7 mL, approximately 21.8 mL, approximately 21.9 mL, approximately 22 mL, approximately 22.1 mL, approximately 22.2 mL, approximately 22.3 mL, approximately 22.4 mL, approximately 22.5 mL, approximately 22.6 mL, approximately 22.7 mL, approximately 22.8 mL, approximately 22.9 mL, approximately 23 mL, approximately 23.1 mL, approximately 23.2 mL, approximately 23.3 mL, approximately 23.4 mL, approximately 23.5 mL, approximately 23.6 mL, approximately 23.7 mL, approximately 23.8 mL, approximately 23.The formulation can be in the form of 9 mL, about 24 mL, about 24.1 mL, about 24.2 mL, about 24.3 mL, about 24.4 mL, about 24.5 mL, about 24.6 mL, about 24.7 mL, about 24.8 mL, about 24.9 mL, or about 25 mL. In one embodiment, the pre-filled syringe includes a needle of about 20 to about 33 gauge. In one embodiment, the pre-filled syringe includes a 20-gauge needle, a 21-gauge needle, a 22-gauge needle, a 23-gauge needle, a 24-gauge needle, a 25-gauge needle, a 26-gauge needle, a 27-gauge needle, a 28-gauge needle, a 29-gauge needle, a 30-gauge needle, a 31-gauge needle, a 32-gauge needle, or a 33-gauge needle. In one embodiment, the method includes administering the formulation at a rate of about 0.08 mL / s to about 1.00 mL / s. In one embodiment, the method includes administering the formulation at a rate of at least about 0.08 mL / s to about 1.0 mL / s. In one embodiment, the method includes applying the formulation at a rate of at least or faster than about 0.08 mL / s to about 1.00 mL / s. In one embodiment, the application takes about 10 seconds to about 40 seconds. In one embodiment, the application takes at least about 10 seconds to about 40 seconds. In one embodiment, the application takes at least or less than about 10 seconds to about 40 seconds. In one embodiment, the application takes about 15 seconds to about 30 seconds. In one embodiment, the application takes at least about 15 seconds to about 30 seconds. In one embodiment, the application takes at least or less than about 15 seconds to about 30 seconds. In one embodiment, the method includes applying about 5 mL of the formulation at a rate of about 0.14 mL / s to about 0.21 mL / s. In one embodiment, the method includes applying about 10 mL of the formulation at a rate of about 0.32 mL / s to about 0.42 mL / s. In one embodiment, the formulation has a viscosity of about 1 cP to about 50 cP. In one embodiment, the application of this formulation requires less force compared to similar formulations that do not contain hyaluronidase. In one embodiment, the method includes administering about 5 mL of the formulation at a rate of about 0.14 mL / s to about 0.21 mL / s and an application force of about 10 N to about 45 N. In one embodiment, the method includes administering the formulation to the subject using a pre-filled syringe including a 25-gauge needle. In one embodiment, the method includes administering the formulation at a rate of about 0.32 mL / s to about 0.Approximately 10 mL of the formulation is administered to the subject at a rate of 42 mL / s and an application force of approximately 25 N to approximately 50 N. In one embodiment, the method includes administering the formulation to the subject using a pre-filled syringe comprising a 25-gauge needle. In one embodiment, the administration of the formulation is faster compared to similar formulations that do not contain hyaluronidase. In one embodiment, the administration of the formulation causes fewer side effects in the subject compared to similar formulations that do not contain hyaluronidase. In one embodiment, the administration of the formulation causes less pain and discomfort in the subject compared to similar formulations that do not contain hyaluronidase. In one embodiment, the administration of the formulation causes less backflow at the injection site compared to similar formulations that do not contain hyaluronidase. In one embodiment, backflow at the injection site is reduced by approximately 85% to approximately 30% compared to similar formulations that do not contain hyaluronidase. In one embodiment, the administration of the formulation causes a smaller swelling volume and / or swelling height at the injection site compared to similar formulations that do not contain hyaluronidase. In one embodiment, compared to similar formulations that do not contain hyaluronidase, this formulation causes approximately 35% less and approximately 5% less swelling and / or swelling height at the injection site. In one embodiment, compared to similar formulations that do not contain hyaluronidase, application of this formulation produces lower blister size, less blister induration, and / or faster blister resolution. In one embodiment, compared to similar formulations that do not contain hyaluronidase, application of this formulation produces more consistent delivery time. In one embodiment, the subject is human. In one embodiment, the application includes self-administration of the formulation by the subject. In one embodiment, the application includes administration of the formulation to the subject by a healthcare provider or caregiver. In one embodiment, the subcutaneous application includes a single injection. In one embodiment, the subcutaneous application includes two or more injections. In one embodiment, the subcutaneous application is delivered via an on-the-body device.

[0007] In another aspect, this disclosure provides a pharmaceutical kit comprising a high-volume autoinjector and a formulation of about 3 mL to about 50 mL, the formulation comprising a therapeutically effective amount of an active ingredient selected from small molecules, peptide fragments, biologics, nanoparticles, antibodies, antibody fragments, and small-molecule antiviral agents. In one embodiment, the formulation further comprises hyaluronidase. In one embodiment, the kit further comprises instructions for administering hyaluronidase to a subject in need. In one embodiment, the kit further comprises instructions for administering hyaluronidase to a subject in need simultaneously or sequentially with the formulation containing the active ingredient. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to a subject at a rate of about 0.05 mL / s to about 1.0 mL / s. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously from a pre-filled syringe having a volume of about 3 mL to about 15 mL. In one embodiment, the pre-filled syringe comprises a needle with a specification of about 20 to about 33. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.05 mL / s to about 0.10 mL / s. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.10 mL / s to about 0.20 mL / s. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.20 mL / s to about 0.30 mL / s. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.30 mL / s to about 0.40 mL / s. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.40 mL / s to about 0.50 mL / s. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.50 mL / s to about 0.60 mL / s. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.60 mL / s to about 0.70 mL / s. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.70 mL / s to about 0.80 mL / s. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.80 mL / s to about 0.90 mL / s. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.90 mL / s to about 1.00 mL / s. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject with an application force of about 10 N to about 200 N.In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to a subject with an applied force of about 10 N to about 45 N. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to a subject with an applied force of about 25 N to about 50 N. In one embodiment, the high-volume autoinjector is configured for self-administration of the formulation by a subject. Attached Figure Description

[0008] The following detailed description of embodiments of the hyaluronidase preparation for high-volume application will be better understood when read in conjunction with the accompanying drawings of exemplary embodiments.

[0009] Figure 1 The graph shows the force (N) applied during Ig-120 and Ig-120+rHuPH20 injections (mean ± SEM).

[0010] Figure 2 This is a graph showing the individual applied force (N) during injections of Ig-120 and Ig-120+rHuPH20.

[0011] Figure 3 It is a graph of the average (±SEM) backflow and individual weight.

[0012] Figure 4 The single swelling volume (cm²) after SC injection of Ig-120 and Ig-120+rHuPH20 3 - A chart for caliper measurements.

[0013] Figure 5 The single swelling area (cm²) after SC injection of Ig-120 and Ig-120+rHuPH20 2 - A chart for caliper measurements.

[0014] Figure 6 This is a chart showing the individual swelling height (mm) measured by calipers after SC injection of Ig-120 and Ig-120+rHuPH20.

[0015] Figures 7A to 7B It is a composite 3D image of a miniature pig that has been processed. Figure 7A Composite image of miniature pigs processed with Ig-120. Figure 7B Composite 3D images of miniature pigs processed with Ig-120+rHuPH20.

[0016] Figure 8 The volume of a single vesicle (cm³) after SC injection of Ig-120 and Ig-120+rHuPH20 3 - A chart of 3D imaging.

[0017] Figure 9The area of ​​a single vesicle (cm²) after SC injection of Ig-120 and Ig-120+rHuPH20 2 - A chart of 3D imaging.

[0018] Figure 10 This is a graph showing the height (mm) of a single bubble after SC injection of Ig-120 and Ig-120+rHuPH20 - 3D imaging.

[0019] Figure 11 This is a graph showing the change in surface temperature from before to after injection.

[0020] Figure 12 This is a chart for the qualitative assessment of post-injection erythema.

[0021] Figure 13 It is a chart for a qualitative assessment of the swelling size after injection.

[0022] Figure 14 It is a chart for qualitative assessment of post-injection induration (hardness).

[0023] Figures 15A to 15B This is evidenced by the analysis of Ig-120 and rHuPH20 used in Examples 2 to 4 of this disclosure. Figure 15A This is evidenced by the analysis of Ig-120. Figure 15B This is evidenced by the analysis of rHuPH20.

[0024] Figures 16A to 16B Photographs of miniature pig AID#1107 at different intervals before and after the 10mL injection procedure are provided. Figure 16A Images of the injection site after Ig-120 injection are provided. Figure 16B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0025] Figures 17A to 17B Photographs of miniature pig AID#1114 at different intervals before and after the 10mL injection procedure are provided. Figure 17A Images of the injection site after Ig-120 injection are provided. Figure 17B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0026] Figures 18A to 18B Photographs of miniature pig AID#1181 were provided at different intervals before and after the 10 mL injection procedure. Figure 18A Images of the injection site after Ig-120 injection are provided. Figure 18B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0027] Figures 19A to 19BPhotographs of miniature pig AID#1184 were provided at different intervals before and after the 10 mL injection procedure. Figure 19A Images of the injection site after Ig-120 injection are provided. Figure 19B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0028] Figures 20A to 20B Photographs of miniature pig AID#1185 were provided at different intervals before and after the 10 mL injection procedure. Figure 20A Images of the injection site after Ig-120 injection are provided. Figure 20B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0029] Figures 21A to 21B Photographs of miniature pig AID#1188 at different intervals before and after the 10mL injection procedure are provided. Figure 21A Images of the injection site after Ig-120 injection are provided. Figure 21B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0030] Figure 22 The graph shows the force (N) applied during Ig-120 and Ig-120+rHuPH20 injections (mean ± SEM).

[0031] Figure 23 This is a graph showing the individual applied force (N) during injections of Ig-120 and Ig-120+rHuPH20.

[0032] Figure 24 This is a graph showing the average backleakage (mg ± SEM) and individual weights.

[0033] Figure 25 The single swelling volume (cm²) after SC injection of Ig-120 and Ig-120+rHuPH20 3 - A chart for caliper measurements.

[0034] Figure 26 The single swelling area (cm²) after SC injection of Ig-120 and Ig-120+rHuPH20 2 - A chart for caliper measurements.

[0035] Figure 27 This is a chart showing the individual swelling height (mm) measured by calipers after SC injection of Ig-120 and Ig-120+rHuPH20.

[0036] Figures 28A to 28B It is a composite 3D image of a miniature pig that has been processed. Figure 28AComposite image of miniature pigs processed with Ig-120. Figure 28B Composite 3D images of miniature pigs processed with Ig-120+rHuPH20.

[0037] Figure 29 The volume of a single vesicle (cm³) after SC injection of Ig-120 and Ig-120+rHuPH20 3 - A chart of 3D imaging.

[0038] Figure 30 The area of ​​a single vesicle (cm²) after SC injection of Ig-120 and Ig-120+rHuPH20 2 - A chart of 3D imaging.

[0039] Figure 31 This is a graph showing the height (mm) of a single bubble after SC injection of Ig-120 and Ig-120+rHuPH20 - 3D imaging.

[0040] Figure 32 This is a graph showing the change in surface temperature from before to after injection.

[0041] Figure 33 This is a chart for the qualitative assessment of post-injection erythema.

[0042] Figure 34 It is a chart for a qualitative assessment of the swelling size after injection.

[0043] Figure 35 It is a chart for qualitative assessment of post-injection induration (hardness).

[0044] Figures 36A to 36B Photos of miniature pig AID#1359 were provided at different intervals before and after the 10mL injection procedure. Figure 36A Images of the injection site after Ig-120 injection are provided. Figure 36B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0045] Figure 37 Photographs of the injection sites of AID#1361 in miniature pigs at different intervals before and after the 10mLig-120 injection procedure are provided.

[0046] Figure 38 Photographs of injection sites for AID#1361 in miniature pigs at different intervals before and after the 10 mL Ig-120+rHuPH20 injection procedure are provided.

[0047] Figures 39A to 39B Photographs of miniature pig AID#1362 were provided at different intervals before and after the 10 mL injection procedure. Figure 39AImages of the injection site after Ig-120 injection are provided. Figure 39B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0048] Figures 40A to 40B Photographs of miniature pig AID#1363 at different intervals before and after the 10mL injection procedure are provided. Figure 40A Images of the injection site after Ig-120 injection are provided. Figure 40B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0049] Figures 41A to 41B Photographs of miniature pig AID#1396 were provided at different intervals before and after the 10 mL injection procedure. Figure 41A Images of the injection site after Ig-120 injection are provided. Figure 41B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0050] Figures 42A to 42B Photographs of miniature pig AID#1405 were provided at different intervals before and after the 10 mL injection procedure. Figure 42A Images of the injection site after Ig-120 injection are provided. Figure 42B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0051] Figure 43 This is a graph (mean ± SEM) of the force (N) applied during Ig-120 and Ig-120+rHuPH20 injections.

[0052] Figure 44 This is a graph showing the individual applied force (N) during injections of Ig-120 and Ig-120+rHuPH20.

[0053] Figure 45A This is a graph showing the average backleakage (mg ± SEM) and individual weights.

[0054] Figure 45B The single swelling volume (cm²) after SC injection of Ig-120 and Ig-120+rHuPH20 3 - A chart for caliper measurements.

[0055] Figure 46 The single swelling area (cm²) after SC injection of Ig-120 and Ig-120+rHuPH20 2 - A chart for caliper measurements.

[0056] Figure 47This is a chart showing the individual swelling height (mm) measured by calipers after SC injection of Ig-120 and Ig-120+rHuPH20.

[0057] Figure 48 It is a graph showing the volume of bubbles over time (T0-T15-T30).

[0058] Figure 49 It is a chart showing the bubble area over time (T0-T15-T30).

[0059] Figure 50 It is a chart showing the bubble height over time (T0-T15-T30).

[0060] Figures 51A to 51B It is a composite 3D image of a miniature pig that has been processed. Figure 51A Composite image of miniature pigs processed with Ig-120. Figure 51B Composite 3D images of miniature pigs processed with Ig-120+rHuPH20.

[0061] Figure 52 The volume of a single vesicle (cm³) after SC injection of Ig-120 and Ig-120+rHuPH20 3 - A chart of 3D imaging.

[0062] Figure 53 The area of ​​a single vesicle (cm²) after SC injection of Ig-120 and Ig-120+rHuPH20 2 - A chart of 3D imaging.

[0063] Figure 54 This is a graph showing the height (mm) of a single bubble after SC injection of Ig-120 and Ig-120+rHuPH20 - 3D imaging.

[0064] Figure 55 This is a graph showing the change in surface temperature from before to after injection.

[0065] Figure 56 This is a chart for the qualitative assessment of post-injection erythema.

[0066] Figure 57 It is a chart for a qualitative assessment of the swelling size after injection.

[0067] Figure 58 It is a chart for qualitative assessment of post-injection induration (hardness).

[0068] Figures 59A to 59B Photographs of miniature pig AID#1535 were provided at different intervals before and after the 10mL injection procedure. Figure 59A Images of the injection site after Ig-120 injection are provided. Figure 59BImages of the injection site after Ig-120+rHuPH20 injection are provided.

[0069] Figures 60A to 60B Photographs of miniature pig AID#1536 at different intervals before and after the 10mL injection procedure are provided. Figure 60A Images of the injection site after Ig-120 injection are provided. Figure 60B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0070] Figures 61A to 61B Photographs of miniature pig AID#1537 at different intervals before and after the 10mL injection procedure are provided. Figure 61A Images of the injection site after Ig-120 injection are provided. Figure 61B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0071] Figures 62A to 62B Photographs of miniature pig AID#1539 at different intervals before and after the 10mL injection procedure are provided. Figure 62A Images of the injection site after Ig-120 injection are provided. Figure 62B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0072] Figures 63A to 63B Photographs of miniature pig AID#1542 were provided at different intervals before and after the 10 mL injection procedure. Figure 63A Images of the injection site after Ig-120 injection are provided. Figure 63B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0073] Figures 64A to 64B Photographs of miniature pig AID#1543 at different intervals before and after the 10mL injection procedure are provided. Figure 64A Images of the injection site after Ig-120 injection are provided. Figure 64B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0074] Figure 65 It is a graph depicting the injection time (mean ± SEM) of a single animal calculated by video analysis for each configuration of the high-volume autoinjector (HVAI).

[0075] Figure 66 It is a graph depicting the average (mg ± SEM) and individual weight of backleakage.

[0076] Figure 67It is a graph depicting the individual swelling volumes (mL) after SC injection of Ig-120 and Ig-120+rHuPH20, as determined using calipers.

[0077] Figure 68 It is a graph depicting the swelling (bubble) volume over time at time points T0, T15, and T30.

[0078] Figure 69 This depicts the individual swelling area (cm²) after SC injection of Ig-120 and Ig-120+rHuPH20, as determined using calipers. 2 (Charts)

[0079] Figure 70 It is a chart depicting the swelling area over time at time points T0, T15, and T30.

[0080] Figure 71 It is a graph depicting the height (mm) of a single swollen blister after SC injection of Ig-120 and Ig-120+rHuPH20, as determined using calipers.

[0081] Figure 72 It is a chart depicting the swelling height over time at time points T0, T15, and T30.

[0082] Figures 73A to 73B Administered with HVAI and 23G needles ( Figure 73A ) and administration with HVAI and 25G needles ( Figure 73B A composite image of 3D images (colorimetric surface profiles) of each post-injection vesicle of Ig-120 and Ig-120+rHuPH20.

[0083] Figure 74 This is a graph showing the individual swelling volumes (mL) after SC injection of Ig-120 and Ig-120+rHuPH20, determined using 3D imaging.

[0084] Figure 75 The area (cm²) of a single swollen vesicle after injection of Ig-120 and Ig-120+rHuPH20 into SC, determined using 3D imaging. 2 (Charts)

[0085] Figure 76 This is a graph showing the height (mm) of a single swollen vesicle after SC injection of Ig-120 and Ig-120+rHuPH20, determined using 3D imaging.

[0086] Figure 77 This is a graph showing the change in skin temperature from before to after injection.

[0087] Figure 78It is a chart depicting a qualitative assessment of post-injection erythema.

[0088] Figure 79 It is a chart depicting a qualitative assessment of the swelling size after injection.

[0089] Figure 80 It is a chart depicting a qualitative assessment of the induration (hardness) after injection.

[0090] Figures 81A to 81B Photographs of miniature pig AID#1865 were provided at different intervals before and after the 10 mL injection procedure. Figure 81A Images of the injection site after Ig-120 injection are provided. Figure 81B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0091] Figures 82A to 82B Photographs of miniature pig AID#1866 at different intervals before and after the 10mL injection procedure are provided. Figure 82A Images of the injection site after Ig-120 injection are provided. Figure 82B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0092] Figures 83A to 83B Photographs of miniature pig AID#1867 at different intervals before and after the 10mL injection procedure are provided. Figure 83A Images of the injection site after Ig-120 injection are provided. Figure 83B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0093] Figures 84A to 84B Photographs of miniature pig AID#1869 at different intervals before and after the 10mL injection procedure are provided. Figure 84A Images of the injection site after Ig-120 injection are provided. Figure 84B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0094] Figures 85A to 85B Photographs of miniature pigs AID#1870 at different intervals before and after the 10mL injection procedure are provided. Figure 85A Images of the injection site after Ig-120 injection are provided. Figure 85B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0095] Figures 86A to 86B Photographs of miniature pig AID#1926 at different intervals before and after the 10mL injection procedure are provided. Figure 86A Images of the injection site after Ig-120 injection are provided. Figure 86B Images of the injection site after Ig-120+rHuPH20 injection are provided.

[0096] Figure 87 This is evidenced by the analysis of rHuPH20 used in Embodiment 4 of this disclosure.

[0097] Figure 88A This is a graph (mean ± SEM) of the force (N) applied during injection of GAMMAGARD LIQUID (GGL) and GGL+Enhanze drug product (EDP). Figure 88B This is a diagram of a single applied force (N) during GGL+EDP injection.

[0098] Figure 89 This is a graph showing the average injection time (seconds ± SEM) of the 25G-Terumo needle compared to the 25G-BD needle.

[0099] Figure 90 This is a graph showing the average backleakage (mg ± SEM) and individual weight.

[0100] Figure 91 This is a graph showing the single swelling volume (mL) measured by calipers (T0) after SC injection of GGL and GGL+EDP.

[0101] Figure 92 The single swelling area (cm²) after SC injection of GGL and GGL+EDP 2 ) - Diagram of caliper measurement (T0).

[0102] Figure 93 This is a graph showing the individual swelling height (mm) after SC injection of GGL and GGL+EDP, measured by calipers (T0).

[0103] Figure 94 It is a graph showing the average bubble volume over time (T0-T15-T30) measured by calipers.

[0104] Figure 95 It is a graph showing the average bubble volume over time (T0-T15-T30) measured by calipers.

[0105] Figure 96 It is a graph showing the average bubble area over time (T0-T15-T30) measured by calipers.

[0106] Figure 97 A composite image of the 3D image (T0-T15-T30) of the GGL-25G-Terumo is provided.

[0107] Figure 98A composite image of 3D images (T0-T15-T30) of GGL+EDP-25G-Terumo is provided.

[0108] Figure 99 A composite image of 3D images (T0-T15-T30) in GGL+EDP-25G-BD format is provided.

[0109] Figure 100 A composite image (T0-T15-T30) of 3D image (GGL+EDP-23G-BD) is provided.

[0110] Figure 101 The volume of a single vesicle (cm³) after SC injection of GGL and GGL+EDP 3 ) - 3D imaging diagram.

[0111] Figure 102 The area of ​​a single bubble (cm²) after SC injection of GGL and GGL+EDP 2 ) - 3D imaging diagram.

[0112] Figure 103 This is a 3D image showing the height (mm) of a single bubble after SC injection of GGL and GGL+EDP.

[0113] Figure 104 It is a 3D image of the average bubble volume over time (T0-T15-T30).

[0114] Figure 105 It is a 3D imaging diagram of the average bubble area over time (T0-T15-T30).

[0115] Figure 106 It is a 3D imaging diagram showing the average bubble height over time (T0-T15-T30).

[0116] Figure 107 This is a diagram for the qualitative assessment of erythema after injection.

[0117] Figure 108 This is a graph representing a qualitative assessment of post-injection erythema (0 minutes - 120 minutes).

[0118] Figure 109 This is a graph representing a qualitative assessment of the swelling size after injection.

[0119] Figure 110 This is a graph showing the qualitative score of post-injection swelling (0 minutes - 120 minutes).

[0120] Figure 111 This is a graph representing a qualitative assessment of the induration (hardness) after injection.

[0121] Figure 112This is a graph representing a qualitative assessment of post-injection induration (0 minutes - 120 minutes).

[0122] Figures 113A to 113B Photographs of miniature pig AID#2662 were provided at different intervals before and after the 10 mL injection procedure. Figure 113A Images of the injection site after GGL injection using a 25G Terumo needle are provided. Figure 113B Images of the injection site after GGL+EDP injection using a 25G Terumo needle are provided.

[0123] Figures 114A to 114B Photographs of miniature pig AID#2663 were provided at different intervals before and after the 10 mL injection procedure. Figure 114A Images of the injection site after GGL+EDP injection using a 25G BD needle are provided. Figure 114B Images of the injection site after GGL+EDP injection using a 25G BD needle are provided.

[0124] Figures 115A to 115B Photographs of miniature pig AID#2665 were provided at different intervals before and after the 10 mL injection procedure. Figure 115A Images of the injection site after GGL injection using a 25G Terumo needle are provided. Figure 115B Images of the injection site after GGL+EDP injection using a 23G BD needle are provided.

[0125] Figures 116A to 116B Photographs of miniature pig AID#2666 at different intervals before and after the 10mL injection procedure are provided. Figure 116A Images of the injection site after GGL+EDP injection using a 25G BD needle are provided. Figure 116B Images of the injection site after GGL+EDP injection using a 23G BD needle are provided.

[0126] Figures 117A to 117B Photographs of miniature pig AID#2195 were provided at different intervals before and after the 10 mL injection procedure. Figure 117A Images of the injection site after GGL injection using a 25G Terumo needle are provided. Figure 117B Images of the injection site after GGL+EDP injection using a 25G BD needle are provided.

[0127] Figures 118A to 118B Photographs of miniature pig AID#2273 were provided at different intervals before and after the 10 mL injection procedure. Figure 118A Images of the injection site after GGL+EDP injection using a 25G Terumo needle are provided. Figure 118BImages of the injection site after GGL+EDP injection using a 23G BD needle are provided.

[0128] Figures 119A to 119B Photographs of miniature pig AID#2195 were provided at different intervals before and after the 10 mL injection procedure. Figure 119A Images of the injection site after GGL injection using a 25G Terumo needle are provided. Figure 119B Images of the injection site after GGL+EDP injection using a 25G Terumo needle are provided.

[0129] Figures 120A to 120B Photographs of miniature pig AID#2265 were provided at different intervals before and after the 10 mL injection procedure. Figure 120A Images of the injection site after GGL+EDP injection using a 25G BD needle are provided. Figure 120B Images of the injection site after GGL+EDP injection using a 25G Terumo needle are provided.

[0130] Figures 121A to 121B Photographs of miniature pig AID#2272 were provided at different intervals before and after the 10 mL injection procedure. Figure 121A Images of the injection site after GGL injection using a 25G Terumo needle are provided. Figure 121B Images of the injection site after GGL+EDP injection using a 23G BD needle are provided.

[0131] Figures 122A to 122B Photographs of miniature pig AID#2275 were provided at different intervals before and after the 10 mL injection procedure. Figure 122A Images of the injection site after GGL+EDP injection using a 25G BD needle are provided. Figure 122B Images of the injection site after GGL+EDP injection using a 23G BD needle are provided.

[0132] Figures 123A to 123B Photographs of miniature pig AID#2279 were provided at different intervals before and after the 10 mL injection procedure. Figure 123A Images of the injection site after GGL injection using a 25G Terumo needle are provided. Figure 123B Images of the injection site after GGL+EDP injection using a 25G BD needle are provided.

[0133] Figures 124A to 124B Photographs of miniature pig AID#2282 were provided at different intervals before and after the 10 mL injection procedure. Figure 124A Images of the injection site after GGL+EDP injection using a 25G BD needle are provided. Figure 124BImages of the injection site after GGL+EDP injection using a 23G BD needle are provided.

[0134] Figure 125 This is the study protocol for the human trial in Example 6. Note: Sentinel subjects in each group are administered the medication at least 24 hours apart, and the remaining subjects in that group are administered the medication at least 24 hours after the last sentinel subject is administered. *If group B is intolerant to 10 mL / 30 seconds using a syringe pump, add group C and assess group C at 10 mL / 45 seconds using a syringe pump, following the same schedule as days 5 through 8. **If group B is intolerant to 10 mL / 30 seconds using a syringe pump at injection visit 1, but is intolerant to 10 mL / 30 seconds using HVAI at injection visit 2, assess group C at 10 mL / 45 seconds using a syringe pump, following the same schedule as days 5 through 8. ***If group C is intolerant to 10 mL / 45 seconds using a syringe pump, the HVAI dose for group B is 10 mL / 45 seconds. ***If HVAI is tolerated at 10 mL / 30 seconds (injection visit 2 / group B), the volume for group A at injection visit 2 is increased to 10 mL / 30 seconds (or the highest tolerated volume / rate combination).

[0135] Figure 126 This is an illustration of an exemplary high-volume autoinjector (HVAI). In this embodiment, the tip cap shown on the syringe is discarded before the syringe is filled with medication.

[0136] Figure 127 Demographic data for patients in Example 6 are provided.

[0137] Figure 128 The dosing group and arrangement in Example 6 are provided.

[0138] Figure 129 The injection duration for each group in Example 6 is provided.

[0139] Figures 130 to 132 Pain scores from Example 6 are provided.

[0140] Figures 133 to 134 Draize score / erythema from Example 6 is provided.

[0141] Figures 135 to 136 Draize score / edema is provided from Example 6.

[0142] Figures 137 to 138 Draize scores / hardening data from Example 6 are provided.

[0143] Figure 139 Adverse events from Example 6 are provided.

[0144] Figures 140A to 140B A summary of the applied force data from Example 6, Group A (5 mL / 30 s) is provided. Using the Hagen-Poiseuille equation, these results predict that a 2x increase in flow rate will also result in a 2x increase in pressure (and force). Therefore, the predicted applied force for Group B (25 G-Terumo needle) is approximately 40.8 N.

[0145] Figures 141A to 141B A summary of application force data from Example 6, Group B (10 mL / 30 s) is provided. The predicted application force (AF) was approximately twice that of Group B compared to Group A. The comparison of clinical and non-clinical AF values ​​allows for the prediction of HVAI performance using various needle specifications.

[0146] Figure 142 It provides a comparison of the forces applied between preclinical and clinical studies.

[0147] Figure 143 The human clinical trial of HVAI injection was completed and well tolerated.

[0148] Figure 144 The rapid regression time of HVAI injection in human clinical trials was described.

[0149] Figure 145 A modified Draize score was provided for edema, swelling, and induration following HVAI injection.

[0150] Figures 146A to 146B Data are provided demonstrating that the modified Draize treatment for edema, swelling, and induration has a low score and rapid resolution (score ≤1).

[0151] Figures 147 to 149B Data were provided demonstrating that subjects experienced minimal pain during injection and that the pain subsided rapidly using a numerical rating scale (NRS, 0-10 scale).

[0152] Figure 150 This is an illustrative presentation of the two-step patient-friendly 10mL HVAI concept based on the post-stud needle PFS master container.

[0153] Figure 151 This is an overview of the swelling and induration scores in miniature pigs administered 10 mL of IgG (120 mg / mL) with 2,000 U / mL rHuPH20 at a rate of 30 mL / min. As shown, both swelling and induration were “very mild” within 30 minutes of HVAI injection. Swelling and induration subsided rapidly after delivery. The injection time was approximately 30 seconds for 25G-BD and 19 seconds for 25G-Terumo.

[0154] Figure 152This is an overview of the swelling and induration scores of miniature pigs administered 10 mL of IgG (100 mg / mL) with 4,000 U / mL rHuPH20 via HVAI within 30 seconds or less.

[0155] Figure 153 This is an overview of the swelling and induration scores of miniature pigs administered IgG-rHuPH20 (120 mg / mL - 2,000 U / mL) to IgG-rHuPH20 (100 mg / mL - 4,000 U / mL) via HVAI.

[0156] Figure 154 This is an exploded view of a button-actuated autoinjector according to a first exemplary embodiment of the present invention.

[0157] Figure 155 yes Figure 154 A perspective view of an auto-injector actuated by a button.

[0158] Figure 156 yes Figure 154 A cross-sectional view of an auto-injector actuated by a button.

[0159] Figure 157 It is in a locked configuration. Figure 154 A partial cross-sectional view of an auto-injector actuated by a button.

[0160] Figure 158 It is in the unlocked configuration. Figure 154 A partial cross-sectional view of an auto-injector actuated by a button.

[0161] Figure 159 It is in the discharge configuration. Figure 154 A partial cross-sectional view of an auto-injector actuated by a button.

[0162] Figure 160A yes Figure 154 A cross-sectional view of the latch of an autoinjector actuated by a button.

[0163] Figure 160B yes Figure 154 A cross-sectional view of the latch of an autoinjector actuated by a button.

[0164] Figure 161 It is in the discharge configuration. Figure 154 A perspective view of an auto-injector actuated by a button.

[0165] Figure 162A yes Figure 154 A cross-sectional view of the button of an auto-injector that is actuated by a button.

[0166] Figure 162B yes Figure 154A perspective view of the button of an auto-injector that is actuated by a button.

[0167] Figure 163A This is an exploded view of a button-actuated autoinjector according to a second exemplary embodiment of the present invention.

[0168] Figure 163B This is a perspective view of a button-actuated autoinjector according to a second exemplary embodiment of the present invention.

[0169] Figure 163C This is a cross-sectional view of a container support according to a second exemplary embodiment of the present invention.

[0170] Figure 164A This is an exploded view of a button-actuated autoinjector according to a third exemplary embodiment of the present invention.

[0171] Figure 164B This is a perspective view of a button-actuated autoinjector according to a third exemplary embodiment of the present invention.

[0172] Figure 164C This is a cross-sectional view of a container support according to a third exemplary embodiment of the present invention.

[0173] Figure 165 This is a perspective view of a button-actuated autoinjector according to a fourth exemplary embodiment of the present invention.

[0174] Figure 166 This is a perspective view of a button-actuated autoinjector connected to a tubing assembly according to a fifth exemplary embodiment of the present invention.

[0175] Figure 167A This is a perspective view of a button-actuated autoinjector according to a sixth exemplary embodiment of the present invention.

[0176] Figure 167B This is an exploded view of a button-actuated autoinjector according to a sixth exemplary embodiment of the present invention.

[0177] Figure 168 This is a cross-sectional view of a button-actuated autoinjector according to a seventh exemplary embodiment of the present invention.

[0178] Figure 169 This is a partial cross-sectional view of a button-actuated autoinjector in a locked configuration according to a seventh exemplary embodiment of the present invention.

[0179] Figure 170 This is a partial cross-sectional view of a button-actuated autoinjector in a discharge configuration according to a seventh exemplary embodiment of the present invention.

[0180] Figure 171This is a graph of injection time data (mean ± SEM) for a single animal.

[0181] Figure 172 This is a graph of the backflow data (mean ± SEM) for a single animal.

[0182] Figure 173 An example of how to select a needle for use in the human clinical trial in Example 6 is provided. Detailed Implementation

[0183] definition

[0184] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications mentioned herein are incorporated herein by reference in their entirety.

[0185] As used herein, the term “application” means (1) being provided, given, administered and / or prescribed by a health practitioner or their authorized agent or under their guidance, and / or (2) being administered, taken or consumed by a subject (e.g., a mammal, including a human) in accordance with the present disclosure.

[0186] As used herein, the terms “co-administered” and “in combination with”, “simultaneously”, cover the administration of two or more active pharmaceutical ingredients to a subject such that the active pharmaceutical ingredient and / or its metabolites are simultaneously present in the subject. Co-administration includes simultaneous administration in separate compositions, administration in separate compositions at different times, or administration in a composition in which two or more active pharmaceutical ingredients are present. In some embodiments, simultaneous administration in separate compositions and administration in a composition in which two pharmaceutical ingredients are present are preferred.

[0187] The term "effective amount" or "therapeutic effective amount" refers to an amount of a compound or combination of compounds as described herein that is sufficient to achieve the intended application (including, but not limited to, the treatment of a disease). Therapeutic effective amounts can vary depending on the intended application (in vitro or in vivo), the subject being treated and the disease condition (e.g., the subject's weight, age, and sex), the severity of the disease condition, the route of administration, etc., and can be readily determined by those skilled in the art. The term also applies to doses that will induce a specific response (e.g., a reduction in platelet adhesion and / or cell migration) in target cells. Specific doses will vary depending on the subject to whom the dose is to be administered, the specific compound selected, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, the time of administration, the tissue of administration, and the physical delivery system carrying the compound.

