Hyaluronidase enzyme preparation for high-dose administration

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63,476,830, filed December 22, 2022, U.S. Provisional Patent Application No. 63 / 485,108, filed February 15, 2023, U.S. Provisional Patent Application No. 63 / 507,125, filed June 9, 2023, U.S. Provisional Patent Application No. 63 / 516,732, filed July 31, 2023, U.S. Provisional Patent Application No. 63 / 518,057, filed August 7, 2023, and U.S. Provisional Patent Application No. 63 / 520,524, filed August 18, 2023, each of which is incorporated by reference herein in its entirety.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in .XML format and is incorporated herein by reference in its entirety. The .XML copy created on December 20, 2023 is named "063995-5088" and is 83KB in size.

[0003] The present disclosure relates to formulations comprising a hyaluronidase enzyme and an active ingredient, which can be administered in high doses to a subject in need thereof with minimal side effects. Summary of the Invention

[0004] In one embodiment, the disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject via subcutaneous administration about 3 mL to about 50 mL of a formulation comprising a therapeutically effective amount of an active ingredient selected from a small molecule, a peptide fragment, a biologic, a nanoparticle, an antibody, an antibody fragment, and a small molecule antiviral, wherein the subcutaneous administration occurs via a high volume autoinjector at a starting delivery force of about 3 lbf to about 50 lbf, a final delivery force of about 5 lbf to about 20 lbf, a starting 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 a hyaluronidase enzyme. In one embodiment, the hyaluronidase enzyme is a recombinant human hyaluronidase enzyme. In one embodiment, the hyaluronidase enzyme is a recombinant human hyaluronidase PH20 enzyme. In one embodiment, the hyaluronidase enzyme has an activity of about 150 U / mL to about 150 kU / mL. In one embodiment, the hyaluronidase enzyme has an activity of about 500 U / mL to about 5,000 U / mL. In one embodiment, the hyaluronidase enzyme 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, a peptide fragment, a biologic, or a nanoparticle. In one embodiment, the active ingredient is an antibody, an antibody fragment, or a small molecule antiviral. In one embodiment, the method comprises administering to the subject about 10 mL to about 20 mL of the formulation. In one embodiment, the method comprises administering to the subject about 3 mL to about 15 mL of the formulation. In one embodiment, the method comprises administering to the patient a dose of 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 6.0 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, about 6.8 mL, about 6.9 mL, about 7.1 mL, about 7.2 mL, about 7.3 mL, about 7.4 mL, about 7.5 mL, about 7.6 mL, about 7.7 mL, about 7.8 mL, about 7.9 mL, about 8.1 mL, about 8.2 mL, about 8.3 mL, about 8.4 mL, about 8.5 mL, about 8.5 mL, about 8.6 mL, about 8.7 mL, about 8.8 mL, about 8.9 mL, about 9.1 mL, about 9.2 mL, about 9.3 mL, about 9.4 mL, about 9.5 mL, about 9.6 mL, about 9.7 mL, about 9.8 mL, about 9.9 mL, about 9.9 mL, about 9.1 mL, about 9.2 mL, about 9.3 mL, about 9.4 mL, about 9.5 mL, about 9.6 mL, about 9.7 mL, about 9.8 .7mL, about 5.8mL, about 5.9mL, about 6mL, about 6.1mL, about 6.2mL, about 6.3mL, about 6.4mL, about 6.5mL, about 6.6mL, about 6.7mL, about 6.8mL, about 6.9mL, about 7mL, about 7.1mL, about 7.2mL, about 7.3mL, about 7.4mL, about 7.5mL, about 7.6mL, about 7.7mL, about 7.8mL, about 7.9mL, about 8mL, about 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, 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 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, 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. 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 0.9mL, 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 20.9mL, approximately 21mL, approximately 21.1mL, approx. 21.2mL, approx. 21.3mL, approx. 21.4mL, approx. 21.5mL, approx. 21.6mL, approx. 21.7mL, approx. 21.8mL, approx. 21.9mL, approx. 22mL, approx. 22.1m L, approx. 22.2mL, approx. 22.3mL, approx. 22.4mL, approx. 22.5mL, approx. 22.6mL, approx. 22.7mL, approx. 22.8mL, approx. 22.9mL, approx. 23mL, approx. 23.1mL, approx. The method includes administering 23.2 mL, about 23.3 mL, about 23.4 mL, about 23.5 mL, about 23.6 mL, about 23.7 mL, about 23.8 mL, about 23.9 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 to the subject. 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 a starting delivery force of about 3 lbf to about 50 lbf. In one embodiment, the method includes administering the formulation using a high volume autoinjector with a finishing delivery force of about 5 lbf to about 20 lbf. In one embodiment, the method includes administering the formulation using a high volume auto-injector at a starting pressure of about 50 psi to about 200 psi. In one embodiment, the method includes administering the formulation using a high volume auto-injector at a finishing 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 is available in a range of volumes, including 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 ... .8mL, about 5.9mL, about 6mL, about 6.1mL, about 6.2mL, about 6.3mL, about 6.4mL, about 6.5mL, about 6.6mL, about 6.7mL, about 6.8mL, about 6.9mL, about 7mL, about 7. 1mL, about 7.2mL, about 7.3mL, about 7.4mL, about 7.5mL, about 7.6mL, about 7.7mL, about 7.8mL, about 7.9mL, about 8mL, about 8.1mL, about 8.2mL, about 8.3mL, about 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 1 1.8mL, 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 1 5mL, 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 18.8mL, 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 20.9mL, approximately 21mL, approximately 21.1mL, approximately 21.2mL, approximately 21.3mL, approximately 21.4mL, approx. 