[0188] As used herein, the term "therapeutic effect" encompasses therapeutic benefits and / or preventive benefits. Preventive effects include delaying or eliminating the onset of a disease or symptom, delaying or eliminating the onset of symptoms of a disease or symptom, slowing, stopping, or reversing the progression of a disease or symptom, or any combination thereof.

[0189] As used herein, the term "treatment" can refer to the management of a disease, condition, or pathological symptom or its symptoms, with the intent to cure, improve, stabilize, and / or control the disease, condition, pathological symptom, or its symptoms. Regarding the control of a disease, condition, or pathological symptom, more specifically, "control" can include the absence of symptom progression, as assessed by response to the methods described herein, wherein such response can be complete (e.g., disease remission) or partial (e.g., reduction or improvement of any symptoms associated with the symptom). As used herein, the term "prevention" can refer to reducing the risk of developing a disease, condition, or pathological symptom.

[0190] As used herein, soluble hyaluronidase is a form of hyaluronidase that is not GPI-anchored, is soluble under physiological conditions, and is secreted upon expression. Soluble hyaluronidase includes any hyaluronidase secreted from the cell upon expression and present in a soluble form. Human PH20 hyaluronidase does not exist as a soluble hyaluronidase. It is known in the art that removal of all or part of the GPI anchor produces a soluble form. Such soluble hyaluronidases include, but are not limited to, bacterial soluble hyaluronidases, non-human soluble hyaluronidases such as bovine PH20 and sheep PH20, human soluble PH20, and its variants. Typically, a soluble form of PH20 is produced using a protein expression system that promotes proper N-glycosylation to ensure the retention of peptide activity, as glycosylation is important for the catalytic activity and stability of hyaluronidase. Such cells include, for example, Chinese hamster ovary (CHO) cells (e.g., DG44CHO cells).

[0191] As used herein, the term 'rHuPH20' refers to a soluble hyaluronidase composition produced when a nucleic acid encoding residues 36-482 of SEQ ID NO: 1 is expressed in mammalian cells, such as CHO cells or other cells that achieve glycosylation. For expression in cells, the encoding nucleic acid is linked to a native (residues 1-35 of SEQ ID NO: 1) or heterologous signal sequence for transporting and secreting the encoded polypeptide. The resulting secretory soluble glycoprotein is a heterogeneous mixture of polypeptides, including polypeptides terminated at residues 479, 480, 481, and 482, and composed of residues 36-479, 36-480, 36-481, and 36-482 of SEQ ID NO: 1. Shorter C-terminal truncated forms of varying abundance may also be included. Typically, rHuPH20 is produced in cells that promote proper N-glycosylation to preserve activity, such as CHO cells (e.g., DG44CHO cells). In some embodiments, one of the most abundant substances is a 446-amino acid polypeptide corresponding to residues 36-481 of SEQ ID NO: 1. Also included are polypeptides that are soluble or secreted when expressed in mammalian cells and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity with residues 36-482 of SEQ ID NO: 1.

[0192] As used in this article, “combination therapy” refers to a treatment for a single disease in which two or more therapeutic agents (such as at least two or at least three therapeutic agents) are administered to the subject.

[0193] As used herein, “hyaluronidase activity” refers to the ability of an enzyme to catalyze the cleavage of hyaluronic acid. The United States Pharmacopeia (USP) XXII assay for hyaluronidase indirectly determines hyaluronidase activity by measuring the amount of higher molecular weight hyaluronic acid or acetylated hyaluronic acid (HA) substrate remaining after allowing the enzyme to react with HA at 37°C for 30 minutes (USP XXII-NFXVII (1990) 644-645 United States Pharmacopeia Convention, Inc., Rockville, MD). Reference standard solutions can be used in the assay to determine the relative activity (in units) of any hyaluronidase. In vitro assays for determining the hyaluronidase activity of hyaluronidases (such as PH20, including soluble PH20 and esPH20) are known in the art and are described herein. Exemplary assays include a microturbidity assay, which indirectly measures the cleavage of hyaluronidase on hyaluronic acid by detecting the insoluble precipitate formed when uncleaved hyaluronic acid binds to serum albumin, and a biotinylated hyaluronic acid assay, which indirectly measures the cleavage of hyaluronic acid by detecting the remaining biotinylated hyaluronic acid non-covalently bound to the wells of a microtiter plate with a streptavidin-horseradish peroxidase conjugate and a chromogenic substrate. For example, reference standards can be used to generate a standard curve to determine the unit activity of the hyaluronidase being tested.

[0194] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," or "physiologically compatible" carrier or carrier medium are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents, and inert components. The use of such pharmaceutically acceptable carriers or excipients for the active pharmaceutical ingredient is well known in the art. Unless any conventional pharmaceutically acceptable carrier or excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the present invention is contemplated. Additional active pharmaceutical ingredients (such as other drugs) may also be incorporated into the compositions and methods.

[0195] As used in this article, "specific activity" refers to the unit of activity per mg of protein. The milligrams of hyaluronidase are defined by the absorption of the solution at 280 nm, assuming a molar extinction coefficient of approximately 1.7, and the unit is M. -1 cm -1 .

[0196] As used herein, “neutral activity” refers to the ability of the PH20 peptide to enzymatically catalyze the cleavage of hyaluronic acid at a neutral pH (e.g., at pH 7.0 or approximately pH 7.0).

[0197] As used herein, a “GPI anchoring signal sequence” is a C-terminal sequence of an amino acid that guides the addition of a pre-formed GPI anchor to the ER lumen of a polypeptide. GPI anchoring signal sequences are present in precursor polypeptides of GPI-anchored polypeptides, such as the GPI-anchored PH20 polypeptide. C-terminal GPI anchoring signal sequences typically contain a major hydrophobic region of 8–20 amino acids, preceded by a hydrophilic spacer region of 8–12 amino acids, immediately downstream of the ω-site or the GPI anchoring site. GPI anchor attachment signal sequences can be identified using methods well known in the art, such as, but not limited to, computer methods and algorithms (see, for example, Udenfriend et al. (1995) Methods Enzymol. 250: 571-582, Eisenhaber et al. (1999) J. Biol. Chem. 292: 741-758, Fankhauser et al. (2005) Bioinformatics 21: 1846-1852, Omaetxebarria et al. (2007) Proteomics 7: 1951-1960, Pierleoni et al. (2008) BMC Bioinformatics 9: 392), including those readily available on bioinformatics websites, such as the ExPASy proteomics tool site (e.g., the World Wide Web site expasy.ch / tools / ).

[0198] As used in this article, "sequence identity" refers to the correlation between peptides in a nucleic acid molecule. Sequence identity can be assessed by aligning two sequences and calculating the number of differences between the aligned portion and the sequence it was compared to. Whether any two molecules have at least 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% "identical" or "homologous" nucleotide or amino acid sequences can be determined using known computer algorithms (such as the "FASTA" program), using, for example, Pearson et al. (1988) Proc. Natl. Acad. Sci. USA 85: 2444 (other programs include the GCG package (Devereux, J. et al., Nucleic Acids Research 12(I): 387 (1984)), BLASTP, BLASTN, FASTA (Altschul, SF et al., J Mol Biol 215: 403 (1990)); Guide to Huge Computers, edited by Martin J. Bishop, Academic Press, San Diego, 1994, and Carrillo et al. (1988) SIAM J Applied Math The default parameters of (48:1073) are used to determine similarity. For example, the BLAST function of the National Center for Biotechnology Information database can be used to determine identity. Other commercially or publicly available programs include the DNAStar “MegAlign” program (Madison, WI) and the University of Wisconsin-Glass Group of Genetics (UWG) “Gap” program (Madison, WI). The percentage of homology or identity of protein and / or nucleic acid molecules can be determined, for example, by comparing sequence information using the GAP computer program (e.g., Needleman et al. (1970) J. Mol. Biol. 48:443, as revised by Smith and Waterman ((1981) Adv. Appl. Math. 2:482). In short, the GAP program defines similarity as the number of similar alignment symbols (i.e., nucleotides or amino acids) divided by the total number of symbols in the shorter of the two sequences.The default parameters of the GAP procedure may include: (1) a univariate comparison matrix (containing identity values ​​of 1 and non-identity values ​​of 0) and a weighted comparison matrix of Gribkov et al. (1986) Nucl. Acids Res. 14: 6745, as described in Schwartz and Dayhoff, eds., ATLAS OF PROTEIN SEQUENCE AND STRUCTURE, National Biomedical Research Foundation, pp. 353-358 (1979); (2) a penalty of 3.0 for each empty space and an additional penalty of 0.10 for each symbol in each empty space; and (3) no penalty for terminal empty spaces.

[0199] Therefore, as used herein, the term “identity” or “homology” refers to a comparison between a test peptide and a reference peptide or polynucleotide.

[0200] As used herein, the term "at least 90% identical" refers to a percentage of identity of 90 to 99.99% relative to a reference nucleic acid or amino acid sequence of the polypeptide. A level of identity of 90% or higher indicates the following: assuming, for illustrative purposes, comparing 100 amino acid lengths of test and reference polypeptides, no more than 10% (i.e., 10 out of 100) of the amino acids in the test polypeptide differ from those in the reference polypeptide. A similar comparison can be made between the test and reference polynucleotides. This difference can be expressed as point mutations randomly distributed throughout the length of the polypeptide, or they can cluster at one or more sites of different lengths up to a maximum permissible difference, such as 10 / 100 amino acid differences (approximately 90% identity). Difference is defined as nucleic acid or amino acid substitutions, insertions, or deletions. At homology or identity levels higher than approximately 85%–90%, results should be independent of the procedure and the set of vacancy parameters; such high levels of identity can be readily assessed, typically by manual alignment without software dependence.

[0201] As used herein, “aligned sequence” refers to the alignment of corresponding positions in a nucleotide or amino acid sequence using homology (similarity and / or identity). Typically, an alignment is of two or more sequences that are associated with 50% or higher identity. An aligned sequence set refers to two or more sequences aligned at corresponding positions and may include aligned sequences derived from RNA (such as ESTs and other cDNAs) that are aligned to genomic DNA sequences.

[0202] As used herein, “denaturing conditions” refers to any condition or reagent that, when exposed to a protein, typically results in the loss or partial loss of the protein’s tertiary or secondary structure, leading to degradation or denaturation. Denaturing conditions can cause effects such as loss or reduction of activity, loss or reduction of solubility, aggregation, and / or crystallization.

[0203] As used herein, "resistance to denaturing conditions" refers to any reduction or elimination of a protein property or activity associated with or caused by denaturation. For example, denaturation is associated with or causes increased crystallization or aggregation, decreased solubility, or decreased activity. Therefore, resistance to denaturation means that, compared to a reference protein (e.g., an unmodified enzyme), a protein exhibits reduced aggregation or crystallization, increased solubility, or increased or higher activity (e.g., hyaluronidase activity) when exposed to denaturing conditions.

[0204] As used in this article, “stability of modified PH20 hyaluronidase” means that it exhibits resistance to denaturation caused by denaturing conditions or denaturing agents.

[0205] When this document uses ranges to describe, for example, physical or chemical properties (such as molecular weight or chemical formula), it is intended to include all combinations and sub-combinations of ranges, as well as specific embodiments thereof. When referring to a number or numerical range, the term “about” means that the number or numerical range mentioned is an approximation within experimental variability (or within statistical experimental error), and therefore the number or numerical range can vary. Variations are typically 0% to 15%, 0% to 10%, 0% to 5%, etc., of the stated number or numerical range.

[0206] As used herein, the term “about” means that a quantity, size, formulation, parameter, shape, or other quantity and characteristic is not and does not need to be exact, but may be approximate and / or larger or smaller as required, reflecting tolerances, conversion factors, rounding, measurement errors, and other factors known to those skilled in the art. Generally, a quantity, size, formulation, parameter, shape, or other quantity or characteristic is “about” or “approximate,” whether or not explicitly stated. The term “about” typically refers to a specific numerical value within an acceptable range of error as determined by those skilled in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” may represent a range of ±20%, ±10%, or ±5% of a given numerical value.

[0207] When used in the appended claims in both original and modified forms, the transitional terms “comprising,” “substantially consisting of,” and “consisting of” define the scope of the claims with respect to any unlisted additional claim elements or steps (if any) that are excluded from the scope of the claims. The term “comprising” is intended to be inclusive or open-ended and does not exclude any additional, unlisted elements, methods, steps, or materials. The term “consisting of” excludes any elements, steps, or materials other than those specified in the claims, and in the latter case, excludes impurities typically associated with the specified materials. The term “substantially consisting of” limits the scope of the claims to the specified elements, steps, or materials and those that do not substantially affect the essential and novel features of the claimed invention. In alternative embodiments, all compounds, compositions, formulations, and methods embodying the invention described herein may be more specifically defined by any of the transitional terms “comprising,” “substantially consisting of,” and “consisting of.” The term “comprising” (and related terms such as “containing” or “having” or “including”) includes embodiments of any composition of a substance, method or process, such as “consisting of the features” or “consisting substantially of the features”.

[0208] This disclosure generally relates to automated or manually triggered devices for delivering high-volume injectable fluids, such as pharmaceutical agents (e.g., 2 ml, 3 ml, 5 ml, 10 ml, or higher doses), for subcutaneous surface penetration (e.g., subcutaneous and intramuscular injection). Devices for delivering high-volume pharmaceutical agents are susceptible to configurational limitations, such as spring force limitations and syringe container breakage, as the delivery volume of the agent increases. Due to the current configuration of the overall device design and the limitations of bio-uptake factors that restrict injection speed and volume, the injection device will be held for extended periods, often resulting in the use of alternative delivery methods, such as on-the-go delivery systems attached to the patient during delivery.

[0209] Increasingly, biologics are being administered to patients at home. However, for many biologics, the high doses that must be delivered and the resulting high volumes of medication often hinder self-administration due to the length of time required to hold the delivery device in place. Protein hyperconcentration can be used to reduce injection volume, but the resulting medication typically has a much higher viscosity than conventional biologics. High-powered syringes can allow the delivery of these hyperconcentrated proteins. However, typical handheld syringe designs only allow for the injection of up to 2.25 mL of viscous medication within 30 seconds.

[0210] With the development of enzymes that locally degrade hyaluronic acid (HA) in the subcutaneous (SC) space, thereby temporarily eliminating barriers to fluid flow, the traditional limitations imposed by biological uptake factors restricting injection speed and volume can be reduced. Therefore, higher volumes of viscous medications can be delivered. Consequently, there is a need for a handheld device capable of delivering high doses (e.g., 3 mL, 5 mL, 10 mL, 20 mL, and up to 50 mL) of viscous medications within a delivery time suitable for a handheld device.

[0211] Drug delivery technologies for high-dose viscous agents are currently based on proprietary recombinant human hyaluronidase PH20 enzymes (e.g., rHuPH20; Halozyme, Inc.), which facilitate the delivery of co-administered therapeutic agents via the subcutaneous urethrography (SC). rHuPH20 works by degrading HA, thereby reducing resistance to high-volume fluid flow within the SC space and allowing for the delivery, dispersion, and absorption of high-volume SC drugs. Co-administration of rHuPH20 with injectable therapies can overcome the time-and-volume barriers associated with existing SC therapeutic formulations and has been shown to reduce the burden on patients and healthcare providers compared to intravenous formulations. rHuPH20 has numerous applications in the current field of injectable therapies by enhancing the dispersion and absorption of other injectable drugs, such as anticancer therapies (e.g., trastuzumab and rituximab), immunodeficiency therapies, subcutaneous urethrography to improve the absorption of radiopaque agents, and fluid delivery for rehydration.

[0212] Button-operated auto-injector or syringe

[0213] Refer to the accompanying drawings for details, in which the same reference numerals always denote the same elements. Figures 154 to 170 The diagram shows a button-actuated auto-injector or syringe according to a first exemplary embodiment of the invention, generally indicated by 10.

[0214] refer to Figure 154 The syringe 10 is described in more detail below. The syringe 10 may have a button 24, a latch 34, a spring 42, a plunger 38, a housing 12, a container support 46, a stopper 18, a main container 14, a flange 20, and a plug 54.

[0215] refer to Figure 155 The image shows a syringe 10 having a housing 12 configured to allow a user to grasp or handle the syringe 10. The housing 12 may be shaped to fit the user's hand for single-handed use. The housing 12 may have a generally elliptical cross-section to help position the syringe 10 in the user's hand. The housing 12 may also include a ridge (e.g., ribs extending along the longitudinal axis L of the housing) Figure 155(As shown), to help align or position the syringe 10 in the user's hand. The housing 12 can substantially accommodate... Figures 156 to 160B The components shown.

[0216] A main container 14 containing an injectable fluid may be at least partially contained within a housing 12. As used herein, the fluid may include a pharmaceutical agent, drug, biological agent, solution, gel, suspension, or other substance that can be delivered via a syringe or needle, and these terms are used interchangeably as they appear in the specification and claims. The main container 14 may be a pre-filled syringe. In one embodiment, the main container 14 is one of a pre-filled cartridge, a pre-filled post-needle syringe, a vial, or other container containing an injectable fluid. The main container 14 has a distal portion and a proximal portion opposite the distal portion. The main container 14 may include a container portion 16 defining a fluid chamber containing a pharmaceutical agent. In one embodiment, the container portion 16 of the main container 14 has a maximum volume of approximately 5 mL. In one embodiment, the container portion 16 of the main container 14 has a maximum volume selected from approximately the following volumes: 3 mL, 3.5 mL, 4 mL, 4.5 mL, 5.5 mL, 6 mL, 6.5 mL, 7 mL, 7.5 mL, 8 mL, 8.5 mL, 9 mL, 9.5 mL, 10 mL, 10.5 mL, 11 mL, 11.5 mL, 12 mL, 12.5 mL, 13 mL, 13.5 mL, 14 mL, 14.5 mL, 15 mL, 15.5 mL, 16 mL, 16.5 mL, 17 mL, 17.5 mL, 18 mL, 18.5 mL, 19 mL, 19.5 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL, 45 mL, and 50 mL.

[0217] like Figure 156 As shown, the main container 14 may also include a stopper 18 movable relative to the main container 14 within the fluid chamber. The stopper 18 may be positioned at the distal end of the container portion 16 before use or triggering of the syringe 10. The stopper 18 may be a plunger that seals the medication within the container portion 16. The stopper 18 may be made of a rubber material. In one embodiment, the stopper 18 is made of plastic. In one embodiment, the stopper 18 is made of butyl rubber, polyisoprene, polytetrafluoroethylene, high-density polyethylene, or other thermosetting elastomers. Figure 155 and Figure 156As shown, flange 20 can extend outward from the distal portion of the main container 14. In one embodiment, flange 20 is a Luer connector. In another embodiment, flange 20 is a Luer-Lock. In yet another embodiment, flange 20 can be coupled to a needle 19 in fluid communication with a pharmaceutical component 16. In some embodiments, needle 19 can be a regular-walled needle. In some embodiments, needle 19 can be a thin-walled needle. Needle 19 can be a gauge 21-30 needle. In one embodiment, flange 20 can be coupled to a tubing assembly 21 (e.g., [missing information]) in fluid communication with a pharmaceutical component 16. Figure 166 As shown). In one implementation, as Figure 167A and Figure 167B As shown, the stud needle 27 is pre-attached and extends from the distal portion of the main container 14. In one embodiment, a dual-hub pen needle is attached to a drug cartridge, wherein the needle pierces the cartridge's diaphragm to deliver fluid. In one embodiment, the main container with the diaphragm is inserted into a fixed needle hub.

[0218] Needle 19 can be a size 20 needle, needle 19 can be a size 21 needle, needle 19 can be a size 22 needle, needle 19 can be a size 23 needle, needle 19 can be a size 24 needle, needle 19 can be a size 25 needle, needle 19 can be a size 26 needle, needle 19 can be a size 27 needle, needle 19 can be a size 28 needle, needle 19 can be a size 29 needle, needle 19 can be a size 30 needle, and needle 19 can be a size 31 needle.

[0219] Needle 19 may have a length selected from the following:

[0220] a)1 / 8″, 3 / 16″, 1 / 4″, 5 / 16, 3 / 8″, 7 / 16″, 1 / 2″, 9 / 16″, 5 / 8″, 11 / 16″, 3 / 4″, 13 / 16″, 7 / 8″, 15 / 16″, 1″, 1 1 / 8″, 1 3 / 16″, 1 1 / 4″, 1 5 / 16, 1 3 / 8″, 1 7 / 16″, 1 1 / 2″.

[0221] The housing 12 may accommodate at least a portion of the main container 14. In one embodiment, the housing 12 accommodates only the proximal portion of the main container 14. In another embodiment, the housing 12 may accommodate the entire main container 14. The portion of the housing 12 that receives the main container 14 may have a shape substantially the same as the proximal portion of the main container 14 to prevent the main container 14 from rotating relative to the housing 12. As described in more detail below, movement of the main container 14 relative to the housing 12 can be prevented.

[0222] The main container 14 can be selected from:

[0223] a) Luer-coated cyclic olefin copolymer (COC) syringes, glass post needle syringes, polymer post needle syringes, and glass tube syringes.

[0224] The main container 14 can be designed to accommodate volumes corresponding to those selected from the following:

[0225] a) 3mL to 5mL, 3mL to 10mL, 3mL to 15mL, 3mL to 20mL, 3mL to 25mL, 3mL to 30mL, 3mL to 35mL, 3mL to 40mL, 3mL to 45mL, 3mL to 50mL, 5mL to 10mL, 5mL to 15mL, 5mL to 20mL

[0226] 5mL to 25mL, 5mL to 30mL, 5mL to 35mL, 5mL to 40mL; 5mL to 45mL, 5mL to 50mL, 10mL to 15mL; 10mL to 20mL; 10mL to 25mL; 10mL to 30mL; 10mL to 35mL; 10mL to 40mL; 10mL to 50mL;

[0227] b) about 3 mL to about 5 mL, about 3 mL to about 10 mL, about 3 mL to about 15 mL, about 3 mL to about 20 mL, about 3 mL to about 25 mL, about 3 mL to about 30 mL, about 3 mL to about 35 mL, about 3 mL to about 40 mL, about 3 mL to about 45 mL, about 3 mL to about 50 mL, about 5 mL to about 10 mL, about 5 mL to about 15 mL, about 5 mL to about 20 mL, about 5 mL to about 25 mL, about 5 mL to about 30 mL, about 5 mL to about 35 mL, about 5 mL to about 40 mL; about 5 mL to about 45 mL, about 5 mL to about 50 mL, about 10 mL to about 15 mL; about 10 mL to about 20 mL; about 10 mL to about 25 mL; about 10 mL to about 30 mL; about 10 mL to about 35 mL; about 10 mL to about 40 mL, about 10 mL to about 50 mL;

[0228] c) At least about 3 mL, at least about 3.5 mL, at least about 4 mL, at least about 4.5 mL, at least about 5.5 mL, at least about 6 mL, at least about 6.5 mL, at least about 7 mL, at least about 7.5 mL, at least about 8 mL, at least about 8.5 mL, at least about 9 mL, at least about 9.5 mL, at least about 10 mL, at least about 10.5 mL, at least about 11 mL, at least about 11.5 mL, at least about 12 mL, at least about 12.5 mL, at least about 13 mL, at least about 13.5 mL, at least about 14 mL, at least about 14.5 mL, at least about 15 mL, at least about 15.5 mL, at least about 16 mL, at least about 16.5 mL, at least about 17 mL, at least about 17.5 mL, at least about 18 mL, at least about 18.5 mL, at least about 19 mL, at least about 19.5 mL, at least about 20 mL, at least about 25 mL, at least about 30 mL, at least about 35 mL, at least about 40 mL, at least about 45 mL, at least about 50 mL; and

[0229] d) At least 3 mL, at least 3.5 mL, at least 4 mL, at least 4.5 mL, at least 5.5 mL, at least 6 mL, at least 6.5 mL, at least 7 mL, at least 7.5 mL, at least 8 mL, at least 8.5 mL, at least 9 mL, at least 9.5 mL, at least 10 mL, at least 10.5 mL, at least 11 mL, at least 11.5 mL, at least 12 mL, at least 12.5 mL, at least 13 mL, at least 13.5 mL, at least 14 mL, at least 14.5 mL, at least 15 mL, at least 15.5 mL, at least 16 mL, at least 16.5 mL, at least 17 mL, at least 17.5 mL, at least 18 mL, at least 18.5 mL, at least 19 mL, at least 19.5 mL, at least 20 mL, at least 25 mL, at least 30 mL, at least 35 mL, at least 40 mL, at least 45 mL, at least 50 mL.

[0230] The syringe 10 can be configured to deliver the entire amount or a portion of a predetermined quantity of medication within the main container 14. The predetermined quantity of medication may correspond to a volume contained in the main container 14. In one embodiment, the syringe 10 may expel an initial portion of the volume (pre-filled volume), followed by a second step to expel the remaining portion of the volume (deliverable volume). In one embodiment, the medication contained in the main container 14 corresponds to a volume selected from:

[0231] a) 3mL to 5mL, 3mL to 10mL, 3mL to 15mL, 3mL to 20mL, 3mL to 25mL, 3mL to 30mL, 3mL to 35mL, 3mL to 40mL, 3mL to 45mL, 3mL to 50mL, 5mL to 10mL, 5mL to 15mL, 5mL to 20mL

[0232] 5mL to 25mL, 5mL to 30mL, 5mL to 35mL, 5mL to 40mL; 5mL to 45mL, 5mL to 50mL, 10mL to 15mL; 10mL to 20mL; 10mL to 25mL; 10mL to 30mL; 10mL to 35mL; 10mL to 40mL; 10mL to 50mL;

[0233] b) about 3 mL to about 5 mL, about 3 mL to about 10 mL, about 3 mL to about 15 mL, about 3 mL to about 20 mL, about 3 mL to about 25 mL, about 3 mL to about 30 mL, about 3 mL to about 35 mL, about 3 mL to about 40 mL, about 3 mL to about 45 mL, about 3 mL to about 50 mL, about 5 mL to about 10 mL, about 5 mL to about 15 mL, about 5 mL to about 20 mL, about 5 mL to about 25 mL, about 5 mL to about 30 mL, about 5 mL to about 35 mL, about 5 mL to about 40 mL; about 5 mL to about 45 mL, about 5 mL to about 50 mL, about 10 mL to about 15 mL; about 10 mL to about 20 mL; about 10 mL to about 25 mL; about 10 mL to about 30 mL; about 10 mL to about 35 mL; about 10 mL to about 40 mL, about 10 mL to about 50 mL;

[0234] c) At least about 3 mL, at least about 3.5 mL, at least about 4 mL, at least about 4.5 mL, at least about 5.5 mL, at least about 6 mL, at least about 6.5 mL, at least about 7 mL, at least about 7.5 mL, at least about 8 mL, at least about 8.5 mL, at least about 9 mL, at least about 9.5 mL, at least about 10 mL, at least about 10.5 mL, at least about 11 mL, at least about 11.5 mL, at least about 12 mL, at least about 12.5 mL, at least about 13 mL, at least about 13.5 mL, at least about 14 mL, at least about 14.5 mL, at least about 15 mL, at least about 15.5 mL, at least about 16 mL, at least about 16.5 mL, at least about 17 mL, at least about 17.5 mL, at least about 18 mL, at least about 18.5 mL, at least about 19 mL, at least about 19.5 mL, at least about 20 mL, at least about 25 mL, at least about 30 mL, at least about 35 mL, at least about 40 mL, at least about 45 mL, at least about 50 mL; and

[0235] d) At least 3 mL, at least 3.5 mL, at least 4 mL, at least 4.5 mL, at least 5.5 mL, at least 6 mL, at least 6.5 mL, at least 7 mL, at least 7.5 mL, at least 8 mL, at least 8.5 mL, at least 9 mL, at least 9.5 mL, at least 10 mL, at least 10.5 mL, at least 11 mL, at least 11.5 mL, at least 12 mL, at least 12.5 mL, at least 13 mL, at least 13.5 mL, at least 14 mL, at least 14.5 mL, at least 15 mL, at least 15.5 mL

[0236] At least 16 mL, at least 16.5 mL, at least 17 mL, at least 17.5 mL, at least 18 mL, at least 18.5 mL, at least 19 mL, at least 19.5 mL, at least 20 mL, at least 25 mL, at least 30 mL, at least 35 mL, at least 40 mL, at least 45 mL, at least 50 mL.

[0237] The flow rate of syringe 10 depends largely on the viscosity and volume of the drug. However, syringe 10 can deliver the full volume of drug at a rate of approximately 0.08 mL / s to 0.75 mL / s. For example, this would provide a target delivery rate range of 13 to 120 seconds for a 10 mL dose volume. Syringe 10 can deliver 10 mL of drug at a rate of 0.33 mL / s. In one embodiment, syringe 10 delivers the full deliverable volume of drug at the following rates:

[0238] a) 0.5 mL / 10 seconds, 0.75 mL / 10 seconds, 1 mL / 10 seconds, 1.25 mL / 10 seconds, 1.5 mL / 10 seconds, 1.75 mL / 10 seconds, 2 mL / 10 seconds, 2.25 mL / 10 seconds, 2.5 mL / 10 seconds

[0239] 2.75 mL / 10 seconds, 3 mL / 10 seconds, 3.25 mL / 10 seconds, 3.5 mL / 10 seconds, 3.75 mL / 10 seconds, 4 mL / 10 seconds, 4.25 mL / 10 seconds, 4.5 mL / 10 seconds, 4.75 mL / 10 seconds, 5 mL / 10 seconds;

[0240] b) 2mL / 30 seconds, 2.5mL / 30 seconds, 3mL / 30 seconds, 3.5mL / 30 seconds, 4mL / 30 seconds

[0241] 4.5mL / 30 seconds, 5mL / 30 seconds, 5.5mL / 30 seconds, 6mL / 30 seconds, 6.5mL / 30 seconds

[0242] 7mL / 30 seconds, 7.5mL / 30 seconds, 8mL / 30 seconds, 8.5mL / 30 seconds, 9mL / 30 seconds

[0243] 9.5 mL / 30 seconds, 10 mL / 30 seconds, 10.5 mL / 30 seconds; and c) 4 mL / min, 5 mL / min, 6 mL / min, 7 mL / min, 8 mL / min, 9 mL / min

[0244] 10 mL / min, 11 mL / min, 12 mL / min, 13 mL / min, 14 mL / min

[0245] 15 mL / min, 16 mL / min, 17 mL / min, 18 mL / min, 19 mL / min, 20 mL / min, 21 mL / min.

[0246] In one implementation, the viscosity of the agent can be selected from:

[0247] a) 5 centipoise (cP), 6cP, 7cP, 8cP, 9cP, 10cP, 11cP, 12cP, 13cP, 14cP, 15cP, 16cP, 17cP , 18cP, 19cP, 20cP, 21cP, 22cP, 23cP, 24cP, 25cP, 26cP, 27cP, 28cP, 29cP, 30cP;

[0248] b) about 5 cP to about 7 cP, about 5 cP to about 9 cP, about 5 cP to about 11 cP, about 5 cP to about 13 cP, about 5 cP to about 15 cP, about 5 cP to about 17 cP, about 5 cP to about 19 cP, about 5 cP to about 21 cP, about 5 cP to about 23 cP, about 5 cP to about 25 cP, about 5 cP to about 27 cP, about 5 cP to about 29 cP, about 10 cP to about 15 cP, about 10 cP to about 20 cP, about 10 cP to about 25 cP, about 10 cP to about 30 cP.

[0249] c) At least approximately 5 cP, at least approximately 6 cP, at least approximately 7 cP, at least approximately 8 cP, at least approximately 9 cP

[0250] At least approximately 10 cP, at least approximately 11 cP, at least approximately 12 cP, at least approximately 13 cP, at least approximately

[0251] 14 cP, at least about 15 cP, at least about 16 cP, at least about 17 cP, at least about 18 cP, at least about 19 cP, at least about 20 cP, at least about 21 cP, at least about 22 cP, at least about 23 cP, at least about 24 cP, at least about 25 cP, at least about 26 cP, at least about 27 cP, at least about

[0252] 28 cP, at least about 29 cP, at least about 30 cP; and

[0253] d) At least approximately 5 cP, at least 6 cP, at least 7 cP, at least 8 cP, at least 9 cP, at least 10 cP, at least 11 cP, at least 12 cP, at least 13 cP, at least 14 cP, at least 15 cP

[0254] At least 16 cP, at least 17 cP, at least 18 cP, at least 19 cP, at least 20 cP, at least

[0255] 21 cP, at least 22 cP, at least 23 cP, at least 24 cP, at least 25 cP, at least 26 cP

[0256] At least 27 cP, at least 28 cP, at least 29 cP, at least 30 cP.

[0257] The user experience can be improved if syringe 10 can deliver the full volume of medication as quickly as possible. Faster delivery results in less pain and discomfort for the patient. Syringe 10 can deliver the full deliverable volume of medication in 5 seconds. Syringe 10 can deliver the full deliverable volume of medication in 10 seconds. Syringe 10 can deliver the full deliverable volume of medication in 15 seconds. Syringe 10 can deliver the full deliverable volume of medication in 20 seconds. Syringe 10 can deliver the full deliverable volume of medication in 25 seconds. Syringe 10 can deliver the full deliverable volume of medication in 30 seconds. Syringe 10 can deliver the full deliverable volume of medication in 35 seconds. Syringe 10 can deliver the full deliverable volume of medication in 40 seconds. Syringe 10 can deliver the full deliverable volume of medication in 45 seconds. Syringe 10 can deliver the full deliverable volume of medication in 50 seconds. Syringe 10 can deliver the full deliverable volume of medication in 55 seconds. Syringe 10 can deliver the entire deliverable volume of medication within 60 seconds. Syringe 10 can deliver the entire deliverable volume of medication within 70 seconds. Syringe 10 can deliver the entire deliverable volume of medication within 80 seconds. Syringe 10 can deliver the entire deliverable volume of medication within 90 seconds. Syringe 10 can deliver the entire deliverable volume of medication within 100 seconds. Syringe 10 can deliver the entire deliverable volume of medication within 110 seconds. Syringe 10 can deliver the entire deliverable volume of medication within 120 seconds.

[0258] Any number of markings can be displayed on syringe 10. For example, symbol 23 (such as...) Figure 155 The status of the syringe 10 (as shown) can be displayed on the housing 12, or an indicator of the status of the syringe 10 can be displayed on the button 24 (as shown). Figure 155 (As shown). Reference Figure 155 and Figure 161The housing 12 may include a cutout 13 extending therethrough to allow observation of an indicator on a button 24 disposed within the housing 12. The cutout 13 may be located at a proximal portion of the housing 12. The cutout 13 may be generally elliptical in shape. The cutout 13 may expose a portion of the button 24 containing the markings. The button 24 may be at least partially received within the proximal portion of the housing 12. The button 24 may include a locking indicator 15 thereon for indicating the button's locked state and / or for indicating that the syringe 10 is in a locked configuration. The locking indicator 15 may be engraved, etched, printed, or molded in the button 24. In one embodiment, the locking indicator 15 is a decal attached to the button 24 with adhesive. In one embodiment, the locking indicator 15 is applied to the button 24 via spraying, powder coating, screen printing, laser marking, pad printing, or hot-melt application. The locking indicator 15 may be a locking graphic indicating that the syringe 10 is in a locked configuration. The locking indicator 15 may be any combination of shape and / or text.

[0259] Button 24 may also include a rotation indicator 17 for indicating the direction in which button 24 can move about a longitudinal axis L. The rotation indicator 17 may be engraved in button 24. In one embodiment, the rotation indicator 17 is a decal attached to button 24 with adhesive. In one embodiment, the rotation indicator 17 is applied to button 24 via spraying, powder coating, screen printing, laser marking, pad printing, or hot melting. The rotation indicator 17 may be an arrow indicating the direction in which button 24 must rotate relative to housing 12 to change from a locked configuration to an unlocked configuration. The rotation indicator 17 may be any combination of shape and / or text. In one embodiment, the button includes an indication for partial administration of a drug, such as a pre-filled volume in the position of the locking indicator 15. The partial administration indicator may be engraved, etched, printed, or molded in button 24. In one embodiment, the partial administration indicator is a decal attached to button 24 with adhesive. In one embodiment, the partial administration indicator is applied to button 24 via spraying, powder coating, screen printing, laser marking, pad printing, or hot melting.

[0260] To dispensing the medication from the main container 14, the syringe 10 undergoes a series of sequential movements that trigger a specific event. This trigger event is initiated by the user moving button 24 relative to the housing 12. (See reference...) Figures 156 to 160BThe syringe 10 may also include a trigger mechanism 22. The trigger mechanism 22 may include a button 24, a latch 34, a plunger 38, and a spring 42 located on the proximal portion of the housing 12. The button 24 may be rotatably coupled to the housing 12 about its longitudinal axis L. The button 24 can rotate between an unlocked configuration and a locked configuration, which can be indicated to the user by markings visible to the user through the cutout 13. Rotation of the button 24 between the locked and unlocked configurations may not compromise the sterile barrier of the main container 14. This allows the user to rotate the button 24 back to the locked configuration for later use.

[0261] In the locked configuration, button 24 can be prevented from moving distally along the longitudinal axis L of housing 12 by means of an edge along the inner surface of housing 12. In some applications (i.e., laboratory testing), it may be necessary to remove button 24. In one embodiment, button 24 can move proximally along the longitudinal axis L of housing 12. Button 24 may include a through-hole 59 extending through its proximal end, which allows for removal using appropriate equipment. In one embodiment, button 24 is removable by releasing it from the edge by inserting a removal tool (not shown) into the through-hole 59. In the unlocked configuration, button 24 can move distally along the longitudinal axis L of housing 12 to initiate a trigger event. Button 24 may be generally cylindrical in shape. The proximal end of button 24 may be closed, and the distal end of button 24 may be open. Button 24 may have an internal cavity 28 defined therein. Button 24 may be the only feature of syringe 10 that is movable relative to housing 12 prior to a trigger event. The outer surface of button 24 may have one or more ridges extending along its length. In one implementation, button 24 is rotated to the unlock position to cause the device to discharge the pre-charge volume.

[0262] refer to Figures 156 to 160B Button 24 may include a cylinder 26 extending distally within an internal cavity 28. Cylinder 26 may have a proximal and a distal side. Cylinder 26 may include a recess 30 extending radially inwardly on cylinder 26. Cylinder 26 may be generally cylindrical in shape on its distal side. Cylinder 26 may be non-uniformly cylindrical in shape on its proximal side. Cylinder 26 may have a radius smaller than the radius of button 24. The radius of cylinder 26 may be one-third the radius of button 24. Cylinder 26 may have a radius of 0.1 inches to 0.5 inches. Recess 30 may be located on the proximal side of cylinder 26. In one embodiment, cylinder 26 includes two recesses 30 on opposite sides of cylinder 26. The distal side of cylinder 26 may have a smaller diameter than the proximal side of cylinder 26. Cylinder 26 may extend only a portion of the length of button 24 distally. In one embodiment, cylinder 26 extends distally substantially along the length of button 24.

[0263] refer to Figures 160A to 160BThe triggering mechanism 22 may also include a latch 34 for facilitating a triggering event. The latch 34 may have a proximal end and a distal end. The latch 34 may have a generally cylindrical shape. The latch 34 may be disposed within the housing 12. The latch 34 may be secured to the housing 12. The proximal end of the latch 34 may be disposed within the button 24.

[0264] The latch 34 may also include a latch arm 32. The latch arm 32 may extend distally from the proximal end of the latch 34 along the longitudinal axis L. The latch arm 32 may be coupled to the latch 34. The latch arm 32 may be biased in an inward radial direction. The inward radial deflection of the latch arm 32 may be prevented by the cylinder 26 prior to a trigger event. The latch arm 32 may include a protrusion 36. The protrusion 36 may extend radially outward from the latch arm 32. A recess 30 may be configured to align with the latch arm 32 in an unlocked configuration. The latch arm 32 may be received in the recess 30 when the button 24 is moved distally a predetermined distance along the longitudinal axis L in the unlocked configuration. In one embodiment, the latch arm 32 includes two radially opposing latches.

[0265] refer to Figures 156 to 160B The triggering mechanism 22 may also include a push rod 38. The push rod 38 may include a proximal side and a distal side opposite to the proximal side. The push rod 38 may be disposed within the latch 34. The push rod 38 may be configured to engage the plug 18 on its distal side. The push rod 38 may be generally cylindrical in shape, defining an internal cavity 40 therein. A spring 42 may be disposed within the internal cavity 40. In one embodiment, the spring 42 may be disposed outside the push rod 38. The spring 42 may have a proximal end and a distal end opposite to the proximal end. The proximal end of the spring 42 may engage a collar 98 of the latch 34. The collar 98 may be generally cylindrical in shape. The collar 98 may be sized such that the cylinder 26 can pass through it. The radius of the collar 98 may be the same as that of the spring 42 to ensure that the collar 98 engages the spring 42. The distal end of the spring 42 may engage a push rod collar 96 located within the internal cavity 40 on the distal side of the push rod 38. During a triggering event, spring 42 may offset push rod 38 distally relative to housing 12 along longitudinal axis L. In an exemplary embodiment, spring 42 comprises a compression spring; however, other suitable energy sources may be used, such as an electric pump, an elastomer or compressed gas spring, compressed gas cylinder 43, a gas generator, or other suitable energy storage components. Push rod 38 may move stop 18 distally relative to main container 14 along longitudinal axis L.

[0266] In some embodiments, a compressed gas cylinder 43 (not shown) is used in conjunction with or instead of a spring 42 as an energy source for the syringe 10. The compressed gas cylinder 43 may be located proximally within the syringe 10. Energy may be stored in the compressed gas cylinder 43, which can be selectively released when the user moves the button 24 distally along the longitudinal axis L relative to the housing 12. The distal end of the compressed gas cylinder 43 may engage a push rod 38 to move the push rod 38 relative to the main container 14, thereby dispensing medication. In some embodiments, the compressed gas cylinder 43 includes a pin 45 that is movable relative to the compressed gas cylinder 43 when the syringe 10 is actuated and extends distally therefrom. The pin 45 may engage the push rod 38 when the syringe 10 is actuated, causing the push rod 38 to move distally relative to the housing 12. The compressed gas cylinder 43 can increase the accuracy of medication delivery by precisely controlling the force acting on the push rod 38. Compared to alternative embodiments (e.g., spring 42), the compressed gas cylinder 43 can reduce vibration and noise during use. In some embodiments, the length of the syringe 10 using the compressed gas cylinder 43 along the longitudinal axis L is less than that of the syringe 10 in an alternative embodiment that uses an energy source (e.g., a spring 42).

[0267] refer to Figures 156 to 160B The push rod 38 may include a hole 44 extending therethrough. The hole 44 may be located proximal to the push rod 38. The latch arm 32 may prevent the push rod 38 from moving distally relative to the housing 12. The protrusion 36 may engage the hole 44 to prevent the spring 42 from biasing the push rod 38 distally.

[0268] refer to Figure 157 and Figure 158 In the unlocking configuration, the distal movement of button 24 relative to housing 12 along the longitudinal axis L allows latch arm 32 to deflect radially inward into recess 30 of cylinder 26, thereby triggering a trigger event. The radial deflection of latch arm 32 disengages protrusion 36 from hole 44. Disengagement of latch arm 32 from protrusion 36 allows spring 42 to bias push rod 38 distally relative to housing 12 along the longitudinal axis L. Push rod 38 causes stopper 18 to move distally relative to main container 14 along the longitudinal axis L to expel medication in the discharge configuration.

[0269] refer to Figures 156 to 160BSpring 42 can be a compression spring. Spring 42 can have a diameter of 5mm. Spring 42 can have a diameter of 6mm. Spring 42 can have a diameter of 7mm. Spring 42 can have a diameter of 8mm. Spring 42 can have a diameter of 9mm. Spring 42 can have a diameter of 10mm. Spring 42 can have a diameter of 11mm. Spring 42 can have a diameter of 12mm. Spring 42 can have a diameter of 13mm. Spring 42 can have a diameter of 14mm. Spring 42 can have a diameter of 15mm. Spring 42 can have a wire diameter of 0.75mm. Spring 42 can have a wire diameter of 1mm. Spring 42 can have a wire diameter of 1.25mm. Spring 42 can have a wire diameter of 1.5mm. Spring 42 can have a wire diameter of 1.75mm. Spring 42 can have a wire diameter of 2mm.

[0270] A spring can generate 8 lbf of force. A spring can generate 9 lbf of force. A spring can generate 10 lbf of force. A spring can generate 11 lbf of force. A spring can generate 12 lbf of force. A spring can generate 13 lbf of force. A spring can generate 14 lbf of force. A spring can generate 15 lbf of force. A spring can generate 16 lbf of force. A spring can generate 17 lbf of force. A spring can generate 18 lbf of force. A spring can generate 19 lbf of force. A spring can generate 20 lbf of force. A spring can generate 21 lbf of force. A spring can generate 22 lbf of force. A spring can generate 23 lbf of force. A spring can generate 24 lbf of force. A spring can generate 25 lbf of force. A spring can generate 26 lbf of force. A spring can generate 27 lbf of force. A spring can generate 28 lbf of force. A spring can generate 29 lbf of force. A spring can generate a force of 30 lbf. A spring can generate a force of 31 lbf. A spring can generate a force of 32 lbf. A spring can generate a force of 33 lbf. A spring can generate a force of 34 lbf. A spring can generate a force of 35 lbf. A spring can generate a force of 36 lbf. A spring can generate a force of 37 lbf. A spring can generate a force of 38 lbf. A spring can generate a force of 39 lbf. A spring can generate a force of 40 lbf.

[0271] Spring 42 can generate up to 15 lbf of force before a trigger event. Spring 42 can generate up to 17.5 lbf of force before a trigger event. Spring 42 can generate up to 20 lbf of force before a trigger event. Spring 42 can generate up to 22.5 lbf of force before a trigger event. Spring 42 can generate up to 25 lbf of force before a trigger event. Spring 42 can generate up to 27.5 lbf of force before a trigger event. Spring 42 can generate up to 30 lbf of force before a trigger event. Spring 42 can generate up to 32.5 lbf of force before a trigger event. Spring 42 can generate up to 35 lbf of force before a trigger event. Spring 42 can generate up to 37.5 lbf of force before a trigger event. Spring 42 can generate up to 40 lbf of force before a trigger event.

[0272] After the entire volume of fluid is drained from the main container, spring 42 can generate a residual force of 8 lbf. After the entire volume of fluid is drained from the main container, spring 42 can generate a residual force of 10 lbf. After the entire volume of fluid is drained from the main container, spring 42 can generate a residual force of 12 lbf. After the entire volume of fluid is drained from the main container, spring 42 can generate a residual force of 14 lbf. After the entire volume of fluid is drained from the main container, spring 42 can generate a residual force of 16 lbf. After the entire volume of fluid is drained from the main container, spring 42 can generate a residual force of 18 lbf. After the entire volume of fluid is drained from the main container, spring 42 can generate a residual force of 20 lbf. After the entire volume of fluid is drained from the main container, spring 42 can generate a residual force of 22 lbf. After the entire volume of fluid is drained from the main container, spring 42 can generate a residual force of 24 lbf. After the entire volume of fluid is drained from the main container, spring 42 can generate a residual force of 26 lbf. After the entire volume of fluid is drained from the main container, spring 42 can generate a residual force of 28 lbf. After the entire volume of fluid is drained from the main container, spring 42 can generate a residual force of 30 lbf. After the entire volume of fluid is drained from the main container, spring 42 can generate a residual force of 32 lbf. After the entire volume of fluid is drained from the main container, spring 42 can generate a residual force of 34 lbf. After the entire volume of fluid is drained from the main container, spring 42 can generate a residual force of 36 lbf. After the entire volume of fluid is drained from the main container, spring 42 can generate a residual force of 38 lbf. After the entire volume of fluid is drained from the main container, spring 42 can generate a residual force of 40 lbf.

[0273] When the main container 14 can be received within the housing 12, it must be secured to the housing to ensure dispensing of the agent due to a triggering event. If the main container 14 rotates or moves distally due to a triggering event, inconsistent delivery may be compromised. (Reference) Figures 156 to 160B The syringe 10 also includes a container support 46 coupled to the housing 12. The container support 46 secures the main container 14 to the housing 12. The container support 46 prevents the main container 14 from rotating relative to the housing 12 about a longitudinal axis L. The container support 46 can axially support the proximal portion of the main container 14 such that the distal portion of the main container 14 is substantially unsupported in the axial direction. The container support 46 can extend distally along the longitudinal axis L to cover at least a portion of the main container 14. In one embodiment, the container support 46 extends distally along the longitudinal axis L to cover the entire main container 14. The container support 46 may include a window 66 exposing at least a portion of the main container 14 (e.g., a window 66). Figures 164A to 164C and Figure 165 (As shown).

[0274] refer to Figures 156 to 160B The container support 46 includes an extension 48 extending proximally within the housing 12 along a longitudinal axis L. The extension 48 engages a collar 50 at a proximal portion of the main container 14. In some embodiments, the proximal end of the extension 48 may include a pad, cushion, rib, or other feature to suppress forces applied to the collar 50 during a triggering event, thereby reducing the likelihood of breakage. The extension 48 allows the collar 50 to engage a distal portion of the latch 34, thereby securing the main container 14 relative to the housing 12. The container support 46 may extend substantially around the entire circumference of the collar 50 of the main container 14. In one embodiment, the container support 46 extends only partially around the circumference of the collar 50 of the main container 14. The container support 46 can be coupled to the housing 12 via a snap-fit ​​connection. In one embodiment, the container support 46 is threadedly coupled to the housing 12.

[0275] refer to Figure 155 , Figure 156 and Figure 161 The flange 20 may be a Luer lock located at the distal end of the main container 14. The flange 20 may be configured to engage with the needle 19, thereby establishing fluid communication from the main container 14 to the needle 19. The flange 20 may receive a plug 54. The plug 54 prevents the medication from flowing out of the main container 14. The plug 54 may be removed before the needle 19 is engaged with the Luer lock. The needle 19 may be threadedly engaged with the flange 20 to establish fluid communication therethrough. Figure 166In one embodiment shown, the tube assembly 21 is coupled to the flange 20 to establish fluid communication therethrough. In some embodiments, the housing 12 includes a safety cap (not shown) removably coupled to the distal end of the housing 12. The safety cap may include a safety seal that contacts the housing 12 when the safety cap is coupled to the housing 12 to prevent any contaminants (dust, dirt, liquids) from interacting with the needle 19 when the safety cap is coupled to the housing 12. The needle 19 can be exposed when the safety cap is removed.

[0276] The friction between button 24 and housing 12 can provide sufficient resistance to prevent accidental or unintended movement of button 24. In one embodiment, such as Figures 168 to 170 As shown, to prevent accidental or unintended movement of button 24, a button spring 56 is included to bias the button proximally relative to the housing. (Reference) Figures 156 to 160B Button 24 may be at least partially disposed within housing 12. Button 24 may be biased proximally relative to housing 12 along longitudinal axis L by button spring 56. Button spring 56 may have a proximal end and a distal end. The proximal end of button spring 56 may engage button 24. The distal end of button spring 56 may engage latch 34. Button spring 56 may generate a force of 1 lbf to 5 lbf.

[0277] At any time prior to intended use, syringe 10 is preferably in a locked configuration to prevent unexpected or accidental triggering events. (Reference) Figure 157 An embodiment of the syringe 10 of this disclosure in a locked configuration is shown. In the locked configuration, movement of button 24 relative to housing 12 along the longitudinal axis L is prevented. Button 24 can rotate about the longitudinal axis L only in the locked configuration. Latch arm 32 can be configured to align with a portion of button 24 excluding the recess 30 at its proximal end to ensure that a trigger event is not initiated. Button 24 without the recess 30 aligned with latch arm 32 can further prevent accidental ejection due to drop, misuse, or other handling. Cylinder 26 can push latch arm 32 in an outward radial direction. In the locked configuration, protrusion 36 of latch arm 32 can engage hole 44 of push rod 38 to prevent push rod 38 from moving distally relative to housing 12 along the longitudinal axis L. In the locked configuration, spring 42 can be in a compressed configuration. By engaging protrusion 36 of hole 44 of push rod 38, spring 42 can prevent distal biasing of push rod 38 relative to housing 12 along the longitudinal axis L.

[0278] When syringe 10 is to be used, syringe 10 can switch to an unlocked configuration to trigger the event. (See reference) Figure 158An embodiment of the syringe 10 of this disclosure in an unlocked configuration is shown. The syringe 10 can be switched from a locked configuration to an unlocked configuration by rotating button 24 about the longitudinal axis L. Rotation of button 24 to the unlocked configuration causes button 24 to move distally relative to housing 12 along the longitudinal axis L. The distal movement of button 24 relative to housing 12 along the longitudinal axis L can pre-charge the main container 14 by removing any air from the container portion 16 prior to a trigger event. In the unlocked configuration, spring 42 can be in a compressed configuration.

[0279] Rotating button 24 90° around the longitudinal axis L changes the syringe 10 from a locked to an unlocked configuration. Rotating button 24 0°–89° around the longitudinal axis L does not change the syringe 10 from a locked to an unlocked configuration. In one embodiment, rotating button 24 45° around the longitudinal axis L changes the syringe 10 from a locked to an unlocked configuration. In one embodiment, rotating button 24 180° around the longitudinal axis L changes the syringe 10 from a locked to an unlocked configuration. In one embodiment, rotating button 24 90°–180° around the longitudinal axis L changes the syringe 10 from a locked to an unlocked configuration. In one embodiment, rotating button 24 45°–180° around the longitudinal axis L changes the syringe 10 from a locked to an unlocked configuration.

[0280] In the unlocking configuration, button 24 can move proximally relative to housing 12 along the longitudinal axis L. In the unlocking configuration, the recess 30 of cylinder 26 can align with latch arm 32. When button 24 moves proximally a predetermined distance relative to housing 12 along the longitudinal axis L, latch arm 32 can be radially deflected inward into recess 30, thereby triggering a trigger event. The radially inward deflection of latch arm 32 disengages protrusion 36 from hole 44 in push rod 38. Disengagement of latch arm 32 from hole 44 allows spring 42 to bias push rod 38 distally relative to housing 12 along the longitudinal axis L. Distal movement of push rod 38 relative to housing 12 along the longitudinal axis L causes stopper 18 to move through container portion 16 of main container 14, thereby forcing medication through flange 20. The container support 46, which abuts against the latch 34 and engages the collar 50 of the main container 14, can prevent the main container 14 from moving distally relative to the housing 12 along the longitudinal axis L during a triggering event.

[0281] After an event is triggered, syringe 10 can be disabled to prevent further actuation or triggering of events. (See reference) Figure 159The diagram illustrates an embodiment of the syringe 10 of this disclosure in a discharge configuration. In the discharge configuration, button 24 can be fixed relative to housing 12. A latch arm 32 deflected in recess 30 prevents button spring 56 from biasing button 24 distally relative to housing 12 along longitudinal axis L. During a trigger event, push rod 38 can be moved distally relative to housing 12 along longitudinal axis L such that push rod 38 is fully disposed within container portion 16 of main container 14 in the discharge configuration. In one embodiment, in the discharge configuration, push rod 38 is partially disposed within container portion 16 of main container 14.

[0282] refer to Figure 161 The diagram illustrates an embodiment of the syringe 10 of this disclosure in a discharge configuration. The main container 14 may be made of a transparent material. The main container 14 may be made of glass. In one embodiment, the main container 14 is made of plastic. In the discharge configuration, the plunger 38 is visible through the main container 14. The plunger 38 and the stopper 18 are also visible through the main container 14.

[0283] refer to Figure 161 The button 24 may include a trigger indicator 52. The trigger indicator 52 may be engraved in the button 24. The trigger indicator 52 may be a decal attached to the button 24 with adhesive. The trigger indicator 52 may be an arrow indicating the direction in which the button 24 must be moved relative to the housing 12 to initiate a trigger event. The trigger indicator 52 may be any combination of shape and / or text. When the syringe 10 is in the discharge configuration, the trigger indicator 52 may be visible in the cutout 13.

[0284] refer to Figure 161 The container support 46 may include a release mechanism. The release mechanism allows a user to disassemble the syringe 10 to replace and reset any of its components prior to a triggered event. The housing 12 may include a hole 62 extending therethrough. The container support 46 may include a latch 64 extending radially outward from the extension 48 through the hole 62 in an engaged configuration. In the engaged configuration, the latch 64 prevents movement of the container support 46 relative to the housing 12. When the latch 64 is pushed radially inward to a disengaged configuration, the latch 64 allows movement of the container support 46 relative to the housing 12. The container support 46 can move along the longitudinal axis L in the disengaged configuration. Figures 164A to 164C and Figure 165 As shown, container support 46 can be removed and replaced with an alternative container support 46 embodiment. Removal of container support 46 allows for the replacement of any component of trigger mechanism 22 to accommodate different agent viscosities and volumes.

[0285] Figures 160A to 160BAn embodiment of the button 24 of this disclosure is shown. The button 24 may include a wing 58 projecting radially outward therefrom. The wing 58 may be located at a proximal portion of the button 24. The wing 58 prevents the button 24 from rotating about a predetermined threshold about a longitudinal axis L. A buffer 60 (not shown) may be included on the inner surface of the housing 12 to engage the wing 58 during rotation of the button 24 about the longitudinal axis L, preventing the wing 58 from passing through it. The wing 58 and the buffer 60 may be aligned when the syringe 10 is in a locked and unlocked configuration. When the wing 58 engages the buffer 60 in the unlocked configuration, the inner surface of the housing 12, the latch arm 32, may be aligned with the recess 30 of the barrel 26. In one embodiment, two wings are present. In one embodiment, a maximum torque of 1 inch-pound to 15 inch-pounds is required to overcome the buffer 60 and rotate from the locked position to the unlocked position.

[0286] The buffer 60 allows the button 24 to rotate 90° about the longitudinal axis L before the wing 58 engages the buffer 60. In one embodiment, the buffer 60 allows the button 24 to rotate 45° about the longitudinal axis L before the wing 58 engages the buffer 60. In one embodiment, the buffer 60 allows the button 24 to rotate 180° about the longitudinal axis L before the wing 58 engages the buffer 60. In one embodiment, the buffer 60 allows the button 24 to rotate 1°–180° about the longitudinal axis L before the wing 58 engages the buffer 60.

[0287] refer to Figures 163A to 163C A second embodiment of the syringe 10 is shown. The syringe 10 can be similar to... Figures 154 to 161 The embodiment of the syringe 10 shown includes a container support 46 that can substantially cover the entire length of the main container 14. In one embodiment, the container support 46 partially covers the main container 14.

[0288] like Figures 163A to 163C As shown, the container support 46 can extend from the proximal portion of the housing 12 to the flange 20. The container support 46 may have approximately the same thickness as the housing 12. The container support 46 may include a window 66. The window 66 may be an opening extending through the container support 46 to expose the main container 14. The window 66 may be of a generally elliptical shape. The window 66 may extend substantially along the entire length of the container support 46.

[0289] refer to Figures 164A to 164C A third embodiment of the syringe 10 is shown. The syringe 10 can be similar to... Figures 163A to 163C The embodiment of the syringe 10 shown differs in that the container support 46 may have approximately the same thickness as the container portion 16 of the main container 14. In one embodiment, the thickness of the container support 46 is less than the thickness of the housing 12.

[0290] like Figures 164A to 164C As shown, the container support 46 can extend from the proximal portion of the housing 12 to the flange 20. The container support 46 may have a thickness generally less than that of the housing 12. The container support 46 may include a window 66. The window 66 may be an opening extending through the container support 46 to expose the main container 14. The window 66 may be of a generally elliptical shape. The window 66 may extend substantially along the entire length of the container support 46.

[0291] refer to Figure 165 A fourth embodiment of the syringe 10 is shown. The syringe 10 can be similar to... Figures 163A to 163C In the illustrated embodiment of syringe 10, the container support 46 may have a cap 68 covering the container support 46. The thickness of the cap 68 may be less than the thickness of the housing 12. In one embodiment, the cap 68 has a thickness approximately the same as the thickness of the housing 12.

[0292] refer to Figure 165 The image shows a cap 68 on a syringe 10. The cap 68 is removably attached to the syringe 10. The cap 68 may be generally cylindrical in shape. The cap 68 may have a proximal end and a distal end opposite the proximal end. The proximal end of the cap 68 may define an orifice. The distal end of the cap 68 may be generally flat. The diameter of the flat distal end of the cap 68 may be larger than the diameter of the proximal end of the cap 68. The flat distal end of the cap 68 may allow the syringe 10 to stand upright in a vertical orientation.

[0293] The cap 68 can be designed to receive the container support 46 through a hole at its proximal end. For example... Figures 164A to 164C As shown, the container support 46 may include a lip 70 extending radially outward from the container support 46. The lip 70 may extend circumferentially around the container support 46. The lip 70 may extend only partially circumferentially around the container support 46. The lip 70 may be close to the proximal end of the container support 46. The lip 70 may engage a cap lip 72 (not shown) on the inner surface of the cap 68 to connect the cap 68 and the container support 46. The cap 68 may cover the flange 20 of the main container 14 to prevent damage to or accidental removal of the plug 54 when the cap 68 is connected to the container support 46.

[0294] refer to Figure 166 A fifth embodiment of the syringe 10 is shown. The syringe 10 can be similar to... Figures 154 to 161 The embodiment of syringe 10 shown, except that flange 20 can be coupled to tubing 21, is for applications where needle 19 may be insufficient or unsuitable for drug delivery. The plug 54 can be removed before tubing 21 is coupled to the Luer lock. Tubing 21 can be threaded onto flange 20 to establish fluid communication therethrough.

[0295] refer to Figures 167A to 167B The sixth embodiment of syringe 10 is shown. Syringe 10 can be similar to Figures 154 to 161 The embodiment of the syringe 10 shown differs from the one in that the post needle 27 is pre-attached and extends from the distal portion of the main container 14. The post needle 27 is in fluid communication with the main container 14 containing the drug.

[0296] refer to Figures 168 to 170 A seventh embodiment of the syringe 10 is shown. The syringe 10 can be similar to... Figures 154 to 161 The embodiment of syringe 10 shown includes a button spring 56 to bias button 24 in the proximal direction to prevent unintended or accidental triggering events. As discussed in more detail above, button spring 56 may be disposed between housing 12 and latch 34, and engage the distal end of latch 34 to bias the distal end of button 24 in the proximal direction relative to housing 12. In the discharge configuration, as Figure 170 As shown, the latch arm 32 can engage the recess 30 to prevent the button spring 56 from biasing the button 24 proximally relative to the housing.

[0297] Formulations for high-dose injection

[0298] This disclosure provides a formulation for high-dose injection comprising hyaluronidase. In one embodiment, the formulation is an aqueous formulation. In another embodiment, the formulation comprises one or more pharmaceutically acceptable carriers.

[0299] soluble hyaluronidase form

[0300] Soluble hyaluronidases include any hyaluronidase that is secreted from the cell at the time of expression and exists in a soluble form. Such soluble hyaluronidases include, for example, but not limited to, bacterial soluble hyaluronidases, non-human soluble hyaluronidases such as bovine PH20 and sheep PH20, human soluble PH20, and their variants. Typically, a soluble form of PH20 is produced using a protein expression system that promotes proper N-glycosylation to ensure the retention of peptide activity, as glycosylation is important for the catalytic activity and stability of hyaluronidases. Such cells include, for example, Chinese hamster ovary (CHO) cells (e.g., DG44CHO cells).

[0301] Vorhyaluronidaseα is a recombinant human hyaluronidase PH-20 analogue, corresponding to the amino acid sequence of human hyaluronidase PH-20 at positions 36-482. Vorhyaluronidaseα is produced in Chinese hamster ovary cells. Vorhyaluronidaseα is a glycoprotein composed of 447 amino acid residues (molecular weight: 60,000-65,000). In one embodiment, the soluble PH20 product is produced by expressing a composition encoding nucleic acids at residues 36-482 in CHO cells, resulting in a mixture of polypeptides having C-termini at residues 477, 478, 479, 480, 481, and 482.

[0302] Soluble pH20 hyaluronidase is available, and for example, under brand names. For sale (CAS name of 36-482 Hyaluronic Acid Glucosylase PH20 (Human)). The product is a mixture of polypeptides produced by expressing nucleic acids encoding amino acids 36-482 (SEQ ID NO: 2). The product is a mixture of polypeptides produced by expressing nucleic acids encoding amino acids 36-477 (SEQ ID NO: 3), 36-478 (SEQ ID NO: 4), 36-479 (SEQ ID NO: 5), 36-480 (SEQ ID NO: 6), 36-481 (SEQ ID NO: 7), and 36-482 (SEQ ID NO: 2). The technology provides a drug delivery technique that utilizes soluble hyaluronidase to facilitate the delivery of injected drugs and fluids. When formulated with or administered with other drugs, The technology reduces the treatment burden on patients. It allows for large-volume subcutaneous injections while increasing the dispersion and absorption of co-administered therapies.

[0303] In one embodiment, one or more of N47, N131, N200, N219, N333, N358, or T440 in SEQ ID NO: 2-7 are glycosylation sites. In one embodiment, one or more of Q444, I445, F446, or Y447 in SEQ ID NO: 2-7 are partial processing sites. In one embodiment, one or more of C25-C316, C189-C203, C341-C352, C346-C400, C402-C408, or C423-C429 in SEQ ID NO: 2-7 are disulfides.

[0304] rHuPH20 refers to a composition produced when a nucleic acid encoding residues 36-482 of SEQ ID NO: 8 is expressed in cells (such as CHO cells), typically linked to a native or heterologous signal sequence (residues 1-35 of SEQ ID NO: 8). rHuPH20 is produced by expressing nucleic acid molecules (such as those encoding amino acids 1-482, as shown in SEQ ID NO: 8) in mammalian cells. Translational processing removes the 35-amino acid signal sequence. As produced in culture media, heterogeneity exists at the C-terminus, such that the product named rHuPH20 comprises a mixture of substances that may include any or more of peptides 36-480, 36-481, and 36-482 of SEQ ID NO: 8, as well as some shorter peptides of varying abundance. rHuPH20 and soluble hyaluronidase are produced in cells that promote N-glycosylation, such as CHO cells (e.g., DG44CHO cells). PH20 is a glycoprotein and, as is known in the art, requires glycosylation retention activity. See, for example, U.S. Patent Nos. 8,927,249 and 9,284,543 (and PCT Publication No. WO2010 / 077297), which describe the effects of glycosylation and partial glycosylation, as well as the elimination of glycosylation, on the activity of the soluble form of PH20. These patents and publications also describe and exemplify soluble C-terminal truncated forms of PH20.

[0305] Soluble human pH 20 form

[0306] Soluble hyaluronidases include bovine and ovine PH20, as well as their recombinant and humanized forms. Human PH20 in nature contains a GPI anchor and is attached to sperm cells; it is insoluble. Its C-terminal truncated form is soluble. Soluble forms of recombinant human PH20 have been produced and can be used in the compositions, combinations, and methods described herein. Descriptions and production of such soluble forms of PH20 are described in, for example, U.S. Patent Nos. 7,767,429, 8,202,517, 8,431,380, 8,431,124, 8,450,470, 8,765,685, 8,772,246, 7,871,607, 7,846,431, 7,829,081, 8,105,586, 8,187,855, 8,257,699, 8,580,252, 9,677,061, and 9,677,062, each of which is incorporated herein by reference. Therefore, soluble hyaluronidases include the form of human PH20, which has neutral hyaluronidase activity and whose activity requires glycosylation.

[0307] SEQ ID NO: 1 shows the sequence of the precursor polypeptide; the mature PH20 polypeptide (residues 36-509); the soluble form also includes those with amino acid truncation at the N-terminus, such as the deletion of the first one, two, three or four residues, such that the resulting polypeptide has an N-terminus, for example at residues 36, 37, 38, 39 or 40, and a C-terminus at residues 465 to 500, and variants thereof, including but not limited to variants discussed below, variants known in the art and allele variants.

[0308] The hyaluronidase used in the compositions, combinations, and methods described herein is a soluble, neutral-active hyaluronidase. An example is the soluble C-terminal truncated form of mature human PH20. Soluble forms having hyaluronidase activity include, but are not limited to, those truncated at residues 465 to 500 of SEQ ID NO: 1 and secreted upon expression. An example is a hyaluronidase containing SEQ ID NO: 1. Sequence of NO: 1 36-465, 36-466, 36-467, 36-468, 36-469, 35-470, 36-471, 36-472, 36-474, 36-475, 36-476, 35 -477, 36-478, 36-479, 36-480, 36-481, 36-482, 36-483, 35-484, 36-485, 36-486, 36-487, 36-488, 36-48 9. Polypeptides of 36-490, 35-491, 36-492, 36-493, 36-494, 36-495, 36-496, 36-497, 35-498, 36-499 and 36-500, and N-terminal truncated forms of each of the above lacking two to five residues at the N-terminus, such as, for example, 37-368, 38-468, and any other form exhibiting hyaluronidase activity at neutral pH (such as pH in the range of 7.0-7.4).

[0309] Therefore, this soluble form includes truncated forms of the mature human PH20 form, lacking all or part of the C-terminal GPI anchor, provided the hyaluronidase is soluble and retains hyaluronidase activity. The soluble form is secreted when expressed in mammalian cells and encodes a signal sequence, such as residues 1-35 of SEQ ID NO. 1, or a heterologous signal sequence cleaved by cells to achieve secretion. The soluble form is the form lacking the signal peptide when expressed in cells. Soluble hyaluronidases also include variants of the soluble PH20 polypeptide that exhibit hyaluronidase activity. Variants include those related to SEQ ID NO. 1. PH20 peptides with NO: 1: 36-465, 36-466, 36-467, 36-468, 36-469, 35-470, 36-471, 36-472, 36-474, 36-475, 36-476, 35-477, 36-478, 36-479, 36-480, 36-481, 36-482, 36-483, 35-484, 36-485, 36-486, 36-487 The polypeptides of any one of 36-488, 36-489, 36-490, 35-491, 36-492, 36-493, 36-494, 36-495, 36-496, 36-497, 35-498, 36-499, and 36-500 have at least 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher sequence identity. Amino acid variants include conserved and non-conserved insertions, deletions, or substitutions, and include modifications, alone or in combination, such as those detailed in U.S. Patent No. 11,041,149 and International PCT Publication No. WO 2013 / 102144. US Patent No. 11,041,149 and International PCT Publication No. WO 2013 / 102144 describe a systematic analysis and results identifying the effects of amino acid modifications at each residue in PH20, thereby providing a structure / function map of PH20; those skilled in the art can identify substituted residues and subsequent changes in properties and activities, such as those used to achieve increased enzyme activity, increased stability under denaturing conditions, and residues that are substituted or deleted that reduce or eliminate enzyme activity.

[0310] It should be understood that residues important or otherwise required for hyaluronidase activity (such as those described above or known to those skilled in the art) are generally unchanged and cannot be altered except for possible conserved amino acid substitutions. These include, for example, active site residues. For instance, amino acid residues 111, 113, and 176 of the human PH20 polypeptide or its soluble form (corresponding to residues in the mature PH20 polypeptide) are generally unchanged and do not change. Other residues that impart disulfide bonds necessary for glycosylation and proper folding may also remain unchanged.

[0311] Soluble human PH20 hyaluronidase is GPI-anchored and becomes soluble by removing all or part of the GPI anchor at the C-terminus. This truncation may remove all or only some of the GPI anchor attachment sequence. However, the resulting polypeptide is soluble. In cases where soluble hyaluronidase retains a portion of the GPI anchor attachment signal sequence, 1, 2, 3, 4, 5, 6, 7, or more amino acid residues in the GPI anchor attachment signal sequence may be retained, provided the polypeptide is soluble. Polypeptides containing one or more amino acids of the GPI anchor are referred to as extended soluble hyaluronidase. Those skilled in the art can determine whether a polypeptide is GPI-anchored using methods well known in the art. These methods include, but are not limited to, using known algorithms to predict the presence and location of the GPI anchor attachment signal sequence and ω-site, and performing solubility analysis before and after digestion with phosphatidylinositol-specific phospholipase C (PI-PLC) or D (PI-PLD).

[0312] Extended soluble hyaluronidases (terminating, for example, at residues 495, 496, 497, 498, 499, and 500, see SEQ ID NO: 1, such as those shown in SEQ ID NO: 9 (residues 1-495), SEQ ID NO: 10 (residues 1-496), SEQ ID NO: 11 (residues 1-497), SEQ ID NO: 12 (residues 1-498), SEQ ID NO: 13 (residues 1-499), and SEQ ID NO: 14 (residues 1-500)) can be produced by C-terminal truncation of any naturally occurring GPI-anchored hyaluronidase such that the resulting polypeptide is soluble and contains one or more amino acid residues from the GPI anchoring signal sequence (see, for example, U.S. Patent No. 8,927,249). These include hyaluronidases that are neutral in activity, soluble, contain amino acid substitutions, and have at least 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95% or higher sequence identity with any of SEQ ID NO: 9-14.

[0313] Typically, soluble human hyaluronidases, such as soluble human PH20, and variants of PH20 having, for example, at least 91%, 95%, or 98% sequence identity with it, including those lacking 1 to 5 N-terminal residues, are used in the compositions, combinations, and methods described herein. The hyaluronidases used in the schemes, combinations, compositions, and methods described herein can be recombinantly generated or purified or partially purified from natural sources (e.g., from testicular extracts). Methods for generating recombinant proteins, including recombinant hyaluronidases, are well known in the art.

[0314] Recombinant soluble forms of human PH20 have been produced and can be used in the compositions, combinations, and methods provided herein. For example, refer to SEQ ID NO: 1, which describes the sequence of the full-length precursor PH20, including the signal sequence (residues 1-35), and soluble forms including, but not limited to, the C-terminal truncated polypeptide of human PH20 shown in SEQ ID NO: 1, which has SEQ ID NO: 1 The polypeptide having C-terminal amino acid residues 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, or 500 of the amino acid sequence shown in NO:1, or exhibiting at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher sequence identity when compared with an unmodified sequence at soluble pH 20, is active at neutral pH, and is soluble (secreted into the culture medium when expressed in mammalian cells). The soluble form of human PH20 typically comprises amino acids 36-464 as shown in SEQ ID NO: 1, terminating at residues 465-500, and optionally includes a deletion of 1-3 amino acids at the N-terminus (i.e., lacking residues 36, 36-37, or 36-38 of SEQ ID NO: 1). For example, when expressed in mammalian cells, the 35-amino acid N-terminal signal sequence (residues 1-35 of SEQ ID NO: 1) is cleaved during processing, and a soluble form of the protein is secreted. Therefore, mature soluble polypeptides comprise amino acids 36 to 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, and up to and including 500 of SEQ ID NO: 1. Examples of soluble hyaluronidases are soluble human PH20 polypeptides of length 442, 443, 444, 445, 446, or 447 amino acids, such as those shown above, and their variants, which have, for example, at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity and retain hyaluronidase activity.The production of such soluble forms of recombinant human PH20 is described, for example, in U.S. Patent Nos. 7,767,429, 8,202,517, 8,431,380, 8,431,124, 8,450,470, 8,765,685, 8,772,246, 7,871,607, 7,846,431, 7,829,081, 8,105,586, 8,187,855, 8,257,699, 8,580,252, 9,677,061, and 9,677,062.

[0315] Typically, protein expression systems that promote proper N-glycosylation to ensure the retention of peptide activity are used to produce the soluble form of PH20, as glycosylation is important for the catalytic activity and stability of hyaluronidase. Such cells include, for example, Chinese hamster ovary (CHO) cells (e.g., DG44CHO cells).

[0316] Compositions recombinantly derived from mammalian cells (such as CHO cells) are referred to as rHuPH20. It refers to the composition produced by expressing a nucleic acid encoding residues 36-482 of SEQ ID NO: 1 in cells (such as CHO cells), typically linked to a native (residues 1-35 of SEQ ID NO: 1) or heterologous signal sequence. rHuPH20 is produced by expressing nucleic acid molecules (such as amino acids 1-482 (as shown in SEQ ID NO: 1) or 36-482) with a heterologous signal sequence. Post-translational processing removes the 35-amino acid signal sequence, producing a polypeptide or mixture of polypeptides, including those shown in SEQ ID NO: 2 (residues 36-482), SEQ ID NO: 3 (residues 36-477), SEQ ID NO: 4 (residues 36-478), SEQ ID NO: 5 (residues 36-479), SEQ ID NO: 6 (residues 36-480), and SEQ ID NO: 7 (residues 36-481). As produced in a culture medium, heterogeneity exists at the C-terminus, such that the product named rHuPH20 comprises a mixture of substances that may include any or more of SEQ ID NO: 3 and 44-49 in varying abundances. Typically, soluble hyaluronidase rHuPH20 is produced in cells that promote proper N-glycosylation to preserve activity (such as CHO cells (e.g., DG44CHO cells)). Human soluble PH20 hyaluronidase activity requires glycosylation. When recombinantly generated from a vector encoding residues 36-582, the most abundant substance is a 446-amino acid polypeptide corresponding to residues 36-481 of SEQ ID NO: 1. The specific distribution of the resulting polypeptide may depend on the specific production method. Exemplary methods for producing high levels of PH20 are detailed, for example, in U.S. Patent Nos. 8,187,855 and 8,343,487.

[0317] Glycosylation of hyaluronidase

[0318] Glycosylation (including N-linked and O-linked glycosylation) can be important for the catalytic activity and stability of some hyaluronidases, including soluble PH20 hyaluronidase. For some hyaluronidases, removal of N-linked glycosylation can lead to near-complete inactivation of hyaluronidase activity. For such hyaluronidases, the presence of N-linked glycans may be important for the production of active enzymes.

[0319] N-linked oligosaccharides are classified into several major types (oligomannoses, complexes, hybrids, and sulfateds), all of which have an amide-nitrogen-linked (Man)3-GlcNAc-GlcNAc-core via an Asn residue belonging to the -Asn-Xaa-Thr / Ser- sequence (where Xaa is not Pro). Glycosylation of thrombin C at the -Asn-Xaa-Cys- site has been reported. In some cases, hyaluronidases (such as PH20 hyaluronidase) may contain both N-glycosidic bonds and O-glycosidic bonds. For example, PH20 has both O-linked and N-linked oligosaccharides. Six potential N-linked glycosylation sites are present at N82, N166, N235, N254, N368, and N393 of human PH20, illustrated in SEQ ID NO: 1.

[0320] Variants of PH20

[0321] As mentioned above, variants of PH20 are known to those skilled in the art or can be readily prepared based on the techniques and knowledge available in the art. Variants include those with amino acid substitutions, insertions, and deletions. Variants of soluble PH20 peptides with altered properties, such as increased stability and / or activity, have been produced. U.S. Patent No. 9,447,401 and family members U.S. Patent Nos. 10,865,400, 11,041,149, and 11,066,656 describe and provide a structural / functional diagram of human PH20, detailing the role of amino acid substitutions at each residue in the catalytic domain of PH20. These patents provide approximately 7,000 examples in which the effects of substituting each amino acid with 15 other amino acids on activity and stability are identified and described. Based on these patents and earlier publications / patents, virtually all variants of soluble PH20 peptides known in the art are described. Those skilled in the art can readily prepare soluble hyaluronidases and their variants and know the properties of the resulting hyaluronidases.

[0322] Other variants are also known to those skilled in the art and can be used in the combinations, schemes, and methods described herein. For example, see International PCT Publications WO2020 / 022791 and WO2020 / 197230, which are incorporated by reference and describe modified PH20 peptides. These peptides include variants of PH20 peptides that typically span residues 38-468 and include substitutions, insertions, and deletions. Variants include, for example, changes to one or more amino acid residues S343E, I344N, M345T, M348K, K349E, L353A, L354I, N356E, and I361T (refer to SEQ ID NO: 1), as well as others including about 15 amino acid changes and truncation at the N-terminus and C-terminus. Variants containing such modifications and other modifications are shown in SEQ ID NO: 60-115 of International PCT Publication WO2020 / 022791. Examples of these peptides are the peptide of SEQ ID NO: 99, which, and reproduced herein, is SEQ ID NO: 15. International PCT Publication No. WO2021 / 150079 provides variant PH20 peptides, which are described as having increased stability relative to unmodified PH20 (such as those in rHuPH20). These variant peptides have been shown to possess PH20 activity and are described as having use in co-administration with other pharmaceutical agents.

[0323] In one embodiment, the variant of PH20 is a variant of human PH20 or rHuPH20 selected from any of SEQ ID NO: 16-47.

[0324] In one embodiment, the hyaluronidase is a human hyaluronidase. Exemplary human hyaluronidases include HYAL1, HYAL2, HYAL3, HYAL4, HYAL5 (also known as SPAM1 or PH20), and HYAL6 (also known as HYALP1). In one embodiment, the hyaluronidase is a recombinant hyaluronidase. In one embodiment, the hyaluronidase is a recombinant human hyaluronidase. In one embodiment, the hyaluronidase is a recombinant human hyaluronidase PH20 enzyme. Exemplary hyaluronidases that can be used in this disclosure can be found in the following patents and applications (which are incorporated herein by reference in their entirety): US2022 / 0289864 (Alteogen), US9,084,743 (Baxter), US9,993,529 (Halozyme), US8,795,654, US2009 / 0311237 (Gregorian patent). Frost), US9,284,543 (Halozyme), US10,265,410 (Halozyme), US10,137,104 (Halozyme), US2013 / 0022592, US 2019 / 0284263 (GregFrost), US11,0653,09, WO2017 / 185383, US11,041,149 (Halozyme), US2010 / 0003238 (Greg Frost), US8,343,487 (Halozyme), US10,301,376 (Baxalta), US2013 / 0344048, US2021 / 0363270 (Alteogen), US2021 / 0155913 (Alteogen), WO2021 / 150079 (Dassault Systems SolidWorks) and WO2022 / 031093 (Toshiba TEC Kabushiki Kaisha).

[0325] In one embodiment, the hyaluronidase has values ​​of about 150 U / mL to about 1,000 kU / mL, about 150 U / mL to about 900 kU / mL, about 150 U / mL to about 800 kU / mL, about 150 U / mL to about 700 kU / mL, about 150 U / mL to about 600 kU / mL, about 150 U / mL to about 500 kU / mL, about 150 U / mL to about 400 kU / mL, and about 150 U / mL to about 300 kU / mL. L, with activities of about 150 U / mL to about 200 kU / mL, about 500 U / mL to about 200 kU / mL, about 1 kU / mL to about 200 kU / mL, about 10 kU / mL to about 200 kU / mL, about 25 kU / mL to about 200 kU / mL, about 50 kU / mL to about 200 kU / mL, about 100 kU / mL to about 200 kU / mL, about 100 kU / mL to about 150 kU / mL, or about 120 kU / mL. In one embodiment, the hyaluronidase has an activity of about 10 kU / mL for a 5 mL formulation or about 5 kU / mL for a 10 mL formulation. In one embodiment, the hyaluronidase has a minimum activity of about 150 U / mL and a maximum activity of about 110,000 U / mL (110 kU / mL). In one embodiment, the hyaluronidase is a recombinant human hyaluronidase PH20 enzyme with an activity of about 120 kU / mL. In another embodiment, the hyaluronidase is a recombinant human hyaluronidase PH20 enzyme with a minimum activity of about 150 U / mL and a maximum activity of about 110,000 U / mL.

[0326] In one embodiment, the concentration of hyaluronidase in the formulation is about 10 U / mL to about 50,000 U / mL, about 10 U / mL to about 45,000 U / mL, about 10 U / mL to about 40,000 U / mL, about 10 U / mL to about 35,000 U / mL, about 10 U / mL to about 30,000 U / mL, about 10 U / mL to about 25,000 U / mL, about 10 U / mL to about 20,000 U / mL, about 10 U / mL to about 15,000 U / mL, about 10 U / mL to about 10,000 U / mL, or about 100 U / mL to about 9,000 U / mL. L, about 100 U / mL to about 8,000 U / mL, about 100 U / mL to about 7,000 U / mL, about 100 U / mL to about 6,000 U / mL, about 100 U / mL to about 5,000 U / mL, about 500 U / mL to about 5,000 U / mL, about 500 U / mL to about 4,000 U / mL, about 500 U / mL to about 3,000 U / mL, about 1,000 U / mL to about 3,000 U / mL, about 1,500 U / mL to about 3,000 U / mL, about 1,500 U / mL to about 2,500 U / mL, or about 2,000 U / mL. In one embodiment, the formulation comprises hyaluronidase at a concentration of about 1,500 U / mL to about 10,000 U / mL. In one embodiment, the formulation comprises about 1,500 U / mL to about 10,000 U / mL of recombinant human hyaluronidase PH20 enzyme. In one embodiment, the formulation comprises about 2,000 U / mL of recombinant human hyaluronidase PH20 enzyme. In one embodiment, the formulation comprises about 5,000 U / mL of recombinant human hyaluronidase PH20 enzyme. In another embodiment, the formulation comprises at least 4,000 U / mL of recombinant human hyaluronidase PH20 enzyme. In another embodiment, the formulation comprises at least 7,500 U / mL of recombinant human hyaluronidase PH20 enzyme. In yet another embodiment, the formulation comprises at least 10,000 U / mL of recombinant human hyaluronidase PH20 enzyme.

[0327] In one embodiment, the formulation comprises approximately 4,000 U / mL of recombinant human hyaluronidase PH20.

[0328] In one embodiment, the formulation comprises hyaluronidase, which allows for the injection of high-volume formulations into subjects in need at a high flow rate. In another embodiment, the formulation comprises a concentration and / or activity of hyaluronidase, which allows for the injection of high-volume formulations into subjects in need at a high flow rate.

[0329] In one embodiment, the formulation comprises one or more pharmaceutically acceptable additives, including but not limited to carriers, excipients, fillers, preservatives, stabilizers, and antioxidants. Pharmaceutically acceptable additives can be any pharmaceutically acceptable additive known to those skilled in the art for use in injectable formulations. In one embodiment, the formulation comprises histidine. In one embodiment, the formulation comprises sodium chloride. In one embodiment, the formulation comprises polysorbate. In one embodiment, the polysorbate comprises polysorbate 80. In one embodiment, the formulation comprises about 0.001% to about 5%, about 0.001% to about 4.5%, about 0.001% to about 4.0%, about 0.001% to about 3.5%, about 0.001% to about 3.0%, about 0.001% to about 2.5%, about 0.001% to about 2.0%, about 0.001% to about 1.5%, about 0.001% to about 1.0%, about 0.001% to about 0.5%, about 0.005% to about 0.5%, about 0.005% to about 0.1%, about 0.005% to about 0.05%, about 0.01% to about 0.05%, or about 0.02% of polysorbate 80. In one embodiment, the formulation comprises an antioxidant. In one embodiment, the antioxidant comprises methionine. In one embodiment, the formulation comprises an antioxidant at amounts of about 0.5 mM to about 50 mM, about 0.5 mM to about 45 mM, about 0.5 mM to about 40 mM, about 0.5 mM to about 35 mM, about 0.5 mM to about 30 mM, about 0.5 mM to about 25 mM, about 0.5 mM to about 20 mM, about 5 mM to about 20 mM, about 5 mM to about 15 mM, or about 10 mM. In one embodiment, the formulation comprises about 10 mM methionine. In one embodiment, the formulation comprises a carrier protein.

[0330] In one embodiment, the formulation has a pH of about 4.0 to about 8.0, about 4.2 to about 8.0, about 4.4 to about 7.8, about 4.6 to about 7.8, about 4.6 to about 7.6, about 4.8 to about 7.8, about 5.0 to about 7.8, about 5.2 to about 7.8, about 5.4 to about 7.6, about 5.6 to about 7.4, about 5.8 to about 7.2, about 6.0 to about 7.0, about 6.2 to about 6.8, about 6.4 to about 6.6, or about 6.5. In one embodiment, the formulation has a pH of about 4.6 to about 7.6. In one embodiment, the formulation has a pH of about 4.0 to about 8.0.

[0331] In one embodiment, the formulation comprises an active ingredient. The active ingredient can be any active ingredient that treats a disease or condition of the subject in need, provided that the active ingredient can be administered to the subject in need via injection. In one embodiment, the active ingredient is selected from small molecules, peptide fragments, biologics, nanoparticles, antibodies, antibody fragments, or small molecule antiviral agents.

[0332] Treatment

[0333] In one aspect, this disclosure provides a method of treating a disease or condition in a subject in need, the method comprising administering, via injection, a formulation comprising hyaluronidase and a therapeutically effective amount of an active ingredient to the subject. The formulation is described elsewhere herein. In one embodiment, the hyaluronidase is recombinant human hyaluronidase PH20. In one embodiment, the subject is a mammal. In one embodiment, the subject is a human. In one embodiment, the formulation is administered to the subject via subcutaneous injection. In one embodiment, the formulation is self-administered. In another embodiment, the formulation is administered to the subject by a healthcare professional. In yet another embodiment, the formulation is administered to the subject by a non-professional (such as a caregiver). In one embodiment, the formulation is administered using an auto-injector. In one embodiment, the formulation is administered using an HVAI. In one embodiment, the formulation is administered using an HVAI from a pre-filled syringe. In another embodiment, the formulation is administered manually using a manually triggered injection device. In another embodiment, the formulation is administered from an on-the-go device.

[0334] In one embodiment, the formulation is applied to the abdomen or thigh of the subject. In another embodiment, the formulation is applied subcutaneously to the abdomen or thigh of the subject.

[0335] In one embodiment, the amount of the disclosed formulation administered to the subject depends on the subject being treated, the severity of the condition or symptom, the rate of administration, the disposal of the compound, and / or the judgment of the prescribing physician. In one embodiment, the effective dose of the active ingredient in the disclosed formulation is in the range of about 0.001 mg / kg body weight / day to about 100 mg / kg body weight / day, such as about 1 mg / kg / day to about 35 mg / kg / day, in a single dose or divided doses. For a 70 kg human, this would amount to about 0.05 g / day to 7 g / day, such as about 0.05 g / day to about 2.5 g / day. In some cases, dose levels below the lower limit of the above range may be sufficient, while in other cases, larger doses may be used without causing any harmful side effects, for example by dividing such a larger dose into several smaller doses administered within a day.

[0336] In one embodiment, the disclosed formulation is administered to the subject in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times daily. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In one embodiment, the disclosed formulation is administered from about once daily to about six times daily. In one embodiment, administration of the disclosed formulation lasts for less than about seven days. In another embodiment, administration lasts for more than about six, ten, fourteen, twenty-eight days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

[0337] In one embodiment, the effective dose of the active ingredient in the disclosed formulation is in the range of about 1 mg / mL to about 500 mg / mL, about 10 mg / mL to about 450 mg / mL, about 20 mg / mL to about 400 mg / mL, about 30 mg / mL to about 350 mg / mL, about 50 mg / mL to about 300 mg / mL, about 75 mg / mL to about 250 mg / mL, about 100 mg / mL to about 200 mg / mL, or about 150 mg / mL.

[0338] In one embodiment, the formulation is administered using an HVAI fitted with a needle. In one embodiment, the needle is a 20-gauge needle, 21-gauge needle, 22-gauge needle, 23-gauge needle, 24-gauge needle, 25-gauge needle, 26-gauge needle, 27-gauge needle, 28-gauge needle, 29-gauge needle, 30-gauge needle, or 31-gauge needle. In one implementation, the needle is a 27-gauge standard wall needle × 1 / 2″, a 27-gauge standard wall needle × 5 / 8″, a 27-gauge standard wall needle × 3 / 4″, a 27-gauge standard wall needle × 1″, a 27-gauge thin wall needle × 1 / 2″, a 27-gauge thin wall needle × 5 / 8″, a 27-gauge thin wall needle × 3 / 4″, a 27-gauge thin wall needle × 1″, a 25-gauge standard wall needle × 1 / 2″, a 25-gauge standard wall needle × 5 / 8″, a 25-gauge standard wall needle × 3 / 4″, a 25-gauge thin wall needle × 1″, a 23-gauge standard wall needle × 1 / 2″, a 23-gauge standard wall needle × 5 / 8″, a 23-gauge standard wall needle × 3 / 4″, or a 23-gauge standard wall needle × 1″. In one embodiment, the needle is a 25 gauge thin-walled 1 / 2″ needle. In another embodiment, the needle is a 25 gauge thin-walled 5 / 8″ needle.

[0339] In one embodiment, a high-volume formulation is administered to the subject. In one embodiment, "high volume" means greater than 2.25 mL in a single administration. In one embodiment, 3 mL to 5 mL, 3 mL to 10 mL, 3 mL to 15 mL, 3 mL to 20 mL, 3 mL to 25 mL, 3 mL to 30 mL, 3 mL to 35 mL, 3 mL to 40 mL, 3 mL to 45 mL, 3 mL to 50 mL, 5 mL to 10 mL, 5 mL to 15 mL, 5 mL to 20 mL, 5 mL to 25 mL, 5 mL to 30 mL, 5 mL to 35 mL, 5 mL to 40 mL; 5 mL to 45 mL, 5 mL to 50 mL, 10 mL to 15 mL; 10 mL to 20 mL; 10 mL to 25 mL; 10 mL to 30 mL; 10 mL to 35 mL; 10 mL to 40 mL or 10 mL to 50 mL are administered to the subject in a single administration. In one embodiment, about 3 mL to about 5 mL, about 3 mL to about 10 mL, about 3 mL to about 15 mL, about 3 mL to about 20 mL, about 3 mL to about 25 mL, about 3 mL to about 30 mL, about 3 mL to about 35 mL, about 3 mL to about 40 mL, about 3 mL to about 45 mL, about 3 mL to about 50 mL, about 5 mL to about 10 mL, about 5 mL to about 15 mL, about 5 mL to about 20 mL, about 5 mL to about 25 mL, about 5 mL to about 30 mL, about 5 mL to about 35 mL, about 5 mL to about 40 mL; about 5 mL to about 45 mL, about 5 mL to about 50 mL, about 10 mL to about 15 mL; about 10 mL to about 20 mL; about 10 mL to about 25 mL; about 10 mL to about 30 mL; about 10 mL to about 35 mL; about 10 mL to about 40 mL or about 10 mL to about 50 mL are administered to the subject in a single administration. In one embodiment, at least about 3 mL, at least about 3.5 mL, at least about 4 mL, at least about 4.5 mL, at least about 5.5 mL, at least about 6 mL, at least about 6.5 mL, at least about 7 mL, at least about 7.5 mL, at least about 8 mL, at least about 8.5 mL, at least about 9 mL, at least about 9.5 mL, at least about 10 mL, at least about 10.5 mL, at least about 11 mL, at least about 11.5 mL, at least about 12 mL, at least about 12.5 mL, at least about 13 mL, at least about 13 0.5 mL, at least about 14 mL, at least about 14.5 mL, at least about 15 mL, at least about 15.5 mL, at least about 16 mL, at least about 16.5 mL, at least about 17 mL, at least about 17.5 mL, at least about 18 mL, at least about 18.5 mL, at least about 19 mL, at least about 19.5 mL, at least about 20 mL, at least about 25 mL, at least about 30 mL, at least about 35 mL, at least about 40 mL, at least about 45 mL, or at least about 50 mL may be administered to the subject in a single dose.In one implementation, at least 3 mL, at least 3.5 mL, at least 4 mL, at least 4.5 mL, at least 5.5 mL, at least 6 mL, at least 6.5 mL, at least 7 mL, at least 7.5 mL, at least 8 mL, at least 8.5 mL, at least 9 mL, at least 9.5 mL, at least 10 mL, at least 10.5 mL, at least 11 mL, at least 11.5 mL, at least 12 mL, at least 12.5 mL, at least 13 mL, at least 13.5 mL, at least 14 mL, at least 14.5 mL, at least 15 mL, at least 15.5 mL, at least 16 mL, at least 16.5 mL, at least 17 mL, at least 17.5 mL, at least 18 mL, at least 18.5 mL, at least 19 mL, at least 19.5 mL, at least 20 mL, at least 25 mL, at least 30 mL, at least 35 mL, at least 40 mL, at least 45 mL, or at least 50 mL are administered to the subject in a single administration.

[0340] In one embodiment, a formulation of more than about 2.25 mL, about 2.5 mL, about 3.0 mL, about 3.5 mL, about 4.0 mL, about 4.5 mL, about 5.0 mL, about 5.5 mL, about 6.0 mL, about 6.5 mL, about 7.0 mL, about 7.5 mL, about 8.0 mL, about 8.5 mL, about 9.5 mL, about 10 mL, about 12 mL, about 14 mL, about 16 mL, about 18 mL, or about 20 mL is administered to the subject in a single dose. In one embodiment, formulations of greater than about 2.5 mL, about 3.0 mL, about 3.5 mL, about 4.0 mL, about 4.5 mL, about 5.0 mL, about 5.5 mL, about 6.0 mL, about 6.5 mL, about 7.0 mL, about 7.5 mL, about 8.0 mL, about 8.5 mL, about 9.5 mL, about 10 mL, about 12 mL, about 14 mL, about 16 mL, about 18 mL, or about 20 mL are dispensed in about 10 seconds, about 12 seconds, about 16 seconds, about 18 seconds, or about 20 seconds. The drug is administered to the subject within approximately 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 120 seconds.

[0341] In one implementation, about 5 mL of the formulation may be administered to the subject within about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, or about 60 seconds.

[0342] In one implementation, about 10 mL of the formulation may be administered to the subject within about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, or about 60 seconds.

[0343] In one implementation, about 10.5 mL of the formulation may be administered to the subject within about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, or about 60 seconds.

[0344] In some embodiments, the rate at which a high volume of formulation can be administered to a subject depends on the gauge of the needle used to inject the formulation. In one embodiment, an autoinjector and a 23-gauge needle are used to administer the formulation to the subject. In one embodiment, approximately 10 mL of the formulation can be administered to the subject using an autoinjector and a 23-gauge needle in approximately 5 to 45 seconds, approximately 5 to 40 seconds, approximately 10 to 40 seconds, approximately 10 to 35 seconds, approximately 15 to 35 seconds, approximately 15 to 30 seconds, approximately 20 to 30 seconds, approximately 15 to 25 seconds, or approximately 20 seconds. In one embodiment, approximately 5.5 mL of the formulation can be administered to the subject using an autoinjector and a 23-gauge needle in approximately 5 to 45 seconds, approximately 5 to 40 seconds, approximately 10 to 40 seconds, approximately 10 to 35 seconds, approximately 15 to 35 seconds, approximately 15 to 30 seconds, approximately 15 to 25 seconds, or approximately 20 seconds. In one embodiment, about 5.5 mL of the formulation may be administered to the subject using an autoinjector and a 23-gauge needle over a period of about 15 to about 60 seconds, about 20 to about 60 seconds, about 25 to about 60 seconds, about 25 to about 55 seconds, about 30 to about 55 seconds, about 30 to about 50 seconds, about 35 to about 50 seconds, about 40 to about 50 seconds, or about 45 seconds. In another embodiment, the formulation may be administered to the subject using an autoinjector and a 25-gauge needle. In one embodiment, about 10 mL of the formulation may be administered to the subject using an autoinjector and a 25-gauge needle over a period of about 15 to about 60 seconds, about 20 to about 60 seconds, about 25 to about 60 seconds, about 25 to about 55 seconds, about 30 to about 55 seconds, about 30 to about 50 seconds, about 35 to about 50 seconds, about 40 to about 50 seconds, or about 45 seconds. In one embodiment, approximately 5.5 mL of the formulation is administered to the subject using an autoinjector and a 23-gauge needle within approximately 5 to 45 seconds, approximately 5 to 40 seconds, approximately 10 to 40 seconds, approximately 10 to 35 seconds, approximately 15 to 35 seconds, approximately 15 to 30 seconds, approximately 15 to 25 seconds, or approximately 20 seconds. In another embodiment, approximately 5.5 mL of the formulation is administered to the subject using an autoinjector and a 25-gauge needle within approximately 15 to 60 seconds, approximately 20 to 60 seconds, approximately 25 to 60 seconds, approximately 25 to 55 seconds, approximately 30 to 55 seconds, approximately 30 to 50 seconds, approximately 35 to 50 seconds, approximately 40 to 50 seconds, or approximately 45 seconds. In yet another embodiment, the formulation is administered to the subject using an autoinjector and a 27-gauge needle. In one embodiment, about 10 mL of the formulation can be administered to the subject using an autoinjector and a 27-gauge needle over a period of about 15 to about 60 seconds, about 20 to about 60 seconds, about 25 to about 60 seconds, about 25 to about 55 seconds, about 30 to about 55 seconds, about 30 to about 50 seconds, about 35 to about 50 seconds, about 40 to about 50 seconds, or about 45 seconds.In one embodiment, about 5.5 mL of the formulation can be administered to the subject using an autoinjector and a 27-gauge needle over a period of about 15 to about 60 seconds, about 20 to about 60 seconds, about 25 to about 60 seconds, about 25 to about 55 seconds, about 30 to about 55 seconds, about 30 to about 50 seconds, about 35 to about 50 seconds, about 40 to about 50 seconds, or about 45 seconds.

[0345] In one embodiment, using a 23-gauge needle with an HVAI and the disclosed formulation provides an injection time that is approximately 40%, 42%, 44%, 46%, 48%, 50%, 52%, 54%, 56%, 58%, or 60% faster than using a 25-gauge needle with an HVAI.

[0346] In one embodiment, the device has a variable delivery rate, which can deliver the formulation faster at the start of injection and slower at the end of injection. In another embodiment, the device has a variable delivery rate, which delivers the formulation slower at the start of injection and faster at the end of injection.

[0347] In one embodiment, the viscosity and volume of the disclosed formulation affect the time required to inject the formulation into the subject. However, the full volume of formulation can be delivered from the HVAI at a rate of approximately 0.08 mL / s to 1.0 mL / s. For example, this would provide a target delivery rate range of 10 to 120 seconds for a 10 mL dose volume. The HVAI can deliver 10 mL of formulation at a rate of 0.33 mL / s. In one embodiment, the HVAI delivers the full deliverable volume of formulation at the following rates: 0.5 mL / 10 sec, 0.75 mL / 10 sec, 1 mL / 10 sec, 1.25 mL / 10 sec, 1.5 mL / 10 sec, 1.75 mL / 10 sec, 2 mL / 10 sec, 2.25 mL / 10 sec, 2.5 mL / 10 sec, 2.75 mL / 10 sec, 3 mL / 10 sec, 3.25 mL / 10 sec, 3.5 mL / 10 sec, 3.75 mL / 10 sec, 4 mL / 10 sec, 4.25 mL / 10 sec, 4.5 mL / 10 sec, 4.75 mL / 10 sec, or about 5 mL / 10 sec. In one embodiment, the HVAI delivers the full deliverable volume of formulation at the following rates: 2 mL / 30 sec, 2.5 mL / 30 sec, 3 mL / 30 sec, 3.5 mL / 30 sec, 4 mL / 30 sec, 4.5 mL / 30 sec, 5 mL / 30 sec, 5.5 mL / 30 sec, 6 mL / 30 sec, 6.5 mL / 30 sec, 7 mL / 30 sec, 7.5 mL / 30 sec, 8 mL / 30 sec, 8.5 mL / 30 sec, 9 mL / 30 sec, 9.5 mL / 30 sec, 10 mL / 30 sec, or 10.5 mL / 30 sec. In one embodiment, the entire deliverable volume of the formulation is delivered at the following rates: 4 mL / min, 5 mL / min, 6 mL / min, 7 mL / min, 8 mL / min, 9 mL / min, 10 mL / min, 11 mL / min, 12 mL / min, 13 mL / min, 14 mL / min, 15 mL / min, 16 mL / min, 17 mL / min, 18 mL / min, 19 mL / min, 20 mL / min, and 21 mL / min.

[0348] In one embodiment, the disclosed formulation operates at flow rates of approximately 0.05 mL / s, approximately 0.06 mL / s, approximately 0.07 mL / s, approximately 0.08 mL / s, approximately 0.09 mL / s, approximately 0.10 mL / s, approximately 0.11 mL / s, approximately 0.12 mL / s, approximately 0.13 mL / s, approximately 0.14 mL / s, approximately 0.15 mL / s, approximately 0.16 mL / s, approximately 0.17 mL / s, approximately 0.18 mL / s, approximately 0.19 mL / s, approximately 0.20 mL / s, approximately 0.21 mL / s, approximately 0.22 mL / s, approximately 0.23 mL / s, approximately 0.24 mL / s, approximately 0.25 mL / s, approximately 0.26 mL / s, and approximately 0.27 mL / s. Approximately 0.28 mL / s, approximately 0.29 mL / s, approximately 0.30 mL / s, approximately 0.31 mL / s, approximately 0.32 mL / s, approximately 0.33 mL / s, approximately 0.34 mL / s, approximately 0.35 mL / s, approximately 0.36 mL / s, approximately 0.37 mL / s, approximately 0.38 mL / s, approximately 0.39 mL / s, approximately 0.4 mL / s, approximately 0.41 mL / s, approximately 0.42 mL / s, approximately 0.43 mL / s, approximately 0.44 mL / s, approximately 0.45 mL / s, approximately 0.46 mL / s, approximately 0.47 mL / s, approximately 0.48 mL / s, approximately 0.49 mL / s, approximately 0.50 mL / s, approximately 0.51 mL / s, approximately 0.52 mL / s L / s, approximately 0.53 mL / s, approximately 0.54 mL / s, approximately 0.55 mL / s, approximately 0.56 mL / s, approximately 0.57 mL / s, approximately 0.58 mL / s, approximately 0.59 mL / s, approximately 0.60 mL / s, approximately 0.61 mL / s, approximately 0.62 mL / s, approximately 0.63 mL / s, approximately 0.64 mL / s, approximately 0.65 mL / s, approximately 0.66 mL / s, approximately 0.67 mL / s, 0.68 mL / s, approximately 0.69 mL / s, approximately 0.70 mL / s, approximately 0.71 mL / s, approximately 0.72 mL / s, approximately 0.73 mL / s, approximately 0.74 mL / s, approximately 0.75 mL / s, approximately 0.76 mL / s, approximately 0 Approximately 0.77 mL / s, 0.78 mL / s, 0.79 mL / s, 0.80 mL / s, 0.81 mL / s, 0.82 mL / s, 0.83 mL / s, 0.84 mL / s, 0.85 mL / s, 0.86 mL / s, 0.87 mL / s, 0.88 mL / s, 0.89 mL / s, 0.90 mL / s, 0.91 mL / s, 0.92 mL / s, 0.93 mL / s, 0.94 mL / s, 0.95 mL / s, 0.96 mL / s, 0.97 mL / s, 0.98 mL / s, 0.99 mL / s, or 1.0 mL / s are administered to the subject.

[0349] In one embodiment, the disclosed formulation uses a pre-filled syringe equipped with a needle of specification 20 to 33 at a rate of approximately 0.05 mL / s, approximately 0.06 mL / s, approximately 0.07 mL / s, approximately 0.08 mL / s, approximately 0.09 mL / s, approximately 0.10 mL / s, approximately 0.11 mL / s, approximately 0.12 mL / s, approximately 0.13 mL / s, approximately 0.14 mL / s, approximately 0.15 mL / s, approximately 0.16 mL / s, approximately 0.17 mL / s, approximately 0.18 mL / s, approximately 0.19 mL / s, approximately 0.20 mL / s, approximately 0.21 mL / s, approximately 0.22 mL / s, approximately 0.23 mL / s, approximately 0.24 mL / s, and approximately 0.25 mL / s. Approximately 0.26 mL / s, approximately 0.27 mL / s, approximately 0.28 mL / s, approximately 0.29 mL / s, approximately 0.30 mL / s, approximately 0.31 mL / s, approximately 0.32 mL / s, approximately 0.33 mL / s, approximately 0.34 mL / s, approximately 0.35 mL / s, approximately 0.36 mL / s, approximately 0.37 mL / s, approximately 0.38 mL / s, approximately 0.39 mL / s, approximately 0.4 mL / s, approximately 0.41 mL / s, approximately 0.42 mL / s, approximately 0.43 mL / s, approximately 0.44 mL / s, approximately 0.45 mL / s, approximately 0.46 mL / s, approximately 0.47 mL / s, approximately 0.48 mL / s, approximately 0.49 mL / s, approximately 0.50 mL / s 0.51 mL / s, 0.52 mL / s, 0.53 mL / s, 0.54 mL / s, 0.55 mL / s, 0.56 mL / s, 0.57 mL / s, 0.58 mL / s, 0.59 mL / s, 0.60 mL / s, 0.61 mL / s, 0.62 mL / s, 0.63 mL / s, 0.64 mL / s, 0.65 mL / s, 0.66 mL / s, 0.67 mL / s, 0.68 mL / s, 0.69 mL / s, 0.70 mL / s, 0.71 mL / s, 0.72 mL / s, 0.73 mL / s, 0.74 mL / s, 0.75 m L / s, approximately 0.76 mL / s, approximately 0.77 mL / s, approximately 0.78 mL / s, approximately 0.79 mL / s, approximately 0.80 mL / s, approximately 0.81 mL / s, approximately 0.82 mL / s, approximately 0.83 mL / s, approximately 0.84 mL / s, approximately 0.85 mL / s, approximately 0.86 mL / s, approximately 0.87 mL / s, approximately 0.88 mL / s, approximately 0.89 mL / s, approximately 0.90 mL / s, approximately 0.91 mL / s, approximately 0.92 mL / s, approximately 0.93 mL / s, approximately 0.94 mL / s, approximately 0.95 mL / s, approximately 0.96 mL / s, approximately 0.97 mL / s, approximately 0.98 mL / s, approximately 0.99 mL / s, or approximately 1.The medication was administered to the subject at a rate of 0 mL / s.

[0350] In one embodiment, the disclosed formulation is dispensed from the high-volume autoinjector disclosed herein at rates of approximately 0.05 mL / s, approximately 0.06 mL / s, approximately 0.07 mL / s, approximately 0.08 mL / s, approximately 0.09 mL / s, approximately 0.10 mL / s, approximately 0.11 mL / s, approximately 0.12 mL / s, approximately 0.13 mL / s, approximately 0.14 mL / s, approximately 0.15 mL / s, approximately 0.16 mL / s, approximately 0.17 mL / s, approximately 0.18 mL / s, approximately 0.19 mL / s, approximately 0.20 mL / s, approximately 0.21 mL / s, approximately 0.22 mL / s, approximately 0.23 mL / s, approximately 0.24 mL / s, approximately 0.25 mL / s, and approximately 0.26 mL / s. Approximately 0.27 mL / s, approximately 0.28 mL / s, approximately 0.29 mL / s, approximately 0.30 mL / s, approximately 0.31 mL / s, approximately 0.32 mL / s, approximately 0.33 mL / s, approximately 0.34 mL / s, approximately 0.35 mL / s, approximately 0.36 mL / s, approximately 0.37 mL / s, approximately 0.38 mL / s, approximately 0.39 mL / s, approximately 0.4 mL / s, approximately 0.41 mL / s, approximately 0.42 mL / s, approximately 0.43 mL / s, approximately 0.44 mL / s, approximately 0.45 mL / s, approximately 0.46 mL / s, approximately 0.47 mL / s, approximately 0.48 mL / s, approximately 0.49 mL / s, approximately 0.50 mL / s, approximately 0.51 mL / s Approximately 0.52 mL / s, approximately 0.53 mL / s, approximately 0.54 mL / s, approximately 0.55 mL / s, approximately 0.56 mL / s, approximately 0.57 mL / s, approximately 0.58 mL / s, approximately 0.59 mL / s, approximately 0.60 mL / s, approximately 0.61 mL / s, approximately 0.62 mL / s, approximately 0.63 mL / s, approximately 0.64 mL / s, approximately 0.65 mL / s, approximately 0.66 mL / s, approximately 0.67 mL / s, 0.68 mL / s, approximately 0.69 mL / s, approximately 0.70 mL / s, approximately 0.71 mL / s, approximately 0.72 mL / s, approximately 0.73 mL / s, approximately 0.74 mL / s, approximately 0.75 mL / s, approximately 0.76 mL / s The solution is administered to the subject at rates of approximately 0.77 mL / s, approximately 0.78 mL / s, approximately 0.79 mL / s, approximately 0.80 mL / s, approximately 0.81 mL / s, approximately 0.82 mL / s, approximately 0.83 mL / s, approximately 0.84 mL / s, approximately 0.85 mL / s, approximately 0.86 mL / s, approximately 0.87 mL / s, approximately 0.88 mL / s, approximately 0.89 mL / s, approximately 0.90 mL / s, approximately 0.91 mL / s, approximately 0.92 mL / s, approximately 0.93 mL / s, approximately 0.94 mL / s, approximately 0.95 mL / s, approximately 0.96 mL / s, approximately 0.97 mL / s, approximately 0.98 mL / s, approximately 0.99 mL / s, or approximately 1.0 mL / s.

[0351] In one embodiment, the disclosed formulation is contained in a pre-filled syringe equipped with a needle of specification 20 to 33, wherein the pre-filled syringe is contained in a high-volume autoinjector disclosed herein, and the formulation is delivered at a rate of approximately 0.05 mL / s, approximately 0.06 mL / s, approximately 0.07 mL / s, approximately 0.08 mL / s, approximately 0.09 mL / s, approximately 0.10 mL / s, approximately 0.11 mL / s, approximately 0.12 mL / s, approximately 0.13 mL / s, approximately 0.14 mL / s, approximately 0.15 mL / s, approximately 0.16 mL / s, approximately 0.17 mL / s, approximately 0.18 mL / s, approximately 0.19 mL / s, approximately 0.20 mL / s, approximately 0.21 mL / s, and approximately 0.22 mL / s. Approximately 0.23 mL / s, approximately 0.24 mL / s, approximately 0.25 mL / s, approximately 0.26 mL / s, approximately 0.27 mL / s, approximately 0.28 mL / s, approximately 0.29 mL / s, approximately 0.30 mL / s, approximately 0.31 mL / s, approximately 0.32 mL / s, approximately 0.33 mL / s, approximately 0.34 mL / s, approximately 0.35 mL / s, approximately 0.36 mL / s, approximately 0.37 mL / s, approximately 0.38 mL / s, approximately 0.39 mL / s, approximately 0.4 mL / s, approximately 0.41 mL / s, approximately 0.42 mL / s, approximately 0.43 mL / s, approximately 0.44 mL / s, approximately 0.45 mL / s, approximately 0.46 mL / s, approximately 0.47 mL / s, approximately... 0.48 mL / s, approximately 0.49 mL / s, approximately 0.50 mL / s, approximately 0.51 mL / s, approximately 0.52 mL / s, approximately 0.53 mL / s, approximately 0.54 mL / s, approximately 0.55 mL / s, approximately 0.56 mL / s, approximately 0.57 mL / s, approximately 0.58 mL / s, approximately 0.59 mL / s, approximately 0.60 mL / s, approximately 0.61 mL / s, approximately 0.62 mL / s, approximately 0.63 mL / s, approximately 0.64 mL / s, approximately 0.65 mL / s, approximately 0.66 mL / s, approximately 0.67 mL / s, 0.68 mL / s, approximately 0.69 mL / s, approximately 0.70 mL / s, approximately 0.71 mL / s, approximately 0.72 mL / s, approximately 0 0.73 mL / s, approximately 0.74 mL / s, approximately 0.75 mL / s, approximately 0.76 mL / s, approximately 0.77 mL / s, approximately 0.78 mL / s, approximately 0.79 mL / s, approximately 0.80 mL / s, approximately 0.81 mL / s, approximately 0.82 mL / s, approximately 0.83 mL / s, approximately 0.84 mL / s, approximately 0.85 mL / s, approximately 0.86 mL / s, approximately 0.87 mL / s, approximately 0.88 mL / s, approximately 0.89 mL / s, approximately 0.90 mL / s, approximately 0.91 mL / s, approximately 0.92 mL / s, approximately 0.93 mL / s, approximately 0.94 mL / s, approximately 0.95 mL / s, approximately 0.96 mL / s, approximately 0.97 mL / s, approximately 0.The medication was administered to the subject at a rate of 98 mL / s, approximately 0.99 mL / s, or approximately 1.0 mL / s.

[0352] In one embodiment, about 3 mL to about 50 mL of the formulation is administered to the subject subcutaneously at a rate of about 0.10 mL / s to about 1.0 mL / s. In one embodiment, about 3 mL to about 15 mL of the formulation is administered to the subject subcutaneously at a rate of about 0.10 mL / s to about 1.0 mL / s. In one embodiment, the formulation is administered subcutaneously to the subject from a pre-filled syringe. In one embodiment, the pre-filled syringe includes a needle of about 20 to about 31 gauge. In one embodiment, the pre-filled syringe includes a needle of about 23, about 25, or about 27 gauge. In one embodiment, the formulation is administered to the subject from the pre-filled syringe using an HVAI described elsewhere herein.

[0353] In one embodiment, about 5 mL of the formulation is administered to the subject at a rate of about 0.14 mL / s to about 0.21 mL / s. In one embodiment, about 5 mL of the formulation is administered to the subject using an HVAI from a pre-filled syringe at a rate of about 0.14 mL / s to about 0.21 mL / s. In one embodiment, about 5 mL of the formulation is administered to the subject at a rate of about 0.28 mL / s to about 0.42 mL / s. In one embodiment, about 5 mL of the formulation is administered to the subject using an HVAI from a pre-filled syringe at a rate of about 0.28 mL / s to about 0.42 mL / s. In one embodiment, about 10 mL of the formulation is administered to the subject at a rate of about 0.32 mL / s to about 0.42 mL / s. In one embodiment, about 10 mL of the formulation is administered to the subject using an HVAI from a pre-filled syringe at a rate of about 0.32 mL / s to about 0.42 mL / s. In one embodiment, about 10.5 mL of the formulation is administered to the subject at a rate of about 0.40 mL / s to about 1.0 mL / s. In one embodiment, approximately 10.5 mL of the formulation is administered to the subject using an HVAI from a pre-filled syringe at a rate of approximately 0.40 mL / s to approximately 1.0 mL / s. In another embodiment, approximately 10.5 mL of the formulation is administered to the subject at a rate of at least 0.7 mL / s. In yet another embodiment, approximately 10.5 mL of the formulation is administered to the subject using an HVAI from a pre-filled syringe at a rate of at least 0.7 mL / s.

[0354] In one embodiment, about 5 mL, about 5.5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 10.5 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, or about 15 mL of the disclosed formulation can be administered to a subject using a needle of gauge 20 to 31 in 15 seconds or less. In one embodiment, about 5 mL, about 5.5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 10.5 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, or about 15 mL of the disclosed formulation can be administered to a subject using a gauge 27 needle in 15 seconds or less. In one embodiment, about 10.5 mL of the disclosed formulation can be administered to a subject using a gauge 27 needle in 15 seconds or less. In one embodiment, the needle is connected to a syringe pre-filled with the disclosed formulation. In one embodiment, the pre-filled syringe is included in an auto-injector. In one embodiment, the pre-filled syringe is included in the HVAI described elsewhere herein.

[0355] In one embodiment, about 3 mL to about 50 mL of the formulation disclosed herein is administered to the subject using an HVAI from a prefilled syringe with an initial delivery force of about 1 lbf to about 200 lbf, about 1 lbf to about 190 lbf, about 1 lbf to about 180 lbf, about 1 lbf to about 170 lbf, about 1 lbf to about 160 lbf, about 1 lbf to about 150 lbf, about 1 lbf to about 140 lbf, about 1 lbf to about 130 lbf, about 1 lbf to about 120 lbf, about 1 lbf to about 110 lbf, about 1 lbf to about 100 lbf, about 1 lbf to about 100 lbf, about 1 lbf to about 90 lbf, about 1 lbf to about 80 lbf, about 1 lbf to about 70 lbf, about 1 lbf to about 60 lbf, about 1 lbf to about 50 lbf, about 1 lbf to about 40 lbf, about 1 lbf to about 30 lbf, or about 25 lbf. In one embodiment, approximately 3 mL to approximately 50 mL of the formulation disclosed herein is dispensed from a pre-filled syringe using an HVAI at doses of approximately 1 lbf, approximately 2 lbf, approximately 3 lbf, approximately 4 lbf, 5 lbf, approximately 6 lbf, approximately 7 lbf, approximately 8 lbf, approximately 9 lbf, approximately 10 lbf, approximately 11 lbf, approximately 12 lbf, approximately 13 lbf, approximately 14 lbf, approximately 15 lbf, approximately 16 lbf, approximately 17 lbf, approximately 18 lbf, approximately 19 lbf, and approximately 20 lbf. Approximately 21 lbf, approximately 22 lbf, approximately 23 lbf, approximately 24 lbf, approximately 25 lbf, approximately 26 lbf, approximately 27 lbf, approximately 28 lbf, approximately 29 lbf, approximately 30 lbf, approximately 31 lbf, approximately 32 lbf, approximately 33 lbf, approximately 34 lbf, approximately 35 lbf, approximately 36 lbf, approximately 37 lbf, approximately 38 lbf, approximately 39 lbf, approximately 40 lbf, approximately 41 lbf, approximately 42 lbf, approximately 43 lbf, approximately 44 lbf, approximately 4 5 lbf, approximately 46 lbf, approximately 47 lbf, approximately 48 lbf, approximately 49 lbf, approximately 50 lbf, approximately 51 lbf, approximately 52 lbf, approximately 53 lbf, approximately 54 lbf, approximately 55 lbf, approximately 56 lbf, approximately 57 lbf, approximately 58 lbf, approximately 59 lbf, approximately 60 lbf, approximately 61 lbf, approximately 62 lbf, approximately 63 lbf, approximately 64 lbf, approximately 65 lbf, approximately 66 lbf, approximately 67 lbf, approximately 68 lbf, approximately 69 lbf bf, approximately 70 lbf, approximately 71 lbf, approximately 72 lbf, approximately 73 lbf, approximately 74 lbf, approximately 75 lbf, approximately 76 lbf, approximately 77 lbf, approximately 78 lbf, approximately 79 lbf, approximately 80 lbf, approximately 81 lbf, approximately 82 lbf, approximately 83 lbf, approximately 84 lbf, approximately 85 lbf, approximately 86 lbf, approximately 87 lbf, approximately 88 lbf, approximately 89 lbf, approximately 90 lbf, approximately 91 lbf, approximately 92 lbf, approximately 93 lbf,Approximately 94 lbf, approximately 95 lbf, approximately 96 lbf, approximately 97 lbf, approximately 98 lbf, approximately 99 lbf, approximately 100 lbf, approximately 101 lbf, approximately 102 lbf, approximately 103 lbf, approximately 104 lbf, approximately 105 lbf, approximately 106 lbf, approximately 107 lbf, approximately 108 lbf, approximately 109 lbf, approximately 110 lbf, approximately 111 lbf, approximately 112 lbf, approximately 113 lbf, approximately 114 lbf, approximately 115 lbf, approximately 116 lbf, approximately 117 lbf, approximately 118 lbf, approximately 119 lbf, approximately 120 lbf, approximately 121 lbf bf, approximately 122 lbf, approximately 123 lbf, approximately 124 lbf, approximately 125 lbf, approximately 126 lbf, approximately 127 lbf, approximately 128 lbf, approximately 129 lbf, approximately 130 lbf, approximately 131 lbf, approximately 132 lbf, approximately 133 lbf, approximately 134 lbf, approximately 135 lbf, approximately 136 lbf, approximately 137 lbf, approximately 138 lbf, approximately 139 lbf, approximately 140 lbf, approximately 141 lbf, approximately 142 lbf, approximately 143 lbf, approximately 144 lbf, approximately 145 lbf, approximately 146 lbf, approximately 147 lbf, approximately 148 lbf bf, approximately 149 lbf, approximately 150 lbf, approximately 151 lbf, approximately 152 lbf, approximately 153 lbf, approximately 154 lbf, approximately 155 lbf, approximately 156 lbf, approximately 157 lbf, approximately 158 lbf, approximately 159 lbf, approximately 160 lbf, approximately 161 lbf, approximately 162 lbf, approximately 163 lbf, approximately 164 lbf, approximately 165 lbf, approximately 166 lbf, approximately 167 lbf, approximately 168 lbf, approximately 169 lbf, approximately 170 lbf, approximately 171 lbf, approximately 172 lbf, approximately 173 lbf, approximately 174 lbf, approximately 175 An initial delivery force of approximately 176 lbf, 177 lbf, 178 lbf, 179 lbf, 180 lbf, 181 lbf, 182 lbf, 183 lbf, 184 lbf, 185 lbf, 186 lbf, 187 lbf, 188 lbf, 189 lbf, 190 lbf, 191 lbf, 192 lbf, 193 lbf, 194 lbf, 195 lbf, 196 lbf, 197 lbf, 198 lbf, 199 lbf, or 200 lbf was applied to the subject.

[0356] In one embodiment, the initial delivery force refers to the initial delivery force applied to the subject's tissue when administering the formulation from a pre-filled syringe using an HVAI. In one embodiment, the initial delivery force refers to the initial delivery force applied by the syringe stopper of the pre-filled syringe within the HVAI when the disclosed formulation is delivered to the subject. In one embodiment, the initial delivery force refers to the initial delivery force applied to the formulation when administering the formulation from a pre-filled syringe using an HVAI. In one embodiment, the initial delivery force refers to the initial delivery force applied to the pre-filled syringe when administering the formulation from a pre-filled syringe using an HVAI. In one embodiment, the initial delivery force refers to the initial delivery force generated by the HVAI device when administering the formulation from a pre-filled syringe using an HVAI.

[0357] In one embodiment, about 3 mL to about 50 mL of the formulation disclosed herein is dispensed from a pre-filled syringe using an HVAI at rates of about 1 lbf to about 200 lbf, about 1 lbf to about 190 lbf, about 1 lbf to about 180 lbf, about 1 lbf to about 170 lbf, about 1 lbf to about 160 lbf, about 1 lbf to about 150 lbf, about 1 lbf to about 140 lbf, about 1 lbf to about 130 lbf, about 1 lbf to about 120 lbf, about... The final delivery force of 1 lbf to about 110 lbf, 1 lbf to about 100 lbf, 1 lbf to about 100 lbf, about 1 lbf to about 90 lbf, about 1 lbf to about 80 lbf, about 1 lbf to about 70 lbf, about 1 lbf to about 60 lbf, about 1 lbf to about 50 lbf, about 1 lbf to about 40 lbf, about 1 lbf to about 30 lbf, about 5 lbf to about 30 lbf, or about 5 lbf to about 20 lbf is applied to the subject. In one embodiment, approximately 3 mL to approximately 50 mL of the formulation disclosed herein is dispensed from a pre-filled syringe using an HVAI at doses of approximately 1 lbf, approximately 2 lbf, approximately 3 lbf, approximately 4 lbf, 5 lbf, approximately 6 lbf, approximately 7 lbf, approximately 8 lbf, approximately 9 lbf, approximately 10 lbf, approximately 11 lbf, approximately 12 lbf, approximately 13 lbf, approximately 14 lbf, approximately 15 lbf, approximately 16 lbf, approximately 17 lbf, approximately 18 lbf, approximately 19 lbf, approximately... 20 lbf, approximately 21 lbf, approximately 22 lbf, approximately 23 lbf, approximately 24 lbf, approximately 25 lbf, approximately 26 lbf, approximately 27 lbf, approximately 28 lbf, approximately 29 lbf, approximately 30 lbf, approximately 31 lbf, approximately 32 lbf, approximately 33 lbf, approximately 34 lbf, approximately 35 lbf, approximately 36 lbf, approximately 37 lbf, approximately 38 lbf, approximately 39 lbf, approximately 40 lbf, approximately 41 lbf, approximately 42 lbf, approximately 43 lbf f, approximately 44 lbf, approximately 45 lbf, approximately 46 lbf, approximately 47 lbf, approximately 48 lbf, approximately 49 lbf, approximately 50 lbf, approximately 51 lbf, approximately 52 lbf, approximately 53 lbf, approximately 54 lbf, approximately 55 lbf, approximately 56 lbf, approximately 57 lbf, approximately 58 lbf, approximately 59 lbf, approximately 60 lbf, approximately 61 lbf, approximately 62 lbf, approximately 63 lbf, approximately 64 lbf, approximately 65 lbf, approximately 66 lbf, approximately 6 7 lbf, approximately 68 lbf, approximately 69 lbf, approximately 70 lbf, approximately 71 lbf, approximately 72 lbf, approximately 73 lbf, approximately 74 lbf, approximately 75 lbf, approximately 76 lbf, approximately 77 lbf, approximately 78 lbf, approximately 79 lbf, approximately 80 lbf, approximately 81 lbf, approximately 82 lbf, approximately 83 lbf, approximately 84 lbf, approximately 85 lbf, approximately 86 lbf, approximately 87 lbf, approximately 88 lbf, approximately 89 lbf, approximately 90 lbfApproximately 91 lbf, approximately 92 lbf, approximately 93 lbf, approximately 94 lbf, approximately 95 lbf, approximately 96 lbf, approximately 97 lbf, approximately 98 lbf, approximately 99 lbf, approximately 100 lbf, approximately 101 lbf, approximately 102 lbf, approximately 103 lbf, approximately 104 lbf, approximately 105 lbf, approximately 106 lbf, approximately 107 lbf, approximately 108 lbf, approximately 109 lbf, approximately 110 lbf, approximately 111 lbf, approximately 112 lbf, approximately 113 lbf, approximately 114 lbf, approximately 115 lbf, approximately 116 lbf, approximately 117 lbf, approximately 118 lbf, approximately 119 lbf bf, approximately 120 lbf, approximately 121 lbf, approximately 122 lbf, approximately 123 lbf, approximately 124 lbf, approximately 125 lbf, approximately 126 lbf, approximately 127 lbf, approximately 128 lbf, approximately 129 lbf, approximately 130 lbf, approximately 131 lbf, approximately 132 lbf, approximately 133 lbf, approximately 134 lbf, approximately 135 lbf, approximately 136 lbf, approximately 137 lbf, approximately 138 lbf, approximately 139 lbf, approximately 140 lbf, approximately 141 lbf, approximately 142 lbf, approximately 143 lbf, approximately 144 lbf, approximately 145 lbf, approximately 146 lbf, approximately 1 47 lbf, approximately 148 lbf, approximately 149 lbf, approximately 150 lbf, approximately 151 lbf, approximately 152 lbf, approximately 153 lbf, approximately 154 lbf, approximately 155 lbf, approximately 156 lbf, approximately 157 lbf, approximately 158 lbf, approximately 159 lbf, approximately 160 lbf, approximately 161 lbf, approximately 162 lbf, approximately 163 lbf, approximately 164 lbf, approximately 165 lbf, approximately 166 lbf, approximately 167 lbf, approximately 168 lbf, approximately 169 lbf, approximately 170 lbf, approximately 171 lbf, approximately 172 lbf, approximately 173 lbf, approximately 174 lbf A final delivery force of approximately 175 lbf, 176 lbf, 177 lbf, 178 lbf, 179 lbf, 180 lbf, 181 lbf, 182 lbf, 183 lbf, 184 lbf, 185 lbf, 186 lbf, 187 lbf, 188 lbf, 189 lbf, 190 lbf, 191 lbf, 192 lbf, 193 lbf, 194 lbf, 195 lbf, 196 lbf, 197 lbf, 198 lbf, 199 lbf, or 200 lbf is applied to the subject.

[0358] In one embodiment, the final delivery force refers to the final delivery force exerted on the subject's tissue when administering the formulation from a pre-filled syringe using an HVAI. In one embodiment, the final delivery force refers to the final delivery force exerted by the syringe stopper of the pre-filled syringe within the HVAI when the disclosed formulation is delivered to the subject. In one embodiment, the final delivery force refers to the final delivery force exerted on the formulation when administering the formulation from a pre-filled syringe using an HVAI. In one embodiment, the final delivery force refers to the final delivery force exerted on the pre-filled syringe when administering the formulation from a pre-filled syringe using an HVAI. In one embodiment, the final delivery force refers to the final delivery force generated by the HVAI device when administering the formulation from a pre-filled syringe using an HVAI.

[0359] In one embodiment, about 3 mL to about 50 mL of the formulation disclosed herein is administered to the subject using an HVAI from a prefilled syringe at an initial pressure of about 10 psi to about 500 psi, about 10 psi to about 475 psi, about 10 psi to about 450 psi, about 10 psi to about 400 psi, about 10 psi to about 375 psi, about 10 psi to about 350 psi, about 10 psi to about 325 psi, about 10 psi to about 300 psi, about 20 psi to about 300 psi, about 20 psi to about 275 psi, about 30 psi to about 275 psi, about 30 psi to about 250 psi, about 40 psi to about 250 psi, about 40 psi to about 225 psi, about 50 psi to about 225 psi, or about 50 psi to about 200 psi. In one embodiment, about 3 mL to about 50 mL of the formulation disclosed herein is administered to the subject using an HVAI from a prefilled syringe at an initial pressure of about 50 psi, about 55 psi, about 60 psi, about 65 psi, about 70 psi, about 75 psi, about 80 psi, about 85 psi, about 90 psi, about 95 psi, about 100 psi, about 105 psi, about 110 psi, about 115 psi, about 120 psi, about 125 psi, about 130 psi, about 135 psi, about 140 psi, about 145 psi, about 150 psi, about 155 psi, about 160 psi, about 165 psi, about 170 psi, about 175 psi, about 180 psi, about 185 psi, about 190 psi, about 195 psi, or about 200 psi. In one embodiment, approximately 3 mL to approximately 50 mL of the formulation disclosed herein is dispensed from a pre-filled syringe using an HVAI at approximately 50 psi, approximately 51 psi, approximately 52 psi, approximately 53 psi, approximately 54 psi, approximately 55 psi, approximately 56 psi, approximately 57 psi, approximately 58 psi, approximately 59 psi, approximately 60 psi, approximately 61 psi, approximately 62 psi, approximately 63 psi, approximately 64 psi, approximately 65 psi, approximately 66 psi, approximately 67 psi, approximately 68 psi, approximately 69 psi, approximately 70 psi, approximately 71 psi, approximately 72 psi, approximately 73 psi i. Approximately 74 psi, approximately 75 psi, approximately 76 psi, approximately 77 psi, approximately 78 psi, approximately 79 psi, approximately 80 psi, approximately 81 psi, approximately 82 psi, approximately 83 psi, approximately 84 psi, approximately 85 psi, approximately 86 psi, approximately 87 psi, approximately 88 psi, approximately 89 psi, approximately 90 psi, approximately 91 psi, approximately 92 psi, approximately 93 psi, approximately 94 psi, approximately 95 psi, approximately 96 psi, approximately 97 psi, approximately 98 psi, approximately 99 psi, approximately 100 psi, approximately 101 psi, approximately 102 psiApproximately 103 psi, approximately 104 psi, approximately 105 psi, approximately 106 psi, approximately 107 psi, approximately 108 psi, approximately 109 psi, approximately 110 psi, approximately 111 psi, approximately 112 psi, approximately 113 psi, approximately 114 psi, approximately 115 psi, approximately 116 psi, approximately 117 psi, approximately 118 psi, approximately 119 psi, approximately 120 psi, approximately 121 psi, approximately 122 psi, approximately 123 psi, approximately 124 psi, approximately 125 psi, approximately 126 psi, approximately 127 ps i, approximately 128 psi, approximately 129 psi, approximately 130 psi, approximately 131 psi, approximately 132 psi, approximately 133 psi, approximately 134 psi, approximately 135 psi, approximately 136 psi, approximately 137 psi, approximately 138 psi, approximately 139 psi, approximately 140 psi, approximately 141 psi, approximately 142 psi, approximately 143 psi, approximately 144 psi, approximately 145 psi, approximately 146 psi, approximately 147 psi, approximately 148 psi, approximately 149 psi, approximately 150 psi, approximately 151 psi, approximately 152 psi 153 psi, approximately 154 psi, approximately 155 psi, approximately 156 psi, approximately 157 psi, approximately 158 psi, approximately 159 psi, approximately 160 psi, approximately 161 psi, approximately 162 psi, approximately 163 psi, approximately 164 psi, approximately 165 psi, approximately 166 psi, approximately 167 psi, approximately 168 psi, approximately 169 psi, approximately 170 psi, approximately 171 psi, approximately 172 psi, approximately 173 psi, approximately 174 psi, approximately 175 psi, approximately 176 psi, approximately 177 An initial pressure of approximately 178 psi, 179 psi, 180 psi, 181 psi, 182 psi, 183 psi, 184 psi, 185 psi, 186 psi, 187 psi, 188 psi, 189 psi, 190 psi, 191 psi, 192 psi, 193 psi, 194 psi, 195 psi, 196 psi, 197 psi, 198 psi, 199 psi, or 200 psi was applied to the subject.

[0360] In one embodiment, the starting pressure refers to the initial pressure applied to the subject's tissue when administering the formulation from a pre-filled syringe using an HVAI. In one embodiment, the starting pressure refers to the initial pressure applied by the syringe stopper of the pre-filled syringe within the HVAI when the disclosed formulation is delivered to the subject. In one embodiment, the starting pressure refers to the initial pressure applied to the formulation when administering the formulation from a pre-filled syringe using an HVAI. In one embodiment, the starting pressure refers to the initial pressure applied to the pre-filled syringe when administering the formulation from a pre-filled syringe using an HVAI. In one embodiment, the starting pressure refers to the initial pressure generated by the HVAI device when administering the formulation from a pre-filled syringe using an HVAI.

[0361] In one embodiment, about 3 mL to about 50 mL of the formulation disclosed herein is administered to a subject using an HVAI from a pre-filled syringe at a final pressure of about 1 psi to about 250 psi, about 1 psi to about 225 psi, about 1 psi to about 200 psi, about 10 psi to about 200 psi, about 10 psi to about 175 psi, about 10 psi to about 150 psi, about 10 psi to about 125 psi, about 15 psi to about 125 psi, about 15 psi to about 100 psi, about 15 psi to about 80 psi, about 15 psi to about 75 psi, or about 20 psi to about 75 psi. In one embodiment, about 3 mL to about 50 mL of the formulation disclosed herein is administered to a subject using an HVAI from a pre-filled syringe at a final pressure of about 20 psi, about 25 psi, about 30 psi, about 35 psi, about 40 psi, about 45 psi, about 50 psi, about 55 psi, about 60 psi, about 65 psi, about 70 psi, or about 75 psi. In one embodiment, approximately 3 mL to approximately 50 mL of the formulation disclosed herein is dispensed from a pre-filled syringe using an HVAI at approximately 20 psi, approximately 21 psi, approximately 22 psi, approximately 23 psi, approximately 24 psi, approximately 25 psi, approximately 26 psi, approximately 27 psi, approximately 28 psi, approximately 29 psi, approximately 30 psi, approximately 31 psi, approximately 32 psi, approximately 33 psi, approximately 34 psi, approximately 35 psi, approximately 36 psi, approximately 37 psi, approximately 38 psi, approximately 39 psi, approximately 40 psi, approximately 41 psi, approximately 42 psi, approximately 43 psi, approximately 44 psi, approximately 45 psi. Approximately 46 psi, approximately 47 psi, approximately 48 psi, approximately 49 psi, approximately 50 psi, approximately 51 psi, approximately 52 psi, approximately 53 psi, approximately 54 psi, approximately 55 psi, approximately 56 psi, approximately 57 psi, approximately 58 psi, approximately 59 psi, approximately 60 psi, approximately 61 psi, approximately 62 psi, approximately 63 psi, approximately 64 psi, approximately 65 psi, approximately 66 psi, approximately 67 psi, approximately 68 psi, approximately 69 psi, approximately 70 psi, approximately 71 psi, approximately 72 psi, approximately 73 psi, approximately 74 psi, or approximately 75 psi were applied to the subject.

[0362] In one embodiment, the final pressure refers to the final pressure applied to the subject's tissue when administering the disclosed formulation from a pre-filled syringe using an HVAI. In one embodiment, the final pressure refers to the final pressure applied by the syringe stopper of the pre-filled syringe within the HVAI when the disclosed formulation is delivered to the subject. In one embodiment, the final pressure refers to the final pressure applied to the formulation when administering the formulation from a pre-filled syringe using an HVAI. In one embodiment, the final pressure refers to the final pressure applied to the pre-filled syringe when administering the formulation from a pre-filled syringe using an HVAI. In one embodiment, the final pressure refers to the final pressure generated by the HVAI device when administering the formulation from a pre-filled syringe using an HVAI.

[0363] In one implementation, less force is required to administer the formulation to a subject compared to similar formulations that do not contain hyaluronidase.

[0364] In one embodiment, about 3 mL to about 50 mL of the formulation disclosed herein is applied at a rate of about 0.05 mL / s to about 1.0 mL / s with an application force of about 10 N to about 200 N, about 20 N to about 150 N, about 10 N, about 20 N, about 30 N, about 40 N, about 50 N, about 60 N, about 70 N, about 80 N, about 90 N, about 100 N, about 110 N, about 120 N, about 130 N, about 140 N, about 150 N, about 160 N, about 170 N, about 180 N, about 190 N, or about 200 N.

[0365] In one embodiment, about 5 mL of the formulation is administered to the subject at a rate of about 0.14 mL / s to about 0.21 mL / s with an application force of about 10 N to about 45 N. In one embodiment, about 5 mL of the formulation is administered to the subject using a 25-gauge needle at a rate of about 0.14 mL / s to about 0.21 mL / s with an application force of about 10 N to about 45 N. In one embodiment, about 5 mL of the formulation is administered to the subject using a 25-gauge needle at a rate of about 0.14 mL / s to about 0.21 mL / s with an application force of about 15 N to about 25 N. In one embodiment, about 5 mL of the formulation is administered to the subject using a 25-gauge needle at a rate of about 0.14 mL / s to about 0.21 mL / s with an application force of about 22 N to about 40 N. In one embodiment, about 10 mL of the formulation is administered to the subject at a rate of about 0.32 mL / s to about 0.42 mL / s with an application force of about 25 N to about 50 N.

[0366] In one embodiment, the application force for administering the formulation to the subject at a specific rate depends on the gauge of the needle used to deliver the formulation to the subject. In another embodiment, the application force for administering the formulation to the subject at a specific rate depends on the gauge of the needle used to deliver the formulation to the subject and the inner diameter of the needle. Therefore, in one embodiment, using a 25-gauge needle with a larger inner diameter (i.e., a thin-walled needle, such as a Terumo needle) would require a smaller application force to administer the disclosed formulation to the subject at a specific rate compared to using a 25-gauge needle (such as a BD needle) with a smaller inner diameter. In one embodiment, approximately 5 mL of the formulation is administered to the subject using a 25-gauge needle at a rate of approximately 0.14 mL / s to approximately 0.21 mL / s with an application force of approximately 15 N to approximately 25 N, wherein the needle is a thin-walled needle (e.g., a Terumo needle). In another embodiment, about 5 mL of the formulation is applied to the subject with an application force of about 22 N to about 40 N using a 25 gauge needle at a rate of about 0.14 mL / s to about 0.21 mL / s, wherein the needle is not a thin-walled needle (e.g., a BD needle).

[0367] In one embodiment, about 10 mL of the formulation is applied to the subject using a 25-gauge needle at a rate of about 0.32 mL / s to about 0.42 mL / s with an application force of about 25 N to about 50 N.

[0368] In one embodiment, about 5 mL of the formulation is applied to the subject at a rate of about 0.14 mL / s to about 0.21 mL / s with an application force of about 10 N, about 11 N, about 12 N, about 13 N, about 14 N, about 15 N, about 16 N, about 17 N, about 18 N, about 19 N, about 20 N, about 21 N, about 22 N, about 23 N, about 24 N, about 25 N, about 26 N, about 27 N, about 28 N, about 29 N, about 30 N, about 31 N, about 32 N, about 33 N, about 35 N, about 36 N, about 37 N, about 38 N, about 39 N, about 40 N, about 41 N, about 42 N, about 43 N, about 44 N, or about 45 N. In one embodiment, about 5 mL of the formulation is applied to the subject using a 25-gauge needle at a rate of about 0.14 mL / s to about 0.21 mL / s with an application force of about 10 N, about 11 N, about 12 N, about 13 N, about 14 N, about 15 N, about 16 N, about 17 N, about 18 N, about 19 N, about 20 N, about 21 N, about 22 N, about 23 N, about 24 N, about 25 N, about 26 N, about 27 N, about 28 N, about 29 N, about 30 N, about 31 N, about 32 N, about 33 N, about 35 N, about 36 N, about 37 N, about 38 N, about 39 N, about 40 N, about 41 N, about 42 N, about 43 N, about 44 N, or about 45 N.

[0369] In one embodiment, about 10 mL of the formulation is applied to the subject at a rate of about 0.32 mL / s to about 0.42 mL / s with an application force of about 25 N, about 26 N, about 27 N, about 28 N, about 29 N, about 30 N, about 31 N, about 32 N, about 33 N, about 35 N, about 36 N, about 37 N, about 38 N, about 39 N, about 40 N, about 41 N, about 42 N, about 43 N, about 44 N, about 46 N, about 47 N, about 48 N, about 49 N, or about 50 N. In one embodiment, about 10 mL of the formulation is applied to the subject using a 25-gauge needle at a rate of about 0.32 mL / s to about 0.42 mL / s with an application force of about 25 N, about 26 N, about 27 N, about 28 N, about 29 N, about 30 N, about 31 N, about 32 N, about 33 N, about 35 N, about 36 N, about 37 N, about 38 N, about 39 N, about 40 N, about 41 N, about 42 N, about 43 N, about 44 N, about 45 N, about 46 N, about 47 N, about 48 N, about 49 N, or about 50 N.

[0370] HVAI can deliver the entire deliverable volume of formulation within 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 110, or 120 seconds.

[0371] In one embodiment, the hyaluronidase allows the formulation to be administered to the subject more rapidly than similar formulations that do not contain hyaluronidase. In one embodiment, when administered using the same HVAI equipped with a 23-gauge needle, the disclosed formulation may be administered approximately 20%, approximately 22%, approximately 24%, approximately 26%, approximately 28%, approximately 30%, approximately 32%, approximately 34%, approximately 36%, approximately 38%, approximately 40%, approximately 42%, approximately 44%, approximately 46%, or approximately 48% faster than similar formulations that do not contain hyaluronidase. In one embodiment, when administered using the same HVAI equipped with a 25-gauge needle, the disclosed formulation may be administered approximately 2%, approximately 4%, approximately 6%, approximately 8%, approximately 10%, approximately 12%, approximately 14%, approximately 16%, approximately 18%, or approximately 20% faster than similar formulations that do not contain hyaluronidase.

[0372] In one embodiment, injecting a high volume of the disclosed formulation into a subject results in fewer side effects compared to administering the same volume of a similar formulation without hyaluronidase to the same subject. In one embodiment, injection of a high volume of the disclosed formulation disclosed elsewhere herein has reduced backleakage compared to a similar formulation without hyaluronidase. In one embodiment, when a high volume of the disclosed formulation is administered to a subject using an HVAI equipped with a 23-gauge needle, backleakage is reduced by approximately 54%, approximately 56%, approximately 58%, approximately 60%, approximately 62%, approximately 64%, approximately 66%, approximately 68%, approximately 70%, approximately 72%, approximately 74%, approximately 76%, or approximately 78%, compared to a similar formulation without hyaluronidase. In one embodiment, when a high volume of the disclosed formulation is administered to a subject using an HVAI equipped with a 25-gauge needle, backleakage is reduced by approximately 62%, approximately 64%, approximately 68%, approximately 70%, approximately 72%, approximately 74%, approximately 76%, approximately 78%, approximately 80%, approximately 82%, approximately 84%, or approximately 86%, compared to similar formulations that do not contain hyaluronidase.

[0373] In one embodiment, the swelling (vesicle) volume is reduced after injection of the disclosed formulation into a subject, compared to a similar formulation that does not contain hyaluronidase. In one embodiment, the swelling height is reduced after injection of the disclosed formulation, compared to a similar formulation that does not contain hyaluronidase. In one embodiment, the swelling size is reduced after injection of the disclosed formulation, compared to a similar formulation that does not contain hyaluronidase. In one embodiment, the swelling area is reduced after injection of the disclosed formulation, compared to a similar formulation that does not contain hyaluronidase. In one embodiment, the swelling induration after initial injection of the disclosed formulation is minimized, compared to a similar formulation that does not contain hyaluronidase. In one embodiment, the swelling subsides more quickly upon injection of the disclosed formulation, compared to a similar formulation that does not contain hyaluronidase. In one embodiment, the disclosed formulation allows for more consistent delivery from injection to injection (i.e., reductions in delivery time, vesicle swelling volume, height, and induration), compared to a similar formulation that does not contain hyaluronidase. In one embodiment, the disclosed formulation allows for faster delivery of the full volume of HVAI than similar formulations that do not contain hyaluronidase, resulting in less pain and discomfort for the subject.

[0374] The terms of this disclosure.

[0375] Clause 1. A method for treating a disease or condition in a subject in need, the method comprising administering to the subject via subcutaneous administration of a formulation comprising about 3 mL to about 50 mL of hyaluronidase and a therapeutically effective amount of an active ingredient.

[0376] Clause 2. The method according to Clause 1, wherein the hyaluronidase is recombinant human hyaluronidase.

[0377] Clause 3. The method according to Clause 1, wherein the hyaluronidase is recombinant human hyaluronidase PH20.

[0378] Clause 4. The method according to Clause 1, wherein the hyaluronidase has an activity of about 150 U / mL to about 150 kU / mL.

[0379] Clause 5. The method according to Clauses 1 to 4, wherein the concentration of the hyaluronidase in the preparation is from about 500 U / mL to about 5,000 U / mL.

[0380] Clause 6. The method according to any one of Clauses 1 to 5, wherein the concentration of the hyaluronidase in the preparation is from about 1,500 U / mL to about 10,000 U / mL.

[0381] Clause 7. The method according to any one of Clauses 1 to 6, wherein the active ingredient is a small molecule, peptide fragment, biological agent, or nanoparticle.

[0382] Clause 8. The method according to any one of Clauses 1 to 7, wherein the active ingredient is an antibody, antibody fragment, or small molecule antiviral agent.

[0383] Clause 9. The method according to any one of Clauses 1 to 8, wherein the method comprises administering about 10 mL to about 20 mL of the preparation to the subject.

[0384] Clause 10. The method according to any one of Clauses 1 to 8, the method comprising administering to the subject about 3 mL, about 4 mL, about 5 mL, about 5.5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, about 20 mL, about 21 mL, about 22 mL, about 23 mL, about 24 mL, or about 25 mL.

[0385] Clause 11. The method according to any one of Clauses 1 to 10, wherein the method comprises administering the formulation using a high-volume autoinjector.

[0386] Clause 12. The method according to any one of Clauses 1 to 11, wherein the formulation is in a pre-filled syringe.

[0387] Clause 13. The method according to Clause 12, wherein the prefilled syringe contains 3 mL, about 4 mL, about 5 mL, about 5.5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, about 20 mL, about 21 mL, about 22 mL, about 23 mL, about 24 mL, or about 25 mL of the preparation.

[0388] Clause 14. The method according to Clause 12 or 13, wherein the prefilled syringe comprises a needle of about 20 to about 27 gauge.

[0389] Clause 15. The method according to any one of Clauses 12 to 14, wherein the pre-filled syringe comprises a 20-gauge needle, a 21-gauge needle, a 22-gauge needle, a 23-gauge needle, a 24-gauge needle, a 25-gauge needle, a 26-gauge needle, a 27-gauge needle, a 28-gauge needle, a 29-gauge needle, a 30-gauge needle, or a 31-gauge needle.

[0390] Clause 16. The method according to any one of Clauses 1 to 15, the method comprising administering the formulation at a rate of about 0.08 mL / s to about 0.75 mL / s.

[0391] Clause 17. The method according to any one of Clauses 1 to 16, wherein the formulation has a viscosity of about 1 cP to about 50 cP.

[0392] Clause 18. The method according to any one of Clauses 1 to 17, wherein the application takes about 20 seconds to about 40 seconds.

[0393] Clause 19. The method according to any one of Clauses 1 to 18, wherein the application takes about 26 seconds to about 30 seconds.

[0394] Clause 20. The method according to any one of Clauses 1 to 19, wherein the application of said formulation is faster than that of similar formulations that do not contain hyaluronidase.

[0395] Clause 21. The method according to any one of Clauses 1 to 20, wherein the administration of said formulation causes fewer side effects in said subject when compared with similar formulations that do not contain hyaluronidase.

[0396] Clause 22. The method according to any one of Clauses 1 to 21, wherein the administration of said preparation causes less pain and discomfort in said subject when compared with similar preparations that do not contain hyaluronidase.

[0397] Clause 23. The method according to any one of Clauses 1 to 22, wherein the application of said formulation at the injection site causes less backflow compared to similar formulations that do not contain hyaluronidase.

[0398] Clause 24. The method according to Clause 23, wherein the backleakage at the injection site is reduced by about 85% to about 30% compared to a similar formulation that does not contain hyaluronidase.

[0399] Clause 25. The method according to any one of Clauses 1 to 24, wherein when applied to the injection site, the preparation causes a smaller volume and / or height of swelling compared to a similar preparation that does not contain hyaluronidase.

[0400] Clause 26. The method according to Clause 25, wherein, when compared with a similar formulation that does not contain hyaluronidase, the formulation causes approximately 35% to approximately 5% less swelling and / or swelling height at the injection site.

[0401] Clause 27. The method according to any one of Clauses 1 to 26, wherein, when compared with similar formulations that do not contain hyaluronidase, application of said formulation produces lower vesicle swelling size, less vesicle induration, and / or faster vesicle resolution.

[0402] Clause 28. The method according to any one of Clauses 1 to 27, wherein the subject is a human.

[0403] Clause 29. The method according to any one of Clauses 1 to 28, wherein the subject self-administers the preparation.

[0404] Clause 30. The method according to any one of Clauses 1 to 28, wherein a healthcare provider or caregiver administers the preparation to the subject.

[0405] Clause 31. The method according to any one of Clauses 1 to 30, wherein the subcutaneous administration is a single injection.

[0406] Clause 32. The method according to any one of Clauses 1 to 30, wherein the subcutaneous administration comprises two or more injections.

[0407] Clause 33. The method according to any one of Clauses 1 to 30, wherein the subcutaneous application is delivered via an on-body device.

[0408] Clause 101. A method of treating a disease or condition in a subject in need, the method comprising administering to the subject via subcutaneous injection of a formulation of about 3 mL to about 50 mL, the formulation comprising a therapeutically effective amount of an active ingredient selected from small molecules, peptide fragments, biologics, nanoparticles, antibodies, antibody fragments, and small molecule antiviral agents, wherein the subcutaneous injection is performed via a high-volume autoinjector with an initial delivery force of about 5 lbf to about 50 lbf, a final delivery force of about 5 lbf to about 20 lbf, an initial pressure of about 50 psi to about 200 psi, and / or a final pressure of about 20 psi to about 75 psi.

[0409] Clause 102. The method of claim 101, wherein the formulation further comprises hyaluronidase.

[0410] Clause 103. The method of claim 102, wherein the hyaluronidase is recombinant human hyaluronidase.

[0411] Clause 104. The method according to claim 102 or 103, wherein the hyaluronidase is recombinant human hyaluronidase PH20.

[0412] Clause 105. The method according to any one of claims 102 to 104, wherein the hyaluronidase has an activity of about 150 U / mL to about 150 kU / mL.

[0413] Clause 106. The method according to any one of claims 102 to 104, wherein the hyaluronidase has an activity of about 500 U / mL to about 5,000 U / mL.

[0414] Clause 107. The method according to any one of claims 102 to 104, wherein the hyaluronidase has an activity of about 1,500 U / mL to about 10,000 U / mL.

[0415] Clause 108. The method according to any one of claims 101 to 107, wherein the active ingredient is a small molecule, peptide fragment, biological agent, or nanoparticle.

[0416] Clause 109. The method according to any one of claims 101 to 108, wherein the active ingredient is an antibody, an antibody fragment, or a small molecule antiviral agent.

[0417] Clause 110. The method according to any one of claims 101 to 109, the method comprising administering about 10 mL to about 20 mL of the preparation to the subject.

[0418] Clause 111. The method according to any one of claims 101 to 110, the method comprising administering about 3 mL to about 15 mL of the preparation to the subject.

[0419] Clause 112. The method according to any one of claims 101 to 111, the method comprising administering to the subject about 3 mL, about 3.1 mL, about 3.2 mL, about 3.4 mL, about 3.5 mL, about 3.6 mL, about 3.7 mL, about 3.8 mL, about 3.9 mL, about 4 mL, about 4.1 mL, about 4.2 mL, about 4.3 mL, about 4.4 mL, about 4.5 mL, about 5 mL, about 5.1 mL, about 5.2 mL, about 5.3 mL, about 5.4 mL, about 5.5 mL, about 5.6 mL, about 5.7 mL, about 5.8 mL, about 5.9 mL, about 6 mL, about 6.1 mL, about 6.2 mL, about 6.3 mL, about 6.4 mL, or about 6 mL. 5mL, approximately 6.6mL, approximately 6.7mL, approximately 6.8mL, approximately 6.9mL, approximately 7mL, approximately 7.1mL, approximately 7.2mL, approximately 7.3mL, approximately 7.4mL, approximately 7.5mL, approximately 7.6mL, approximately 7.7mL, approximately 7.8mL, approximately 7.9mL, approximately 8mL, approximately 8.1mL, approximately 8.2mL, approximately 8.3mL, approximately 8.4mL, approximately 8.5mL, approximately 8.6mL, approximately 8.7mL, approximately 8.8mL, approximately 8.9mL, approximately 9mL, approximately 9.1mL, approximately 9.2mL, approximately 9.3mL, approximately 9.4mL, approximately 9.5mL, approximately 9.6mL, approximately 9.7mL, approximately 9.8mL, approximately 9.9mL, approximately 10mL, approximately 10.1mL Approximately 10.2 mL, approximately 10.3 mL, approximately 10.4 mL, approximately 10.5 mL, approximately 10.6 mL, approximately 10.7 mL, approximately 10.8 mL, approximately 10.9 mL, approximately 11 mL, approximately 11.1 mL, approximately 11.2 mL, approximately 11.3 mL, approximately 11.4 mL, approximately 11.5 mL, approximately 11.6 mL, approximately 11.7 mL, approximately 11.8 mL, approximately 11.9 mL, approximately 12 mL, approximately 12.1 mL, approximately 12.2 mL, approximately 12.3 mL, approximately 12.4 mL, approximately 12.5 mL, approximately 12.6 mL, approximately 12.7 mL, approximately 12.8 mL, approximately 12.9 mL, approximately 13 mL, approximately 13.1 mL, approximately 13.2 mL, approximately 13.3 mL mL, approximately 13.4 mL, approximately 13.5 mL, approximately 13.6 mL, approximately 13.7 mL, approximately 13.8 mL, approximately 13.9 mL, approximately 14 mL, approximately 14.1 mL, approximately 14.2 mL, approximately 14.3 mL, approximately 14.4 mL, approximately 14.5 mL, approximately 14.6 mL, approximately 14.7 mL, approximately 14.8 mL, approximately 14.9 mL, approximately 15 mL, approximately 15.1 mL, approximately 15.2 mL, approximately 15.3 mL, approximately 15.4 mL, approximately 15.5 mL, approximately 15.6 mL, approximately 15.7 mL, approximately 15.8 mL, approximately 15.9 mL, approximately 16 mL, approximately 16.1 mL, approximately 16.2 mL, approximately 16.3 mL, approximately 16.4 mL, approximately 16.5mL, approximately 16.6mL, approximately 16.7mL, approximately 16.8mL, approximately 16.9mL, approximately 17mL, approximately 17.1mL, approximately 17.2mL, approximately 17.3mL, approximately 17.4mL, approximately 17.5mL, approximately 17.6mL, approximately 17.7mL, approximately 17.8mL, approximately 17.9mL, approximately 18mL, approximately 18.1mL, approximately 18.2mL, approximately 18.3mL, approximately 18.4mL, approximately 18.5mL, approximately 18.6mL L, approximately 18.7 mL, approximately 18.8 mL, approximately 18.9 mL, approximately 19 mL, approximately 19.1 mL, approximately 19.2 mL, approximately 19.3 mL, approximately 19.4 mL, approximately 19.5 mL, approximately 19.6 mL, approximately 19.7 mL, approximately 19.8 mL, approximately 19.9 mL, approximately 20 mL, approximately 20.1 mL, approximately 20.2 mL, approximately 20.3 mL, approximately 20.4 mL, approximately 20.5 mL, approximately 20.6 mL, approximately 20.7 mL, approximately 20.8mL, approximately 20.9mL, approximately 21mL, approximately 21.1mL, approximately 21.2mL, approximately 21.3mL, approximately 21.4mL, approximately 21.5mL, approximately 21.6mL, approximately 21.7mL, approximately 21.8mL, approximately 21.9mL, approximately 22mL, approximately 22.1mL, approximately 22.2mL, approximately 22.3mL, approximately 22.4mL, approximately 22.5mL, approximately 22.6mL, approximately 22.7mL, approximately 22.8mL, approximately 22... Approximately 0.9 mL, 23 mL, 23.1 mL, 23.2 mL, 23.3 mL, 23.4 mL, 23.5 mL, 23.6 mL, 23.7 mL, 23.8 mL, 23.9 mL, 24 mL, 24.1 mL, 24.2 mL, 24.3 mL, 24.4 mL, 24.5 mL, 24.6 mL, 24.7 mL, 24.8 mL, 24.9 mL, or 25 mL.

[0420] Clause 113. The method according to any one of claims 101 to 112, the method comprising administering the formulation using a high-volume autoinjector.

[0421] Clause 114. The method according to any one of claims 101 to 113, the method comprising administering the formulation using a high-volume autoinjector with an initial delivery force of about 3 lbf to about 50 lbf.

[0422] Clause 115. The method according to any one of claims 101 to 114, the method comprising administering the formulation using a high-volume autoinjector with a final delivery force of about 5 lbf to about 20 lbf.

[0423] Clause 116. The method of any one of claims 101 to 115, the method comprising administering the formulation using a high-volume autoinjector at an initial pressure of about 50 psi to about 200 psi.

[0424] Clause 117. The method of any one of claims 101 to 116, the method comprising administering the formulation using a high-volume autoinjector at a final pressure of about 20 psi to about 75 psi.

[0425] Clause 118. The method according to any one of claims 101 to 117, wherein the formulation is in a pre-filled syringe.

[0426] Clause 119. The method of claim 118, wherein the pre-filled syringe contains about 3 mL, about 3.1 mL, about 3.2 mL, about 3.4 mL, about 3.5 mL, about 3.6 mL, about 3.7 mL, about 3.8 mL, about 3.9 mL, about 4 mL, about 4.1 mL, about 4.2 mL, about 4.3 mL, about 4.4 mL, about 4.5 mL, about 5 mL, about 5.1 mL, about 5.2 mL, about 5.3 mL, about 5.4 mL, about 5.5 mL, about 5.6 mL, about 5.7 mL, about 5.8 mL, about 5.9 mL, about 6 mL, about 6.1 mL, about 6.2 mL, about 6.3 mL, about 6.4 mL, about 6.5 mL, about 6.6 mL, about 3 mL, about 3.1 mL, about 3.2 mL, about 3.4 mL, about 3.5 mL, about 3.5 mL, about 3.6 mL, about 3.7 mL, about 3.8 mL, about 3.9 mL, about 4 mL, about 4.1 mL, about 4.2 mL, about 4.3 mL, about 4.4 mL, about 4.5 mL, about 6.6 mL, about 3 mL, about 3.7 mL, about 3.8 mL, about 3.9 mL, about 4 mL, about 4.7 mL, about 4.8 mL, about 4.9 ...5 mL, about 5.1 mL, about 5.2 mL, about 5.3 mL, about 5.4 mL, about 5.5 mL, about 6.7mL, approximately 6.8mL, approximately 6.9mL, approximately 7mL, approximately 7.1mL, approximately 7.2mL, approximately 7.3mL, approximately 7.4mL, approximately 7.5mL, approximately 7.6mL, approximately 7.7mL, approximately 7.8mL, approximately 7.9mL, approximately 8mL, approximately 8.1mL, approximately 8.2mL, approximately 8.3mL, approximately 8.4mL, approximately 8.5mL, approximately 8.6mL, approximately 8.7mL, approximately 8.8mL, approximately 8.9mL, approximately 9mL, approximately 9.1mL, approximately 9.2mL, approximately 9.3mL, approximately 9.4mL, approximately 9.5mL, approximately 9.6mL, approximately 9.7mL, approximately 9.8mL, approximately 9.9mL, approximately 10mL, approximately 10.1mL, approximately 10.2mL, approximately 10. 3mL, approximately 10.4mL, approximately 10.5mL, approximately 10.6mL, approximately 10.7mL, approximately 10.8mL, approximately 10.9mL, approximately 11mL, approximately 11.1mL, approximately 11.2mL, approximately 11.3mL, approximately 11.4mL, approximately 11.5mL, approximately 11.6mL, approximately 11.7mL, approximately 11.8mL, approximately 11.9mL, approximately 12mL, approximately 12.1mL, approximately 12.2mL, approximately 12.3mL, approximately 12.4mL, approximately 12.5mL, approximately 12.6mL, approximately 12.7mL, approximately 12.8mL, approximately 12.9mL, approximately 13mL, approximately 13.1mL, approximately 13.2mL, approximately 13.3mL, approximately 13.4mL, approximately 13. 5mL, approximately 13.6mL, approximately 13.7mL, approximately 13.8mL, approximately 13.9mL, approximately 14mL, approximately 14.1mL, approximately 14.2mL, approximately 14.3mL, approximately 14.4mL, approximately 14.5mL, approximately 14.6mL, approximately 14.7mL, approximately 14.8mL, approximately 14.9mL, approximately 15mL, approximately 15.1mL, approximately 15.2mL, approximately 15.3mL, approximately 15.4mL, approximately 15.5mL, approximately 15.6mL, approximately 15.7mL, approximately 15.8mL, approximately 15.9mL, approximately 16mL, approximately 16.1mL, approximately 16.2mL, approximately 16.3mL, approximately 16.4mL, approximately 16.5mL, approximately 16.6mL, approximately 16.7mL, approximately 16.8mL, approximately 16.9mL, approximately 17mL, approximately 17.1mL, approximately 17.2mL, approximately 17.3mL, approximately 17.4mL, approximately 17.5mL, approximately 17.6mL, approximately 17.7mL, approximately 17.8mL, approximately 17.9mL, approximately 18mL, approximately 18.1mL, approximately 18.2mL, approximately 18.3mL, approximately 18.4mL, approximately 18.5mL, approximately 18.6mL, approximately 18.7mL, approximately 18 0.8mL, approximately 18.9mL, approximately 19mL, approximately 19.1mL, approximately 19.2mL, approximately 19.3mL, approximately 19.4mL, approximately 19.5mL, approximately 19.6mL, approximately 19.7mL, approximately 19.8mL, approximately 19.9mL, approximately 20mL, approximately 20.1mL, approximately 20.2mL, approximately 20.3mL, approximately 20.4mL, approximately 20.5mL, approximately 20.6mL, approximately 20.7mL, approximately 20.8mL, approximately 20 0.9mL, approximately 21mL, approximately 21.1mL, approximately 21.2mL, approximately 21.3mL, approximately 21.4mL, approximately 21.5mL, approximately 21.6mL, approximately 21.7mL, approximately 21.8mL, approximately 21.9mL, approximately 22mL, approximately 22.1mL, approximately 22.2mL, approximately 22.3mL, approximately 22.4mL, approximately 22.5mL, approximately 22.6mL, approximately 22.7mL, approximately 22.8mL, approximately 22.9mL, approximately 23... The preparation may be expressed in mL, approximately 23.1 mL, approximately 23.2 mL, approximately 23.3 mL, approximately 23.4 mL, approximately 23.5 mL, approximately 23.6 mL, approximately 23.7 mL, approximately 23.8 mL, approximately 23.9 mL, approximately 24 mL, approximately 24.1 mL, approximately 24.2 mL, approximately 24.3 mL, approximately 24.4 mL, approximately 24.5 mL, approximately 24.6 mL, approximately 24.7 mL, approximately 24.8 mL, approximately 24.9 mL, or approximately 25 mL.

[0427] Clause 120. The method of claim 118 or 119, wherein the prefilled syringe comprises a needle of about 20 to about 33.

[0428] Clause 121. The method according to any one of claims 118 to 120, wherein the pre-filled syringe comprises a 20-gauge needle, a 21-gauge needle, a 22-gauge needle, a 23-gauge needle, a 24-gauge needle, a 25-gauge needle, a 26-gauge needle, a 27-gauge needle, a 28-gauge needle, a 29-gauge needle, a 30-gauge needle, a 31-gauge needle, a 32-gauge needle, or a 33-gauge needle.

[0429] Clause 122. The method according to any one of claims 101 to 121, the method comprising administering the formulation at a rate of about 0.08 mL / s to about 1.00 mL / s.

[0430] Clause 123. The method according to any one of claims 101 to 122, the method comprising administering the formulation at a rate of at least about 0.08 mL / s to about 1.0 mL / s.

[0431] Clause 124. The method according to any one of claims 101 to 122, the method comprising administering the formulation at a rate of at least or faster than about 0.08 mL / s to about 1.00 mL / s.

[0432] Clause 125. The method according to any one of claims 101 to 124, wherein the application takes about 10 seconds to about 40 seconds.

[0433] Clause 126. The method according to any one of claims 101 to 124, wherein the application takes at least about 10 seconds to about 40 seconds.

[0434] Clause 127. The method according to any one of claims 101 to 124, wherein the application takes at least or less than about 10 seconds to about 40 seconds.

[0435] Clause 128. The method according to any one of claims 101 to 124, wherein the application takes about 15 seconds to about 30 seconds.

[0436] Clause 129. The method according to any one of claims 101 to 124, wherein the application takes at least about 15 seconds to about 30 seconds.

[0437] Clause 130. The method according to any one of claims 101 to 124, wherein the application takes at least or less than about 15 seconds to about 30 seconds.

[0438] Clause 131. The method according to any one of claims 101 to 124, the method comprising administering about 5 mL of the formulation at a rate of about 0.14 mL / s to about 0.21 mL / s.

[0439] Clause 132. The method according to any one of claims 101 to 124, the method comprising administering about 10 mL of the formulation at a rate of about 0.32 mL / s to about 0.42 mL / s.

[0440] Clause 133. The method according to any one of claims 101 to 132, wherein the formulation has a viscosity of about 1 cP to about 50 cP.

[0441] Clause 134. The method according to any one of claims 101 to 132, wherein the application of said formulation requires less force compared to similar formulations that do not contain hyaluronidase.

[0442] Clause 135. The method according to any one of claims 101 to 134, the method comprising applying about 5 mL of the formulation at a rate of about 0.14 mL / s to about 0.21 mL / s and an application force of about 10 N to about 45 N.

[0443] Clause 136. The method of claim 135, wherein the method comprises administering the formulation to the subject using a pre-filled syringe comprising a 25-gauge needle.

[0444] Clause 137. The method according to any one of claims 101 to 134, the method comprising administering about 10 mL of the formulation to the subject at a rate of about 0.32 mL / s to about 0.42 mL / s and an application force of about 25 N to about 50 N.

[0445] Clause 138. The method of claim 137, the method comprising administering the formulation to the subject using a pre-filled syringe including a 25-gauge needle.

[0446] Clause 139. The method according to any one of claims 102 to 138, wherein the preparation is administered more rapidly when compared with similar preparations that do not contain hyaluronidase.

[0447] Clause 140. The method according to any one of claims 102 to 139, wherein the administration of said formulation causes fewer side effects in the subject compared to similar formulations that do not contain hyaluronidase.

[0448] Clause 141. The method according to any one of claims 102 to 140, wherein the administration of said preparation causes less pain and discomfort in the subject compared to similar preparations that do not contain hyaluronidase.

[0449] Clause 142. The method according to any one of claims 102 to 141, wherein the application of said formulation to the injection site causes less backflow compared to similar formulations that do not contain hyaluronidase.

[0450] Clause 143. The method of claim 142, wherein the backleakage at the injection site is reduced by about 85% to about 30% compared to a similar formulation that does not contain hyaluronidase.

[0451] Clause 144. The method according to any one of claims 102 to 143, wherein when applied to the injection site, the preparation causes a smaller volume and / or height of swelling compared to similar preparations that do not contain hyaluronidase.

[0452] Clause 145. The method of claim 144, wherein, when compared with a similar formulation that does not contain hyaluronidase, the formulation causes approximately 35% to approximately 5% less swelling and / or swelling height at the injection site.

[0453] Clause 146. The method according to any one of claims 102 to 145, wherein, when compared with similar formulations that do not contain hyaluronidase, application of said formulation produces lower blister swelling size, less blister induration, and / or faster blister resolution.

[0454] Clause 147. The method according to any one of claims 101 to 146, wherein the application of the formulation produces a more consistent delivery time compared to similar formulations that do not contain hyaluronidase.

[0455] Clause 148. The method of any one of claims 101 to 147, wherein the subject is a human.

[0456] Clause 149. The method of any one of claims 101 to 148, wherein the administration comprises the subject self-administering the preparation.

[0457] Clause 150. The method of any one of claims 101 to 149, wherein the administration comprises administering the preparation to the subject by a healthcare provider or caregiver.

[0458] Clause 151. The method according to any one of claims 101 to 150, wherein the subcutaneous administration comprises a single injection.

[0459] Clause 152. The method according to any one of claims 101 to 150, wherein the subcutaneous administration comprises two or more injections.

[0460] Clause 153. The method according to any one of claims 101 to 152, wherein the subcutaneous application is delivered via an on-body device.

[0461] Clause 154. A pharmaceutical kit comprising a high-volume autoinjector and a formulation of about 3 mL to about 50 mL, the formulation comprising a therapeutically effective amount of an active ingredient selected from small molecules, peptide fragments, biologics, nanoparticles, antibodies, antibody fragments, and small molecule antiviral agents.

[0462] Clause 155. The pharmaceutical kit of claim 154, wherein the formulation further comprises hyaluronidase.

[0463] Clause 156. The pharmaceutical kit of claim 154, further comprising instructions for administering hyaluronidase to a subject in need.

[0464] Clause 157. The pharmaceutical kit of claim 154, further comprising instructions for administering hyaluronidase to a subject in need, simultaneously or sequentially with the formulation containing the active ingredient.

[0465] Clause 158. The pharmaceutical kit according to any one of claims 154 to 157, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.05 mL / s to about 1.0 mL / s.

[0466] Clause 159. The pharmaceutical kit of claim 158, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously from a pre-filled syringe having a volume of about 3 mL to about 15 mL.

[0467] Clause 160. The pharmaceutical kit of claim 159, wherein the pre-filled syringe comprises a needle of about 20 to about 33.

[0468] Clause 161. The pharmaceutical kit according to any one of claims 154 to 160, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.05 mL / s to about 0.10 mL / s.

[0469] Clause 162. The pharmaceutical kit according to any one of claims 154 to 160, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.10 mL / s to about 0.20 mL / s.

[0470] Clause 163. The pharmaceutical kit according to any one of claims 154 to 160, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.20 mL / s to about 0.30 mL / s.

[0471] Clause 164. The pharmaceutical kit according to any one of claims 154 to 160, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.30 mL / s to about 0.40 mL / s.

[0472] Clause 165. The pharmaceutical kit according to any one of claims 154 to 160, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.40 mL / s to about 0.50 mL / s.

[0473] Clause 166. The pharmaceutical kit according to any one of claims 154 to 160, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.50 mL / s to about 0.60 mL / s.

[0474] Clause 167. The pharmaceutical kit according to any one of claims 154 to 160, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.60 mL / s to about 0.70 mL / s.

[0475] Clause 168. The pharmaceutical kit according to any one of claims 154 to 160, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.70 mL / s to about 0.80 mL / s.

[0476] Clause 169. The pharmaceutical kit according to any one of claims 154 to 160, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.80 mL / s to about 0.90 mL / s.

[0477] Clause 170. The pharmaceutical kit according to any one of claims 154 to 160, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.90 mL / s to about 1.00 mL / s.

[0478] Clause 171. The pharmaceutical kit according to any one of claims 154 to 170, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject with an applied force of about 10 N to about 200 N.

[0479] Clause 172. The pharmaceutical kit according to any one of claims 154 to 171, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject with an application force of about 10 N to about 45 N.

[0480] Clause 173. The pharmaceutical kit according to any one of claims 154 to 171, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject with an application force of about 25 N to about 50 N.

[0481] Clause 174. The pharmaceutical kit according to any one of claims 154 to 173, wherein the high-volume autoinjector is configured for self-administration of the formulation by the subject.

[0482] Example

[0483] Example 1: Evaluation of the use of a 25G needle for vertical subcutaneous injection of 10 ml in an autoinjector

[0484] Grit

[0485] This study examined the delivery of Ig solutions prepared at 120 mg / mL using a simulated autoinjector. Test solutions were delivered at a concentration of 2,000 U / mL with and without rHuPH20. All injections were performed using a handheld device that held the needle in place, allowing it to be inserted vertically into the subcutaneous space to an injection depth of 7.5 mm. The test solution volume was 10 mL, delivered over 30 seconds using a 20 cc syringe and a 25G needle. The force applied to the syringe barrel was measured throughout the injection by attaching a force sensor to the end of the syringe flange. Furthermore, backflow was collected and quantified by weight after injection. Post-injection swelling was measured using calipers and 3D imaging. Following injection, three independent raters evaluated the erythema, swelling size, and induration at the injection site over time (at times T = 0 min, 15 min, 30 min, 2 h, and 24 h) to assess the time to swelling resolution.

[0486] introduce

[0487] Current autoinjectors (AIs) are limited to extremely small volumes (typically ≤2.25 mL), thus limiting their usefulness for delivering larger volumes. For larger volumes, higher flow rates are required for AI practice. Currently, 30 seconds is the recommended time for the device to remain in place during self-administration to prevent fatigue and potential injection interruptions.

[0488] rHuPH20 has been shown to facilitate the subcutaneous (SC) administration of fluids and drugs by transiently and locally depolymerizing hyaluronic acid (HA) in the extracellular matrix (ECM). The depolymerization of HA reduces tissue back pressure in the SC space, allowing for subsequent rapid, large-volume drug administration. Previous work has demonstrated that rHuPH20 can be used with infusion kits to facilitate large-volume delivery into the SC space at high flow rates.

[0489] Miniature pig models were chosen due to the high similarity between the subcutaneous space and the human subcutaneous space. Previous studies using miniature pig models have demonstrated their translatability for preclinical (Kang et al., 2013) and autoinjector studies (Shi et al., 2021).

[0490] In summary, the aim of this study was to determine whether rHuPH20 could enhance the development of high-volume AIs capable of delivering clinically relevant volumes into SC spaces at high flow rates using miniature pigs as an animal model. Specifically, this study evaluated the delivery of an Ig solution prepared at 120 mg / mL via a 25G needle when vertically injected into the SC space using a handheld simulated autoinjector device.

[0491] Test articles and methods

[0492] Test product

[0493] Human gamma globulin (Ig-120: 12% solution)

[0494] Batch number: 1032-17

[0495] Description: Lyophilized powder reconstituted at 120 mg / mL

[0496] Manufacturing date: 21 SEP2020

[0497] Formulation: 10mM histidine, 130mM sodium chloride, pH 6.5

[0498] Storage conditions: 2℃-8℃

[0499] Supplier: BioMed Supply

[0500] Formulated by: Halozyme Product Development

[0501] Recombinant human hyaluronidase rHuPH20

[0502] Batch number: 462-022

[0503] Description: Clear, colorless solution

[0504] Concentration: 10 mg / mL

[0505] Manufacturing date: December 30, 2014

[0506] Retest date: February 2023

[0507] Enzyme activity: 1,229,456 U / mL

[0508] Storage: ≤70℃

[0509] Formulation: 10mM histidine, 130mM sodium chloride, pH 6.5

[0510] Processing conditions: Standard laboratory precautions

[0511] Supplier: Halozyme Therapeutics, Inc.

[0512] preparation

[0513] Preparation of test solution

[0514] The two test solutions used in this study were Ig-120 alone and Ig-120 + rHuPH20. These were prepared by adding rHuPH20 from the concentrated stock solution to a previously prepared Ig solution at 120 mg / mL. The final concentration of rHuPH20 in the test solutions was 2,000 U / mL.

[0515] Ig-120 was thawed overnight at 2°C–8°C. Test solutions for the next day were prepared by adding rHuPH20 to the Ig-120 solution at room temperature. A concentrated stock solution of rHuPH20 was used for test preparation (10 mg / mL; 1,229,456 U / mL). To prepare Ig-120+rHuPH20, 488 μL of rHuPH20 was added to 300 mL of Ig-120. Each test solution was then aliquoted into individual 100 mL vials (75 mL each) and stored at 4°C until use for syringe filling the day before the study.

[0516] Prior to the study, the rHuPH20 activity of the Ig-120+rHuPH20 solution was tested using a microturbidity assay. The activity of the Ig-120+rHuPH20 test solution was within 10% of the target concentration and was considered within the acceptable range for use in the study. Two vials of each test solution (approximately 150 mL) were reserved for a second follow-up study and stored at 2°C–8°C.

[0517] At the end of the study, the rHuPH20 activity of dose retention samples obtained during the study procedure and stock solutions of Ig-120+rHuPH20 that had been used for syringe filling and maintained at 2°C–8°C since formulation were tested. The activity of the Ig-120+rHuPH20 test solutions was considered to be within acceptable ranges. These values ​​are summarized in Tables 1 and 2.

[0518] Table 1. Pre-study activity tests of rHuPH20 activity in test solutions

[0519] Test solution Pre-study concentration (U / mL ± SD) Pre-study Ig-120+rHuPH20 2167±44

[0520] Table 2. Post-study activity tests of rHuPH20 in test solutions

[0521]

[0522] Animal description

[0523] Species: Pig (domestic pig (Sus Scrofa domestica))

[0524] Strain: Yucatan mini

[0525] Sex: Female

[0526] Age: >3 months

[0527] Weight: 12kg-16kg at the time of receipt

[0528] Quantity: 6

[0529] Source: Premier BioSource (Ramona, CA)

[0530] animal husbandry

[0531] Animals were received by the facility on September 2, 2022, and allowed to acclimatize before the start of the study. Animals were grouped and housed in steel enclosures with an automated, readily available water supply. Except for study days (PM only), animals were fed twice daily (AM and PM). The indoor environment was set to maintain a temperature of approximately 17°C–27°C and a relative humidity of 40%–70%.

[0532] A 12-hour light / 12-hour dark cycle was used. Animals were acclimatized to the facility for at least 3 days before the study began.

[0533] Test materials

[0534] Table 3. Overview of Test Materials

[0535]

[0536]

[0537] Experimental Design

[0538] In this study, two 10 mL injections were administered to the abdomen of Yucatan miniature pigs. A test solution of Ig-120 alone was administered on one side of the abdomen. A second test solution of Ig-120 + rHuPH20 was administered on the opposite side of the animal. All test solutions containing rHuPH20 were prepared at 2000 U / mL. Injection sites were randomized between the left and right sides of the animal. The needle was mounted in the handle of a simulated autoinjector and inserted vertically into the SC space. Treatment for each animal is summarized in Table 4.

[0539] Table 4. Description of the process

[0540] Group N / group Test solution (left) Volume (mL) Flow rate (mL / min) 1 6 Ig-120 alone 10 20 2 6 Ig-120+rHuPH20 10 20

[0541] The quantitative endpoints included in this study were the force applied to the syringe barrel during injection, the measurement of post-injection swelling (bubble) volume, area, and height via digital calipers, and the collection of skin temperature changes before and after injection via infrared thermometer. Additionally, post-injection backflow of the test product was collected from the injection site for 30 seconds after needle removal using an ophthalmoscopy to absorb any leakage and quantify by weight. The volume of the injection site bubble was also determined using a 3D camera. Further qualitative post-injection site assessments were performed immediately after injection (T0), and at 15 minutes (T15), 30 minutes (T30), 2 hours (T2h), and approximately 24 hours (T24h) to evaluate erythema, swelling, and induration. Qualitative assessments of the injection site were performed while animals were under anesthesia at T0, T15, T30, and T24h time points, while the T2h assessment was performed while the animals were conscious and held by animal technicians. Standard photographs were obtained before and after injection at T0, T15, T30, T2h, and T24h. Following euthanasia, a 12mm drilled biopsy was obtained from the injection site and fixed in 10% formalin. In summary, the study endpoint was:

[0542] Force applied during injection

[0543] Measurement of post-injection backleakage

[0544] Measurement of bubble dimensions (length / width / height) after injection (using calipers)

[0545] Measurement of bubble size (volume, height, area) using 3D imaging

[0546] The erythema, swelling size, and... were measured at times T0, T15, T30, T2h, and T24h.

[0547] Assessment of induration

[0548] Measurement of injection site temperature (before and after injection)

[0549] Histological evaluation of the injection site 24 hours after injection.

[0550] Research Procedures

[0551] Prior to the study, assess the general health of the animals and collect their weight. The day before the study, aspirate approximately 17 mL of the test product into a 20 mL syringe, cap it, and store it at 2°C–8°C. On the day of the study, remove the syringe from 2°C–8°C and allow it to reach room temperature for at least 30 minutes but no more than 4 hours. The dose retained during the study procedure should be kept at room temperature until transferred back to product development.

[0552] The animal was anesthetized with isoflurane gas and placed in a dorsal lateral recumbent position on a foam wedge placed on a heated operating table, and kept under isoflurane gas for the entire duration of the surgery. The abdominal area was cleaned with Nolvasan, and the injection site was wiped with gauze containing 70% isopropanol and dried with sterile gauze.

[0553] Injection sites were located on the left and right abdominal regions, approximately 5 cm from the inguinal fold towards the midline and 3 cm towards the animal's midline. Each injection site was marked with a permanent marker and then photographed using standard and 3D cameras before needle insertion. Skin temperature at the injection site was recorded using an infrared thermometer before injection. The initial injection for each animal was a control solution (Ig-120 alone). The second injection on the contralateral side of the animal was a test solution containing rHuPH20 (Ig-120 + rHuPH20).

[0554] Assembly of the simulation device

[0555] The simulation device is fabricated by attaching a capped 25G x 1-inch Leur-lok needle to the male end of a 21-inch extension kit. The extension kit is then passed through the interior of the simulation device, and the needle is securely positioned at the end of the device. The simulation device is assembled when the cap is screwed onto the end of the device. The length of the needle protruding from the end of the simulation device is confirmed to be 7.5 mm ± 0.5 mm. The needle remains capped until just before vertical insertion. An uncapped syringe containing test solution is attached to the female end of the extension kit, and the hardware is then infused with the test solution to the needle tip. The syringe is then placed into the syringe pump. A force sensor is then attached to the end of the syringe plunger. After zeroing the force sensor, a force reading is applied. The pump block is positioned such that it abuts the syringe plunger-force sensor end with minimal contact force and is then locked in place. The needle is inserted vertically into the marked injection site and held by hand at a predetermined depth of approximately 7.5 mm. Once the force sensor readings were confirmed, the syringe pump was activated to begin injecting the test article at a specified flow rate of 20 mL / min. After injection, the needle was removed, the pressure on the syringe pump block was released, and force data collection was stopped. The test solution was then back-drained into a balanced lance at the injection site for 30 seconds. The weight of the lance was recorded using an analytical balance with an accuracy of 0.1 mg. The edges of the injection site blister were marked with a permanent marker, and the length, width, and height were measured and recorded using digital calipers. Immediately after injection, photographs were taken with standard and 3D cameras. Three independent evaluators then qualitatively scored the appearance and severity of erythema, swelling / blister size, and hardness (induration) at the injection site using a 5-point scoring system (modified Draize test) based on the 1992 OECD guidelines for grading skin responses (Tables 5, 6, and 7). Evaluators were unaware of each other's scores. The procedure was repeated on the contralateral side of the animal after the first injection using a different test solution (Ig-120 + rHuPH20).

[0556] Table 5. Grading scale for erythema formation

[0557] Scale describe 0 No erythema 1 Very slight erythema (almost imperceptible) 2 Clear erythema 3 moderate erythema 4 Severe erythema (beetroot red) to mild eschar formation

[0558] Table 6. Grading scale for swelling size

[0559]

[0560]

[0561] Table 7. Grading scale for swelling hardness (induration)

[0562] Scale describe 0 No noticeable difference in hardness after injection 1 Very slight hardness (almost imperceptible) 2 Slightly hard 3 moderately hard 4 Very hard

[0563] All three evaluators collected qualitative scores for erythema, swelling, and induration again at 15 minutes, 30 minutes, 2 hours, and approximately 24 hours post-injection. Photographs were taken using a standard camera at each of these time points. Following the final evaluation, sodium pentobarbital and phenytoin sodium were administered as planned. The solution was used to humanely euthanize the animal.

[0564] Computational and statistical methods

[0565] Assessment of applied force

[0566] The SensorVUE software (Loadstar Sensors) is used to record the applied force, such as that measured by a force sensor connected to the end of the syringe plunger, and to calculate the average applied force throughout the injection.

[0567] Assessment of localized swelling volume and area using calipers and 3D imaging

[0568] The volume and area of ​​the swelling after injection were measured using both caliper measurements and 3D camera image analysis. For caliper measurements, digital calipers were used to measure the length, width, and height of the blister formed after injection. Length and width were defined as side-to-side measurements along the longest axis of the blister (i.e., diameter). These values ​​were recorded manually, and the volume was determined using half the formula for an elliptic: Vol = (2 / 3) * π * A * B * C, where A = length / 2, B = width / 2, and C = height.

[0569] 3D imaging was applied as a longitudinal method to measure post-injection swelling. By acquiring high-resolution pre- and post-injection 3D images, the distance between two registered surfaces could be determined. A factory-calibrated bifocal imaging system was used to capture images to measure the distance between the surfaces. Surface registration was performed using a multi-point method leveraging common landmarks between the pre- and post-injection images. Dedicated software was used to calculate the volume, area, and height of post-injection swelling for each injection.

[0570] Caliper measurements and 3D imaging measurements will produce different values ​​for volume, area, and bubble height. The difference is a result of the difference in bubble size measurements. 3D measurements calculate bubble height based on the distance from the top of the bubble to its original skin position, while caliper measurements measure bubble height from the top of the bubble to its edge. Due to skin curvature, this can produce an overall increase in caliper-measured bubble height compared to 3D measurements, resulting in a larger bubble volume and height. However, the measurements are consistent with each other and therefore there is no significant difference.

[0571] Results and discussion

[0572] Quantitative measurements before and after injection

[0573] The applied force was measured during injection. Upon completion of the injection, any backflow of the test solution was collected for 30 seconds and weighed. Additionally, the size of the swollen blister was measured using calipers and 3D imaging employing the methods described above. Temperature readings were also acquired before and after injection to calculate the temperature change at the injection site.

[0574] Evaluation of applied force during injection: The applied force was measured during SC injection by connecting an ultra-miniature force sensor to the end of a 20-cc syringe barrel. The force sensor provided force data electronically recorded throughout the injection at a data capture rate of 2Hz via the DI-100U force sensor interface. The applied force and flow rate for each test solution are summarized in Table 8 and... Figure 1 middle. Figure 2 The figure shows the force applied during injection into a single animal at each flow rate.

[0575] Table 8. Summary of forces applied during injection

[0576]

[0577] Assessment of post-injection backleakage: The amount of backleakage per injection was measured by collecting post-injection fluid at the injection site using a surgical ophthalmoscopy. Each ophthalmoscopy was weighed on an analytical balance prior to collection. Post-injection backleakage from the injection site was collected at 30-second intervals. The ophthalmoscopy was then weighed immediately and the weight recorded. The analytical balance was accurate to 0.1 mg. Backleakage for Ig-120 alone and Ig-120 + rHuPH20 is shown in Table 9, and individual animal data with mean ± SEM are shown in [Table 1]. Figure 3 middle.

[0578] Table 9. Average weight of backleakage (mg ± SEM)

[0579]

[0580] n = (5 animals / group)

[0581] Assessment of blister volume, area, and height after injection (caliper measurement): Swelling at the injection site was marked and measured using digital calipers. The blister volume, dispersion area, and swelling height of each blister were determined as described above, and are summarized in Table 10 for Ig-120 and Ig-120+rHuPH20. Figures 4 to 6 The image shows the volume, area, and height values ​​of a single injection vesicle.

[0582] Table 10. Follicle volume, area, and height after injection of Ig-120+rHuPH20, measured using calipers (mean ± ) SEM)

[0583] Test solution Volume (mL) <![CDATA[Area (cm 2 )]]> Height (mm) Ig-120 16.0±1.6 24.5±1.5 9.7±0.5 Ig-120+rHuPH20 10.1±1.9 21.3±2.2 6.9±0.6 reduce% -36.9 -13.1 -28.9

[0584] Compared with Ig-120 injection alone, Ig-120 + rHuPH20 injection reduced swelling volume, area, and height by 37%, 13%, and 29%, respectively.

[0585] Evaluation of bubble shape, volume, area, and height after injection (3D imaging): Pre- and post-injection photographs were taken using a 3D imaging system. This technique allows for point-to-point alignment of the two images via multi-point surface registration. The distance between any two points is then represented using a colorimetric surface profile map. Areas with no difference between the two images are shown in gray. Where the post-injection image is higher than the pre-injection image, this area is shown in blue shading. Where the post-injection image is lower than the pre-injection image, the distance is shown in orange shading. Color intensity is proportional to the amount of distance measured between the images and the range set for positive and negative measurements. Height measurements outside the range are depicted in white (>6 mm). Bubble volume and height measurements include areas outside the range.

[0586] Each animal has a pre-injection 3D image of the injection site, followed by a second image taken immediately after injection, and these images are mapped to each other using multi-point registration. Using these registered pre-injection / post-injection images, proprietary software was then used to calculate the volume, height, circumference, length, and width of each vesicle. Colorimetric surface profiles of each post-injection vesicle for Ig-120 and Ig-120+rHuPH20 are shown in [image / image / description]. Figures 7A to 7B middle.

[0587] The post-injection vesicle volume, area, and height of Ig-120 and Ig-120+rHuPH20, calculated based on 3D images, are summarized in Table 11. Figures 8 to 10 The diagram shows the volume, area, and height of a single injection vesicle.

[0588] Table 11. Vascular volume, area, and height (mean ± ) after injection of Ig-120+rHuPH20, evaluated using 3D imaging. SEM)

[0589]

[0590] Compared to Ig-120 alone, a reduction in swelling volume and height was observed after injection with Ig-120+rHuPH20. The volume difference appears to be primarily a result of the reduced vesicle height following Ig-120+rHuPH20 injection, as the swelling areas were similar between the two injections.

[0591] Assessment of post-injection temperature changes: The temperature at the injection site is measured using an infrared thermometer just before needle insertion. The measurement is then repeated at the end of the injection to determine if any significant temperature changes might have occurred due to flow rate. Temperature changes are summarized in... Figure 34Although the surface temperature variability of Ig-120 alone was greater, there was no significant difference in the average change of surface temperature between the two test solutions.

[0592] Qualitative evaluation of local injection site

[0593] After the 5 mL injection was completed, the qualitative assessment of erythema, swelling size, and hardness was performed by three different evaluators as described above.

[0594] Qualitative assessment of post-injection erythema: Erythema was minimal with both test solutions. It was most frequently observed at time 15 post-injection but resolved rapidly in all cases, significantly reduced at time 30, and almost completely resolved at time 2h. Erythema scores (mean ± SEM) for each test solution by three evaluators are shown below. Figure 12 The results are summarized in Table 12.

[0595] Table 12. Erythema scores (mean ± SEM) after injection of Ig-120 and Ig-120+rHuPH20

[0596]

[0597] Qualitative assessment of post-injection swelling size: Three evaluators' scores for swelling size (mean ± SEM) over time for each test solution are shown below. Figure 13 The results are summarized in Table 13.

[0598] Table 13. Swelling scores after Ig120+rHuPH20 injection (mean ± SEM)

[0599]

[0600] Injection of Ig-120+rHuPH20 appeared to result in a more rapid reduction in vesicle swelling size over time and near regression at T2h (≤1), while injection of Ig-120 alone remained significant at the T2h time point (approximately 3).

[0601] Qualitative assessment of post-injection hardness (induration): Independent raters also evaluated the hardness (induration) of the blister after injection. Induration scores (mean ± SEM) for each test solution over time are shown in the figure. Figure 14 The results are summarized in Table 14.

[0602] Table 14. Induration score after Ig120+rHuPH20 injection (mean ± SEM)

[0603]

[0604] Compared to Ig-120 injection alone, the induration resulting from post-injection swelling was reduced with Ig-120 + rHuPH20 at T0. Furthermore, compared to Ig-120 alone, the induration with Ig-120 + rHuPH20 showed rapid resolution after injection and near-complete resolution (≤1) by T2h. Conversely, the induration from post-injection blistering resulting from Ig-120 alone remained significant at T2h.

[0605] Photographs were taken of the injection site before and after the 10mL injection procedure. The photographs are shown below. Figures 16A to 21B It should be noted that at the 2-hour time point (T2h), the animal photographs were taken while the animal was not anesthetized and was being held manually by animal technicians. This increased stress on the animal caused some redness of the skin in some animals. Additionally, the injection site may have some increased tension (skin stretching) when photographed. Therefore, qualitative scoring is considered a more accurate assessment of the injection site at the 2-hour time point.

[0606] Summary and Conclusion

[0607] Compared to Ig-120 alone, the Ig-120+rHuPH20 test solution requires approximately 9% less applied force for delivery.

[0608] Compared to Ig-120 alone, Ig-120+rHuPH20 injections reduced backleakage by approximately 43%.

[0609] Compared to Ig-120 alone, post-injection swelling volume, area, and blister height were reduced with Ig-120+rHuPH20 (approximately 37%, 13%, and 29%, respectively).

[0610] Qualitative assessment of post-injection swelling size and induration over time showed that Ig-120+rHuPH20 was reduced compared to Ig-120 alone and subsided more quickly than Ig-120 alone, with most swelling subsiding within 30 minutes.

[0611] Example 2: Evaluation of the use of a 23G needle for vertical subcutaneous injection of 10 ml in an autoinjector

[0612] Grit

[0613] This study examined the delivery of Ig solutions prepared at 120 mg / mL using a simulated autoinjector. Test solutions were delivered at a concentration of 2,000 U / mL with and without rHuPH20. All injections were performed using a handheld device that held the needle in place, allowing for vertical insertion into the subcutaneous space to a depth of 7.5 mm. The test solution volume was 10 mL, delivered over 30 seconds using a 20 cc syringe and a 23G needle. The force applied to the syringe barrel was measured throughout the injection process by attaching a force sensor to the end of the syringe flange. Furthermore, backflow was collected and quantified by weight after injection. Post-injection swelling was measured using calipers and 3D imaging. Following injection, three independent raters evaluated the erythema, swelling size, and induration at the injection site over time (at times T = 0 min, 15 min, 30 min, 2 h, and 24 h) to assess the time to swelling resolution.

[0614] introduce

[0615] Current autoinjectors (AIs) are limited to extremely small volumes (typically ≤2.25 mL), thus limiting their usefulness for delivering larger volumes. For larger volumes, higher flow rates are required for AI practice. Currently, 30 seconds is the recommended time for the device to remain in place during self-administration to prevent device fatigue and potential injection interruptions.

[0616] rHuPH20 has been shown to facilitate fluid and drug delivery to the SC space by transiently and locally depolymerizing hyaluronic acid (HA) in the extracellular matrix (ECM). The depolymerization of HA reduces tissue back pressure in the SC space, subsequently allowing for rapid, large-volume drug delivery. Previous work has demonstrated that rHuPH20 can be used with infusion kits to facilitate large-volume delivery to the SC space at high flow rates.

[0617] Miniature pig models were chosen due to the high similarity between the subcutaneous space and the human subcutaneous space. Previous studies using miniature pig models have demonstrated their translatability for preclinical (Kang et al., 2013) and autoinjector studies (Shi et al., 2021).

[0618] In summary, the aim of this study was to determine whether rHuPH20 could enhance the development of large-volume AIs capable of delivering larger clinically relevant volumes to the SC space at high flow rates using miniature pigs as an animal model. In this study, a handheld, simulated autoinjector device was used to investigate the use of a larger, vertically positioned 23G needle for all injections.

[0619] Test articles and methods

[0620] Test product

[0621] Human gamma globulin (Ig-120: 12% solution)

[0622] Batch number: 1032-17

[0623] Description: Lyophilized powder reconstituted at 120 mg / mL

[0624] Manufacturing date: 21 SEP2020

[0625] Formulation: 10mM histidine, 130mM sodium chloride, pH 6.5

[0626] Storage conditions: 2℃-8℃

[0627] Supplier: BioMed Supply

[0628] Formulated by: Halozyme Product Development

[0629] Recombinant human hyaluronidase rHuPH20 (ENHANZE) TM (pharmaceutical products)

[0630] Batch number: 462-022

[0631] Description: Clear, colorless solution

[0632] Concentration: 10 mg / mL

[0633] Manufacturing date: December 30, 2014

[0634] Retest date: February 2023

[0635] Enzyme activity: 1,229,456 U / mL

[0636] Storage: ≤70℃

[0637] Formulation: 10mM histidine, 130mM sodium chloride, pH 6.5

[0638] Processing conditions: Standard laboratory precautions

[0639] Supplier: Halozyme Therapeutics, Inc.

[0640] Ig dilution buffer

[0641] Description: Clear, colorless liquid

[0642] Formulation: 20mM histidine, 130mM sodium chloride, 0.05% PS 80, pH 6.3

[0643] Batch / Lot Number: 01032-3

[0644] Storage conditions: 2℃-8℃

[0645] Processing conditions: Standard laboratory precautions

[0646] Supplier: Halozyme Therapeutics, Inc.

[0647] preparation

[0648] Preparation of test solution

[0649] The two test solutions used in this study were Ig-120 alone and Ig-120 + rHuPH20. These were prepared by adding rHuPH20 from the concentrated stock solution to a previously prepared Ig solution at 120 mg / mL. The final concentration of rHuPH20 in the test solutions was 2,000 U / mL.

[0650] Ig-120 was thawed overnight at 2°C–8°C. The test solution for the next day was prepared by adding rHuPH20 to the Ig-120 solution at room temperature. A concentrated stock solution of rHuPH20 was used for test preparation (10 mg / mL; 1,229,456 U / mL). To prepare Ig-120+rHuPH20, 270 μL of rHuPH20 was added to 150 mL of Ig-120, and the test solution was stored overnight at 4°C until it was used for syringe filling the day before the study.

[0651] Prior to the study, the rHuPH20 activity of the Ig-120+rHuPH20 solution was tested using a microturbidity assay. The activity of the Ig-120+rHuPH20 test solution was within 10% of the target concentration and was considered within the acceptable range for use in the study. The test solution was prepared and stored at 2°C–8°C, and enzyme activity was tested prior to the start of the study.

[0652] At the end of the study, the rHuPH20 activity of the doses obtained during the study procedure was tested to preserve the samples. The activity of the Ig-120+rHuPH20 test solution was considered to be within acceptable limits. These values ​​are summarized in Tables 15 and 16.

[0653] Table 15. Pre-study activity tests of rHuPH20 activity in test solutions

[0654] Test solution Pre-study concentration (U / mL ± SD) Pre-study Ig-120+rHuPH20 2077±126

[0655] Table 16. Post-study activity tests of rHuPH20 in test solutions

[0656]

[0657]

[0658] Animal description

[0659] Species: Pig (domestic pig)

[0660] Strain: Yucatan mini

[0661] Sex: Female

[0662] Age: >3 months

[0663] Weight: 12kg-16kg at the time of receipt

[0664] Quantity: 6

[0665] Source: Premier BioSource (Ramona, CA)

[0666] animal husbandry

[0667] Animals were received by the facility and allowed to acclimatize before the study began. They were grouped and housed in steel enclosures with an automated, readily available water supply. Except for study days (PM only), animals were fed twice daily (AM and PM). The indoor environment was set to maintain a temperature of approximately 17°C–27°C and a relative humidity of 40%–70%, with a 12-hour light / 12-hour dark cycle. Animals were allowed at least 3 days to acclimatize to the facility before the study began.

[0668] Test materials

[0669] Table 17. Overview of Test Materials

[0670] Test materials supplier High-pressure injector pump KD Scientific, Holliston, MA 23G x 1-inch Precision Glide pin Becton Dickinson.Franklin Lakes.NJ <![CDATA[20mL Luer-Lok TM syringe Becton Dickinson, Franklin Lakes.NJ 21-inch standard hole extension kit B / Braun, Bethlehem.PA Ultra-miniature force sensor Loadstar Sensors; Fremont, CA Force sensor interface Loadstar Sensors; Fremont, CA Force sensor software Loadstar Sensors; Fremont, CA Standard digital camera Canon High-resolution 3D camera Canfield Sciences, Parsippany, NJ 3D-printed simulated automatic injector Halozyme.Inc. 3D-printed autoinjector platform Halozyme.Inc. Digital calipers Fowler Precision Instruments.Switzerland Infrared thermometer Fisher Brand Surgical eye spear Becton Dickinson.Franklin Lakes.NJ

[0671] Experimental Design

[0672] In this study, two 10 mL injections were administered to the abdomen of Yucatan miniature pigs. A test solution of Ig-120 alone was administered on one side of the abdomen. A second test solution of Ig-120 + rHuPH20 was administered on the opposite side of the animal. All test solutions containing rHuPH20 were prepared at 2000 U / mL. Injection sites were randomized, and each test solution was injected three times on both the left and right sides of the animal. The needle was mounted in the handle of a simulated autoinjector and inserted vertically into the SC space. The treatment for each animal is summarized in Table 18, under the treatment description.

[0673] Table 18. Description of the Process

[0674] Group N / group Test solution (left) Volume (mL) Flow rate (mL / min) 1 6 Ig-120 alone 10 20 2 6 Ig-120+rHuPH20 10 20

[0675] The quantitative endpoints included in this study were the force applied to the syringe barrel during injection, the measurement of post-injection swelling (bubble) volume, area, and height, and the collection of skin temperature changes before and after injection via infrared thermometer. Additionally, post-injection backflow of the test product was collected from the injection site for 30 seconds after needle removal using an ophthalmoscopy to absorb any leakage and quantify by weight. Bubble volume at the injection site was determined by digital caliper measurements (length, width, and height) and by 3D camera imaging. Further qualitative post-injection site assessments were performed immediately after injection (T0), and at 15 minutes (T15), 30 minutes (T30), 2 hours (T2h), and approximately 24 hours (T24h) to evaluate erythema, swelling, and induration. Qualitative assessments of the injection site were performed when animals were anesthetized at T0, T15, T30, and T24h, while the T2h assessment was performed when animals were conscious and held by animal technicians. Standard photographs were obtained before and after injection at T0, T15, T30, T2h, and T24h. Following euthanasia, a 12mm drilled biopsy was obtained from the injection site and fixed in 10% formalin. In summary, the study endpoint was:

[0676] Force applied during injection

[0677] Measurement of post-injection backleakage

[0678] Measurement of bubble dimensions (length / width / height) after injection (using calipers)

[0679] Measurement of bubble size (volume, height, area) using 3D imaging

[0680] The erythema, swelling size, and... were measured at times T0, T15, T30, T2h, and T24h.

[0681] Assessment of induration

[0682] Temperature measurements taken at the injection site before and after injection.

[0683] Research Procedures

[0684] Prior to the study, assess the general health of the animals and collect their weight. The day before the study, aspirate approximately 17 mL of the test product into a 20 mL syringe, cap it, and store it at 2°C–8°C. On the day of the study, remove the syringe from 2°C–8°C and allow it to reach room temperature for at least 30 minutes but no more than 2 hours. Retain the dose obtained during the study procedure on ice until transferred back to product development for enzymatic testing on the day following the study procedure.

[0685] The animal was anesthetized with isoflurane gas and placed in a dorsal lateral recumbent position on a foam wedge placed on a heated operating table, and kept under isoflurane gas for the entire duration of the surgery. The abdominal area was cleaned with Nolvasan, and the injection site was wiped with gauze containing 70% isopropanol and dried with sterile gauze.

[0686] Injection sites were located on the left and right abdominal regions, approximately 6 cm from the inguinal fold towards the midline and cranially, and approximately 3 cm towards the animal's midline. Each injection site was marked with a permanent marker and then photographed using standard and 3D cameras before needle insertion. Skin temperature at the injection site was recorded using an infrared thermometer before injection. The initial injection for each animal was a control solution (Ig-120 alone). The second injection on the contralateral side of the animal was a test solution containing rHuPH20 (Ig-120 + rHuPH20).

[0687] Assembly of the simulation device

[0688] A simulation device was prepared by attaching a capped 23G x 1-inch Luer-lok needle to the male end of a 21-inch extension kit. The extension kit was then passed through the interior of the simulation device, and the needle was securely positioned at the end of the device. The device with the needle attached was then inserted into the platform. The length of the needle protruding from the end of the simulation device was confirmed to be 7.5 mm ± 0.5 mm (providing an injection depth of 7.5 mm). The needle remained capped until just before vertical needle insertion. A 20 cc syringe containing the test solution was attached uncapped to the female end of the extension kit, and the hardware was then infused with the test solution into the needle tip, and the syringe was placed into the syringe pump. A force sensor was then attached to the end of the syringe plunger. The applied force reading was initiated, and the force sensor was zeroed. The pump block was positioned such that it abutted the syringe plunger-force sensor end with minimal contact force and then locked in place. Once the applied force reading was confirmed to be recorded, the syringe pump was started to inject the test article at the specified flow rate of 20 mL / min. After injection, the needle was removed, pressure was released from the syringe pump block, and force data collection was stopped. The test solution was then aspirated back into a balanced lance for 30 seconds by aspirating the injection site. The weight of the lance was recorded using an analytical balance with an accuracy of 0.1 mg. The edges of the injection site blister were marked with permanent markers, and the length, width, and height were measured and recorded using digital calipers. The injection site was then photographed using standard and 3D cameras, and three independent evaluators qualitatively scored the appearance and severity of erythema, swelling / blister size, and hardness (induration) at the injection site using a 5-point scoring system (modified Draize test) based on the 1992 OECD guidelines for grading skin responses (Tables 18, 19, and 20). Evaluators were unaware of each other's scores. The procedure was repeated on the contralateral side of the animal after the first injection using a different test solution (Ig-120 + rHuPH20).

[0689] Table 18. Grading scale for erythema formation

[0690] Scale describe 0 No erythema 1 Very slight erythema (almost imperceptible) 2 Clear erythema 3 moderate erythema 4 Severe erythema (beetroot red) to mild eschar formation

[0691] Table 19. Grading scale for swelling size

[0692] Scale describe 0 No swelling 1 Very slight swelling 2 Mild swelling 3 Moderate swelling 4 Severe swelling

[0693] Table 20. Grading scale for swelling hardness (induration)

[0694] Scale describe 0 No noticeable difference in hardness after injection 1 Very slight hardness (almost imperceptible) 2 Slightly hard 3 moderately hard 4 Very hard

[0695] All three evaluators collected qualitative scores for erythema, swelling, and induration again at 15 minutes, 30 minutes, 2 hours, and approximately 24 hours post-injection, and photographs were taken using a standard camera at each of these time points. Following the final evaluation, sodium pentobarbital and phenytoin sodium were administered as planned. The solution was used to humanely euthanize the animal.

[0696] Computational and statistical methods

[0697] Assessment of applied force

[0698] The SensorVUE software (Loadstar Sensors) is used to record the applied force, such as that measured by a force sensor connected to the end of the syringe plunger, and to calculate the average applied force throughout the injection.

[0699] Assessment of localized swelling volume and area using calipers and 3D imaging

[0700] The volume and area of ​​the swelling after injection were measured using both caliper measurements and 3D camera image analysis. For caliper measurements, digital calipers were used to measure the length, width, and height of the blister formed after injection. Length and width were defined as side-to-side measurements along the longest axis of the blister (i.e., diameter). These values ​​were recorded manually, and the volume was determined using half the formula for an elliptic: Vol = (2 / 3) * π * A * B * C, where A = length / 2, B = width / 2, and C = height.

[0701] 3D imaging was applied as a longitudinal method to measure post-injection swelling. By acquiring high-resolution pre- and post-injection 3D images, the distance between two registered surfaces could be determined. A factory-calibrated bifocal imaging system was used to capture images to measure the distance between the surfaces. Surface registration was performed using a multi-point method leveraging common landmarks between the pre- and post-injection images. Dedicated software was used to calculate the volume, area, and height of post-injection swelling for each injection.

[0702] Caliper measurements and 3D imaging measurements will produce different values ​​for volume, area, and bubble height. The difference is a result of the difference in bubble size measurements. 3D measurements calculate bubble height based on the distance from the top of the bubble to its original skin position, while caliper measurements measure bubble height from the top of the bubble to its edge. Due to skin curvature, this results in an overall increase in caliper-measured bubble height compared to 3D measurements, leading to a larger bubble volume and height. However, the measurements are consistent with each other and therefore differ only due to the methodologies.

[0703] Results and discussion

[0704] Quantitative measurements before and after injection

[0705] Quantitative measurements include applied force, backleakage, bubble size (length, width, and height), and pre- and post-injection temperatures (as described above).

[0706] Evaluation of applied force during injection: The applied force is measured during SC injection by connecting an ultra-miniature force sensor to the end of a 20-cc syringe barrel. The force sensor provides force data electronically recorded throughout the injection at a data capture rate of 2Hz via the DI-100U force sensor interface.

[0707] The applied force and flow rate for each test solution are summarized in Table 21 and Figure 22 middle. Figure 23 The figure shows the force applied during injection into a single animal at each flow rate.

[0708] Table 21. Summary of forces applied during injection

[0709]

[0710] n = (5 animals / group)

[0711] Assessment of post-injection backleakage: The amount of backleakage after each injection was measured by collecting post-injection fluid at the injection site using a surgical ophthalmoscopy. Each ophthalmoscopy was weighed on an analytical balance prior to collection. Post-injection backleakage from the injection site was collected at 30-second intervals. The ophthalmoscopy was then weighed immediately and the weight was recorded. The analytical balance was accurate to 0.1 mg. Backleakage for Ig-120 alone and Ig-120 + rHuPH20 is shown in Table 22, and individual animal data with mean ± SEM are shown in [Table 22]. Figure 24 middle.

[0712] Table 22. Average weight of backleakage (mg ± SEM)

[0713]

[0714] Assessment of blister volume, area, and height after injection (caliper measurement): Swelling at the injection site was marked and measured using digital calipers. The blister volume, dispersion area, and swelling height of each blister were determined as described above, and are summarized in Table 23 for Ig-120 and Ig-120+rHuPH20. Figures 25 to 27 The image shows the volume, area, and height values ​​of a single injection vesicle.

[0715] Table 23. Follicle volume, area, and height after injection of Ig-120+rHuPH20, measured using calipers (mean ± ) SEM)

[0716]

[0717]

[0718] Evaluation of blister shape, volume, area, and height after injection (3D imaging):

[0719] Pre- and post-injection photographs were captured using a 3D imaging system. This technique allows for point-to-point alignment of the two images via multi-point surface registration. A colorimetric surface profile map is then used to represent the distance between any two points. Areas with no difference between the two images are shown in gray. Where the post-injection image is higher than the pre-injection image, this area is shown in blue shading. Where the post-injection image is lower than the pre-injection image, the distance is shown in orange shading. The color intensity is proportional to the amount of distance measured between the images and the range set for positive and negative measurements. Measurements outside the range are depicted in white. Bubble measurements of volume and height include areas outside the range.

[0720] Each animal has a pre-injection 3D image of the injection site, followed by a second image taken immediately after injection, and these images are mapped to each other using multi-point registration. Using these registered pre-injection / post-injection images, proprietary software was then used to calculate the volume, height, circumference, length, and width of each vesicle. Colorimetric surface profiles of each post-injection vesicle for Ig-120 and Ig-120+rHuPH20 are shown below. Figure 28A and Figure 28B middle.

[0721] The post-injection vesicle volume, area, and height of Ig-120 and Ig-120+rHuPH20, calculated based on 3D images, are summarized in Table 24. Figures 29 to 31 The diagram shows the volume, area, and height of a single injection vesicle.

[0722] Table 24. Vascular volume, area, and height (mean ± ) after injection of Ig-120+rHuPH20, evaluated using 3D imaging. SEM)

[0723]

[0724] Assessment of post-injection temperature changes: The temperature at the injection site is measured using an infrared thermometer just before needle insertion. The measurement is then repeated at the end of the injection to determine if any significant temperature changes might have occurred due to flow rate. Temperature changes are summarized in... Figure 32 Although the surface temperature variability of Ig-120 alone was greater, there was no significant difference in the average change of surface temperature between the two test solutions.

[0725] Qualitative evaluation of local injection site

[0726] After the 10 mL injection was completed, a qualitative assessment of the erythema, swelling size, and hardness was performed by three different evaluators as described above.

[0727] Qualitative assessment of post-injection erythema: Erythema was minimal with both test solutions. It was most frequently observed at time 15 post-injection but resolved rapidly in all cases, significantly reduced at time 30, and almost completely resolved at time 2h. Erythema scores (mean ± SEM) for each test solution by three evaluators are shown below. Figure 33 The results are summarized in Table 25.

[0728] Table 25. Erythema scores (mean ± SEM) after injection of Ig-120 and Ig-120+rHuPH20

[0729]

[0730] Qualitative assessment of post-injection swelling size: Three evaluators scored the swelling size (mean ± SEM) for each test solution, as shown in the table below. Figure 34 The results are summarized in Table 26.

[0731] Table 26. Swelling scores after Ig120+rHuPH20 injection (mean ± SEM)

[0732]

[0733] Qualitative assessment of post-injection hardness (induration): Independent raters also evaluated the hardness (induration) of the blister after injection. Induration scores (mean ± SEM) for each test solution over time are shown in the figure. Figure 35 The results are summarized in Table 27.

[0734] Table 27. Induration scores after Ig120+rHuPH20 injection (mean ± SEM)

[0735]

[0736]

[0737] Photographs were taken of the injection site before and after the 10mL injection procedure. The photographs are shown below. Figures 36A to 42B It should be noted that at the 2-hour time point (T2h), the animal photographs were taken while the animal was anesthetized and held manually by a veterinarian. This increased stress on the animal caused some redness of the skin in some animals. Additionally, the injection site may have some increased tension (skin stretching) when photographed. Therefore, qualitative scoring is considered a more accurate assessment of the injection site at the 2-hour time point.

[0738] Summary and Conclusion

[0739] By adding rHuPH20, backleakage was reduced by 66%.

[0740] The application force using a 23G needle was reduced by approximately 40% compared to previous studies using a 25G needle; the addition of rHuPH20 reduced the application force by approximately 7% compared to the control injection.

[0741] Compared to Ig-120 injections alone, swelling and induration decreased more rapidly with Ig-120+rHuPH20 injections.

[0742] Example 3: For the development of an autoinjector, a 25G needle was used to inject 10 ml of rHuPH20 at 5000 U / mL. Evaluation of subcutaneous vertical injection

[0743] Grit

[0744] This study examined the delivery of Ig solutions prepared at 120 mg / mL using a handheld simulated autoinjector. Test solutions were delivered at a concentration of 5,000 U / mL with and without rHuPH20. All injections were performed using a handheld device that held the needle in place, allowing for vertical insertion into the subcutaneous space to a depth of 7.5 mm. The test solution volume was 10 mL, delivered over 30 seconds using a 20 cc syringe and a 25G needle. The force applied to the syringe barrel was measured throughout the injection process by attaching a force sensor to the end of the syringe flange. Furthermore, backflow was collected and quantified by weight after injection. Post-injection swelling was measured using calipers and 3D imaging. Following injection, three independent raters evaluated the erythema, swelling size, and induration at the injection site over time (at times T = 0 min, 15 min, 30 min, 2 h, and 24 h) to assess the time to swelling resolution.

[0745] introduce

[0746] Current autoinjectors (AIs) are limited to extremely small volumes (typically ≤2.25 mL), thus limiting their usefulness for delivering larger volumes. For larger volumes, higher flow rates are required for AI practice. Currently, 30 seconds is the recommended time for the device to remain in place during self-administration to prevent fatigue and potential injection interruptions.

[0747] rHuPH20 has been shown to facilitate fluid and drug delivery to the SC space by transiently and locally depolymerizing hyaluronic acid (HA) in the extracellular matrix (ECM). The depolymerization of HA reduces tissue back pressure in the SC space, subsequently allowing for rapid, large-volume drug delivery. Previous work has demonstrated that rHuPH20 can be used with infusion kits to facilitate large-volume delivery to the SC space at high flow rates.

[0748] Miniature pig models were chosen due to the high similarity between the subcutaneous space and the human subcutaneous space. Previous studies using miniature pig models have demonstrated their translatability for preclinical (Kang et al., 2013) and autoinjector studies (Shi et al., 2021).

[0749] In summary, the aim of this study was to determine whether rHuPH20 could enhance the development of large-volume artificial injection (AI) capable of delivering larger clinically relevant volumes to the SC space at high flow rates using miniature pigs as an animal model. In this study, the use of higher concentrations of rHuPH20 with a 25G needle was investigated for all injections (5000 U / mL). This study builds upon data from previous studies that also used a 25G needle for vertical needle insertion injection of Ig-120 ± rHuPH20, but with a lower concentration of rHuPH20 (2,000 U / mL). All injections in this study were performed via a handheld simulated autoinjector device at a depth of 7.5 mm using a vertically positioned 25G needle.

[0750] Test articles and methods

[0751] Test product

[0752] Human gamma globulin (Ig-120: 12% solution)

[0753] Batch number: 1032-17

[0754] Description: Lyophilized powder reconstituted at 120 mg / mL

[0755] Manufacturing date: 21 SEP2020

[0756] Formulation: 10mM histidine, 130mM sodium chloride, pH 6.5

[0757] Storage conditions: 2℃-8℃

[0758] Supplier: BioMed Supply

[0759] Formulated by: Halozyme Product Development

[0760] Recombinant human hyaluronidase rHuPH20 (ENHANZE) TM (pharmaceutical products)

[0761] Batch number: 462-022

[0762] Description: Clear, colorless solution

[0763] Concentration: 10 mg / mL

[0764] Manufacturing date: December 30, 2014

[0765] Retest date: February 2023

[0766] Enzyme activity: 1,229,456 U / mL

[0767] Storage: ≤70℃

[0768] Formulation: 10mM histidine, 130mM sodium chloride, pH 6.5

[0769] Processing conditions: Standard laboratory precautions

[0770] Supplier: Halozyme Therapeutics, Inc.

[0771] preparation

[0772] Preparation of test solution

[0773] The two test solutions used in this study were Ig-120 alone and Ig-120 + rHuPH20. These were prepared by adding rHuPH20 from the concentrated stock solution to a previously prepared Ig solution at 120 mg / mL. The final concentration of rHuPH20 in the test solutions was 5,000 U / mL.

[0774] Ig-120 was thawed overnight at 2°C–8°C. The test solution for the next day was prepared by adding rHuPH20 to the Ig-120 solution at room temperature. A concentrated stock solution of rHuPH20 was used for test preparation (10 mg / mL; 1,229,456 U / mL). To prepare Ig-120+rHuPH20, 675 μL of rHuPH20 was added to 150 mL of Ig-120, and the test solution was used for syringe filling immediately the day before the study.

[0775] Prior to the study, the rHuPH20 activity of the Ig-120+rHuPH20 solution was tested using a microturbidity assay. The activity of the Ig-120+rHuPH20 test solution was within 10% of the target concentration and considered acceptable for use in the study. The test solution was stored at 2°C–8°C until the start of the study. The rHuPH20 activity values ​​are summarized in Table 28.

[0776] Table 28. Pre-study activity tests for rHuPH20 activity in test solutions

[0777] Test solution Pre-study concentration (U / mL ± SD) Pre-study Ig-120+rHuPH20 4941±84

[0778] At the end of the study, the rHuPH20 acti...

Claims

1. A method for treating a disease or condition in a subject in need, the method comprising administering to the subject via subcutaneous administration of a formulation of about 3 mL to about 50 mL, the formulation comprising a therapeutically effective amount of an active ingredient selected from small molecules, peptide fragments, biologics, nanoparticles, antibodies, antibody fragments, and small molecule antiviral agents, wherein the subcutaneous administration is performed via a high-volume autoinjector with an initial delivery force of about 3 lbf to about 50 lbf, a final delivery force of about 5 lbf to about 20 lbf, an initial pressure of about 50 psi to about 200 psi, and / or a final pressure of about 20 psi to about 75 psi.

2. The method according to claim 1, wherein the formulation further comprises hyaluronidase.

3. The method according to claim 2, wherein the hyaluronidase is recombinant human hyaluronidase.

4. The method according to claim 2 or 3, wherein the hyaluronidase is recombinant human hyaluronidase PH20.

5. The method according to any one of claims 2 to 4, wherein the hyaluronidase has an activity of about 150 U / mL to about 150 kU / mL.

6. The method according to any one of claims 2 to 4, wherein the hyaluronidase has an activity of about 500 U / mL to about 5,000 U / mL.

7. The method according to any one of claims 2 to 4, wherein the hyaluronidase has an activity of about 1,500 U / mL to about 10,000 U / mL.

8. The method according to any one of claims 1 to 7, wherein the active ingredient is a small molecule, peptide fragment, biological agent, or nanoparticle.

9. The method according to any one of claims 1 to 8, wherein the active ingredient is an antibody, an antibody fragment, or a small molecule antiviral agent.

10. The method according to any one of claims 1 to 9, the method comprising administering about 10 mL to about 20 mL of the preparation to the subject.

11. The method according to any one of claims 1 to 10, the method comprising administering about 3 mL to about 15 mL of the preparation to the subject.

12. The method according to any one of claims 1 to 11, the method comprising administering to the subject about 3 mL, about 3.1 mL, about 3.2 mL, about 3.4 mL, about 3.5 mL, about 3.6 mL, about 3.7 mL, about 3.8 mL, about 3.9 mL, about 4 mL, about 4.1 mL, about 4.2 mL, about 4.3 mL, about 4.4 mL, about 4.5 mL, about 5 mL, about 5.1 mL, about 5.2 mL, about 5.3 mL, about 5.4 mL, about 5.5 mL, about 5.6 mL, about 5.7 mL, about 5.8 mL, about 5.9 mL, about 6 mL, about 6.1 mL, about 6.2 mL, about 6.3 mL, about 6.4 mL, about 6.5 mL, or about 6 mL. 6mL, approximately 6.7mL, approximately 6.8mL, approximately 6.9mL, approximately 7mL, approximately 7.1mL, approximately 7.2mL, approximately 7.3mL, approximately 7.4mL, approximately 7.5mL, approximately 7.6mL, approximately 7.7mL, approximately 7.8mL, approximately 7.9mL, approximately 8mL, approximately 8.1mL, approximately 8.2mL, approximately 8.3mL, approximately 8.4mL, approximately 8.5mL, approximately 8.6mL, approximately 8.7mL, approximately 8.8mL, approximately 8.9mL, approximately 9mL, approximately 9.1mL, approximately 9.2mL, approximately 9.3mL, approximately 9.4mL, approximately 9.5mL, approximately 9.6mL, approximately 9.7mL, approximately 9.8mL, approximately 9.9mL, approximately 10mL, approximately 10.1mL, approximately 10.2mL L, approximately 10.3 mL, approximately 10.4 mL, approximately 10.5 mL, approximately 10.6 mL, approximately 10.7 mL, approximately 10.8 mL, approximately 10.9 mL, approximately 11 mL, approximately 11.1 mL, approximately 11.2 mL, approximately 11.3 mL, approximately 11.4 mL, approximately 11.5 mL, approximately 11.6 mL, approximately 11.7 mL, approximately 11.8 mL, approximately 11.9 mL, approximately 12 mL, approximately 12.1 mL, approximately 12.2 mL, approximately 12.3 mL, approximately 12.4 mL, approximately 12.5 mL, approximately 12.6 mL, approximately 12.7 mL, approximately 12.8 mL, approximately 12.9 mL, approximately 13 mL, approximately 13.1 mL, approximately 13.2 mL, approximately 13.3 mL, approximately 13.4 mL mL, approximately 13.5 mL, approximately 13.6 mL, approximately 13.7 mL, approximately 13.8 mL, approximately 13.9 mL, approximately 14 mL, approximately 14.1 mL, approximately 14.2 mL, approximately 14.3 mL, approximately 14.4 mL, approximately 14.5 mL, approximately 14.6 mL, approximately 14.7 mL, approximately 14.8 mL, approximately 14.9 mL, approximately 15 mL, approximately 15.1 mL, approximately 15.2 mL, approximately 15.3 mL, approximately 15.4 mL, approximately 15.5 mL, approximately 15.6 mL, approximately 15.7 mL, approximately 15.8 mL, approximately 15.9 mL, approximately 16 mL, approximately 16.1 mL, approximately 16.2 mL, approximately 16.3 mL, approximately 16.4 mL, approximately 16.5 mL, approximately 16.6mL, approximately 16.7mL, approximately 16.8mL, approximately 16.9mL, approximately 17mL, approximately 17.1mL, approximately 17.2mL, approximately 17.3mL, approximately 17.4mL, approximately 17.5mL, approximately 17.6mL, approximately 17.7mL, approximately 17.8mL, approximately 17.9mL, approximately 18mL, approximately 18.1mL, approximately 18.2mL, approximately 18.3mL, approximately 18.4mL, approximately 18.5mL, approximately 18.6mL, approximately 18. 7mL, approximately 18.8mL, approximately 18.9mL, approximately 19mL, approximately 19.1mL, approximately 19.2mL, approximately 19.3mL, approximately 19.4mL, approximately 19.5mL, approximately 19.6mL, approximately 19.7mL, approximately 19.8mL, approximately 19.9mL, approximately 20mL, approximately 20.1mL, approximately 20.2mL, approximately 20.3mL, approximately 20.4mL, approximately 20.5mL, approximately 20.6mL, approximately 20.7mL, approximately 20.8mL Approximately 20.9 mL, approximately 21 mL, approximately 21.1 mL, approximately 21.2 mL, approximately 21.3 mL, approximately 21.4 mL, approximately 21.5 mL, approximately 21.6 mL, approximately 21.7 mL, approximately 21.8 mL, approximately 21.9 mL, approximately 22 mL, approximately 22.1 mL, approximately 22.2 mL, approximately 22.3 mL, approximately 22.4 mL, approximately 22.5 mL, approximately 22.6 mL, approximately 22.7 mL, approximately 22.8 mL, approximately 22.9 mL Approximately 23 mL, 23.1 mL, 23.2 mL, 23.3 mL, 23.4 mL, 23.5 mL, 23.6 mL, 23.7 mL, 23.8 mL, 23.9 mL, 24 mL, 24.1 mL, 24.2 mL, 24.3 mL, 24.4 mL, 24.5 mL, 24.6 mL, 24.7 mL, 24.8 mL, 24.9 mL, or 25 mL.

13. The method according to any one of claims 1 to 12, wherein the method comprises administering the formulation using a high-volume autoinjector.

14. The method according to any one of claims 1 to 13, the method comprising administering the formulation using a high-volume autoinjector with an initial delivery force of about 3 lbf to about 50 lbf.

15. The method according to any one of claims 1 to 14, the method comprising administering the formulation using a high-volume autoinjector with a final delivery force of about 5 lbf to about 20 lbf.

16. The method according to any one of claims 1 to 15, the method comprising administering the formulation using a high-volume autoinjector at an initial pressure of about 50 psi to about 200 psi.

17. The method according to any one of claims 1 to 16, wherein the method comprises administering the formulation using a high-volume autoinjector at a final pressure of about 20 psi to about 75 psi.

18. The method according to any one of claims 1 to 17, wherein the formulation is in a pre-filled syringe.

19. The method of claim 18, wherein the pre-filled syringe contains about 3 mL, about 3.1 mL, about 3.2 mL, about 3.4 mL, about 3.5 mL, about 3.6 mL, about 3.7 mL, about 3.8 mL, about 3.9 mL, about 4 mL, about 4.1 mL, about 4.2 mL, about 4.3 mL, about 4.4 mL, about 4.5 mL, about 5 mL, about 5.1 mL, about 5.2 mL, about 5.3 mL, about 5.4 mL, about 5.5 mL, about 5.6 mL, about 5.7 mL, about 5.8 mL, about 5.9 mL, about 6 mL, about 6.1 mL, about 6.2 mL, about 6.3 mL, about 6.4 mL, about 6.5 mL, about 6.6 mL, about 6.7 mL. mL, approximately 6.8 mL, approximately 6.9 mL, approximately 7 mL, approximately 7.1 mL, approximately 7.2 mL, approximately 7.3 mL, approximately 7.4 mL, approximately 7.5 mL, approximately 7.6 mL, approximately 7.7 mL, approximately 7.8 mL, approximately 7.9 mL, approximately 8 mL, approximately 8.1 mL, approximately 8.2 mL, approximately 8.3 mL, approximately 8.4 mL, approximately 8.5 mL, approximately 8.6 mL, approximately 8.7 mL, approximately 8.8 mL, approximately 8.9 mL, approximately 9 mL, approximately 9.1 mL, approximately 9.2 mL, approximately 9.3 mL, approximately 9.4 mL, approximately 9.5 mL, approximately 9.6 mL, approximately 9.7 mL, approximately 9.8 mL, approximately 9.9 mL, approximately 10 mL, approximately 10.1 mL, approximately 10.2 mL, approximately 10.3 mL L, approximately 10.4 mL, approximately 10.5 mL, approximately 10.6 mL, approximately 10.7 mL, approximately 10.8 mL, approximately 10.9 mL, approximately 11 mL, approximately 11.1 mL, approximately 11.2 mL, approximately 11.3 mL, approximately 11.4 mL, approximately 11.5 mL, approximately 11.6 mL, approximately 11.7 mL, approximately 11.8 mL, approximately 11.9 mL, approximately 12 mL, approximately 12.1 mL, approximately 12.2 mL, approximately 12.3 mL, approximately 12.4 mL, approximately 12.5 mL, approximately 12.6 mL, approximately 12.7 mL, approximately 12.8 mL, approximately 12.9 mL, approximately 13 mL, approximately 13.1 mL, approximately 13.2 mL, approximately 13.3 mL, approximately 13.4 mL, approximately 13.5 mL mL, approximately 13.6 mL, approximately 13.7 mL, approximately 13.8 mL, approximately 13.9 mL, approximately 14 mL, approximately 14.1 mL, approximately 14.2 mL, approximately 14.3 mL, approximately 14.4 mL, approximately 14.5 mL, approximately 14.6 mL, approximately 14.7 mL, approximately 14.8 mL, approximately 14.9 mL, approximately 15 mL, approximately 15.1 mL, approximately 15.2 mL, approximately 15.3 mL, approximately 15.4 mL, approximately 15.5 mL, approximately 15.6 mL, approximately 15.7 mL, approximately 15.8 mL, approximately 15.9 mL, approximately 16 mL, approximately 16.1 mL, approximately 16.2 mL, approximately 16.3 mL, approximately 16.4 mL, approximately 16.5 mL, approximately 16.6 mL, approximately 16.7mL, approximately 16.8mL, approximately 16.9mL, approximately 17mL, approximately 17.1mL, approximately 17.2mL, approximately 17.3mL, approximately 17.4mL, approximately 17.5mL, approximately 17.6mL, approximately 17.7mL, approximately 17.8mL, approximately 17.9mL, approximately 18mL, approximately 18.1mL, approximately 18.2mL, approximately 18.3mL, approximately 18.4mL, approximately 18.5mL, approximately 18.6mL, approximately 18.7mL, approximately 18 0.8mL, approximately 18.9mL, approximately 19mL, approximately 19.1mL, approximately 19.2mL, approximately 19.3mL, approximately 19.4mL, approximately 19.5mL, approximately 19.6mL, approximately 19.7mL, approximately 19.8mL, approximately 19.9mL, approximately 20mL, approximately 20.1mL, approximately 20.2mL, approximately 20.3mL, approximately 20.4mL, approximately 20.5mL, approximately 20.6mL, approximately 20.7mL, approximately 20.8mL, approximately 20 0.9mL, approximately 21mL, approximately 21.1mL, approximately 21.2mL, approximately 21.3mL, approximately 21.4mL, approximately 21.5mL, approximately 21.6mL, approximately 21.7mL, approximately 21.8mL, approximately 21.9mL, approximately 22mL, approximately 22.1mL, approximately 22.2mL, approximately 22.3mL, approximately 22.4mL, approximately 22.5mL, approximately 22.6mL, approximately 22.7mL, approximately 22.8mL, approximately 22.9mL, approximately 23... The preparation may be expressed in mL, approximately 23.1 mL, approximately 23.2 mL, approximately 23.3 mL, approximately 23.4 mL, approximately 23.5 mL, approximately 23.6 mL, approximately 23.7 mL, approximately 23.8 mL, approximately 23.9 mL, approximately 24 mL, approximately 24.1 mL, approximately 24.2 mL, approximately 24.3 mL, approximately 24.4 mL, approximately 24.5 mL, approximately 24.6 mL, approximately 24.7 mL, approximately 24.8 mL, approximately 24.9 mL, or approximately 25 mL.

20. The method of claim 18 or 19, wherein the prefilled syringe comprises a needle having a gauge of about 20 to about 33.

21. The method according to any one of claims 18 to 20, wherein the pre-filled syringe comprises a 20-gauge needle, a 21-gauge needle, a 22-gauge needle, a 23-gauge needle, a 24-gauge needle, a 25-gauge needle, a 26-gauge needle, a 27-gauge needle, a 28-gauge needle, a 29-gauge needle, a 30-gauge needle, a 31-gauge needle, a 32-gauge needle, or a 33-gauge needle.

22. The method according to any one of claims 1 to 21, the method comprising administering the formulation at a rate of about 0.08 mL / s to about 1.00 mL / s.

23. The method according to any one of claims 1 to 22, the method comprising administering the formulation at a rate of at least about 0.08 mL / s to about 1.0 mL / s.

24. The method according to any one of claims 1 to 22, wherein the method comprises administering the formulation at a rate of at least or faster than about 0.08 mL / s to about 1.00 mL / s.

25. The method according to any one of claims 1 to 24, wherein the application takes about 10 seconds to about 40 seconds.

26. The method according to any one of claims 1 to 24, wherein the application takes at least about 10 seconds to about 40 seconds.

27. The method according to any one of claims 1 to 24, wherein the application takes at least or less than about 10 seconds to about 40 seconds.

28. The method according to any one of claims 1 to 24, wherein the application takes about 15 seconds to about 30 seconds.

29. The method according to any one of claims 1 to 24, wherein the application takes at least about 15 seconds to about 30 seconds.

30. The method according to any one of claims 1 to 24, wherein the application takes at least or less than about 15 seconds to about 30 seconds.

31. The method according to any one of claims 1 to 24, the method comprising administering about 5 mL of the formulation at a rate of about 0.14 mL / s to about 0.21 mL / s.

32. The method according to any one of claims 1 to 24, the method comprising administering about 10 mL of the formulation at a rate of about 0.32 mL / s to about 0.42 mL / s.

33. The method according to any one of claims 1 to 32, wherein the formulation has a viscosity of about 1 cP to about 50 cP.

34. The method according to any one of claims 1 to 32, wherein the application of the formulation requires less force compared to similar formulations that do not contain hyaluronidase.

35. The method according to any one of claims 1 to 34, the method comprising applying about 5 mL of the formulation at a rate of about 0.14 mL / s to about 0.21 mL / s and an application force of about 10 N to about 45 N.

36. The method of claim 35, wherein the method comprises administering the formulation to the subject using a pre-filled syringe comprising a 25-gauge needle.

37. The method according to any one of claims 1 to 34, the method comprising administering about 10 mL of the formulation to the subject at a rate of about 0.32 mL / s to about 0.42 mL / s and an application force of about 25 N to about 50 N.

38. The method of claim 37, wherein the method comprises administering the formulation to the subject using a pre-filled syringe comprising a 25-gauge needle.

39. The method according to any one of claims 2 to 38, wherein the preparation is administered more rapidly when compared with similar preparations that do not contain hyaluronidase.

40. The method according to any one of claims 2 to 39, wherein the administration of the formulation causes fewer side effects in the subject compared to similar formulations that do not contain hyaluronidase.

41. The method according to any one of claims 2 to 40, wherein the administration of the preparation causes less pain and discomfort in the subject compared to similar preparations that do not contain hyaluronidase.

42. The method according to any one of claims 2 to 41, wherein the application of the formulation at the injection site causes less backflow compared to similar formulations that do not contain hyaluronidase.

43. The method of claim 42, wherein the backleakage at the injection site is reduced by about 85% to about 30% compared to a similar formulation that does not contain hyaluronidase.

44. The method according to any one of claims 2 to 43, wherein when applied to the injection site, the preparation causes a smaller volume and / or height of swelling compared to similar preparations that do not contain hyaluronidase.

45. The method of claim 44, wherein, compared with a similar formulation that does not contain hyaluronidase, the formulation causes approximately 35% to approximately 5% less swelling and / or swelling height at the injection site.

46. ​​The method according to any one of claims 2 to 45, wherein, when compared with similar formulations that do not contain hyaluronidase, application of the formulation produces lower vesicle swelling size, less vesicle induration, and / or faster vesicle resolution.

47. The method according to any one of claims 1 to 46, wherein the application of the formulation produces a more consistent delivery time compared to similar formulations that do not contain hyaluronidase.

48. The method according to any one of claims 1 to 47, wherein the subject is a human.

49. The method according to any one of claims 1 to 48, wherein the administration comprises the subject self-administering the preparation.

50. The method according to any one of claims 1 to 49, wherein the administration comprises administering the preparation to the subject by a healthcare provider or caregiver.

51. The method according to any one of claims 1 to 50, wherein the subcutaneous administration comprises a single injection.

52. The method according to any one of claims 1 to 50, wherein the subcutaneous administration comprises two or more injections.

53. The method according to any one of claims 1 to 52, wherein the subcutaneous application is delivered via an on-body device.

54. A pharmaceutical kit comprising a high-volume autoinjector and a formulation of about 3 mL to about 50 mL, the formulation comprising a therapeutically effective amount of an active ingredient selected from small molecules, peptide fragments, biological agents, nanoparticles, antibodies, antibody fragments, and small molecule antiviral agents.

55. The pharmaceutical kit of claim 54, wherein the formulation further comprises hyaluronidase.

56. The pharmaceutical kit of claim 54, further comprising instructions for administering hyaluronidase to a subject in need.

57. The pharmaceutical kit of claim 54, further comprising instructions for administering hyaluronidase to a subject in need, simultaneously or sequentially with the formulation containing the active ingredient.

58. The pharmaceutical kit according to any one of claims 54 to 57, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.05 mL / s to about 1.0 mL / s.

59. The pharmaceutical kit of claim 58, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously from a pre-filled syringe having a volume of about 3 mL to about 15 mL.

60. The pharmaceutical kit of claim 59, wherein the pre-filled syringe comprises a needle with a specification of about 20 to about 33.

61. The pharmaceutical kit according to any one of claims 54 to 60, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.05 mL / s to about 0.10 mL / s.

62. The pharmaceutical kit according to any one of claims 54 to 60, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.10 mL / s to about 0.20 mL / s.

63. The pharmaceutical kit according to any one of claims 54 to 60, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.20 mL / s to about 0.30 mL / s.

64. The pharmaceutical kit according to any one of claims 54 to 60, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.30 mL / s to about 0.40 mL / s.

65. The pharmaceutical kit according to any one of claims 54 to 60, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.40 mL / s to about 0.50 mL / s.

66. The pharmaceutical kit according to any one of claims 54 to 60, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.50 mL / s to about 0.60 mL / s.

67. The pharmaceutical kit according to any one of claims 54 to 60, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.60 mL / s to about 0.70 mL / s.

68. The pharmaceutical kit according to any one of claims 54 to 60, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.70 mL / s to about 0.80 mL / s.

69. The pharmaceutical kit according to any one of claims 54 to 60, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.80 mL / s to about 0.90 mL / s.

70. The pharmaceutical kit according to any one of claims 54 to 60, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.90 mL / s to about 1.00 mL / s.

71. The pharmaceutical kit according to any one of claims 54 to 70, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject with an applied force of about 10 N to about 200 N.

72. The pharmaceutical kit according to any one of claims 54 to 71, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject with an application force of about 10 N to about 45 N.

73. The pharmaceutical kit according to any one of claims 54 to 71, wherein the high-volume autoinjector is configured to administer the formulation subcutaneously to the subject with an application force of about 25 N to about 50 N.

74. The pharmaceutical kit according to any one of claims 54 to 73, wherein the high-volume autoinjector is configured for self-administration of the formulation by the subject.

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