21.5mL, approx. 21.6mL, approx. 21.7mL, approx. 21.8mL, approx. 21.9mL, approx. 22mL, approx. 22.1mL, approx. 22.2mL, approx. 22.3mL , about 22.4mL, about 22.5mL, about 22.6mL, about 22.7mL, about 22.8mL, about 22.9mL, about 23mL, about 23.1mL, about 23.2mL, about 23 The prefilled syringe contains about 0.3 mL, about 23.4 mL, about 23.5 mL, about 23.6 mL, about 23.7 mL, about 23.8 mL, about 23.9 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 of formulation. In one embodiment, the prefilled syringe is equipped with a needle having a gauge of about 20 to about 33. In one embodiment, the prefilled syringe is equipped with 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 comprises administering the formulation at a rate of about 0.08 to about 1.00 mL / second. In one embodiment, the method comprises administering the formulation at a rate of at least about 0.08 to about 1.0 mL / second. In one embodiment, the method comprises administering the formulation at a rate of at least about 0.08 to about 1.00 mL / second or faster. In one embodiment, the administration takes a time period of about 10 seconds to about 40 seconds. In one embodiment, the administration takes a time period of at least about 10 seconds to about 40 seconds. In one embodiment, the administration takes a time period of at least about 10 seconds to about 40 seconds or less. In one embodiment, the administration takes a time period of about 15 seconds to about 30 seconds. In one embodiment, the administration takes a time period of at least about 15 seconds to about 30 seconds. In one embodiment, the administration takes a time period of at least about 15 seconds to about 30 seconds or less. In one embodiment, the method comprises administering about 5 mL of the formulation at a rate of about 0.14 mL / second to about 0.21 mL / second. In one embodiment, the method comprises pumping about 10 mL of the formulation at a rate of about 0.32 mL / second to about 0.The method includes administering about 5 mL of the formulation at a rate of about 0.14 mL / sec to about 0.21 mL / sec with 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 with a 25-gauge needle. In one embodiment, the method comprises administering about 10 mL of the formulation to the subject at a rate of about 0.32 mL / second to about 0.42 mL / second with an applied force of about 25 N to about 50 N. In one embodiment, the method comprises administering the formulation to the subject using a pre-filled syringe with a 25-gauge needle. In one embodiment, administration of the formulation is faster than a similar formulation without the hyaluronidase enzyme. In one embodiment, administration of the formulation causes fewer side effects in the subject compared to a similar formulation without the hyaluronidase enzyme. In one embodiment, administration of the formulation causes less pain and discomfort in the subject compared to a similar formulation without the hyaluronidase enzyme. In one embodiment, administration of the formulation causes less backflow leakage at the injection site compared to a similar formulation without the hyaluronidase enzyme. In one embodiment, backflow leakage at the injection site is about 85% to about 30% less than a similar formulation without the hyaluronidase enzyme. In one embodiment, administration of the formulation results in less swelling volume and / or swelling height at the injection site compared to a similar formulation without the hyaluronidase enzyme. In one embodiment, the formulation results in about 35% to about 5% less swelling and / or swelling height at the injection site compared to a similar formulation without the hyaluronidase enzyme. In one embodiment, administration of the formulation results in smaller bleb swelling size, less bleb hardening, and / or more rapid bleb resolution compared to a similar formulation without the hyaluronidase enzyme. In one embodiment, administration of the formulation results in a more consistent delivery time compared to a similar formulation without the hyaluronidase enzyme. In one embodiment, the subject is a human. In one embodiment, administering comprises the subject self-administering the formulation. In one embodiment, administering comprises the subject being administered the formulation by a healthcare provider or caregiver. In one embodiment, subcutaneous administration comprises a single injection. In one embodiment, subcutaneous administration comprises two or more injections. In one embodiment, subcutaneous administration is delivered via an on-body device.

[0005] In another aspect, the present disclosure provides a pharmaceutical kit comprising a high-volume autoinjector and about 3 mL to about 50 mL of a formulation comprising a therapeutically effective amount of an active ingredient selected from a small molecule, a peptide fragment, a biologic, a nanoparticle, an antibody, an antibody fragment, and a small molecule antiviral. In one embodiment, the formulation further comprises a hyaluronidase enzyme. In one embodiment, the kit further comprises instructions for administering the hyaluronidase enzyme to a subject in need thereof. In one embodiment, the kit further comprises instructions for administering the hyaluronidase enzyme to a subject in need thereof, either simultaneously or sequentially with the formulation comprising the active ingredient. In one embodiment, the high-volume autoinjector is configured to subcutaneously administer the formulation to a subject at a rate of about 0.05 mL / sec to about 1.0 mL / sec. In one embodiment, the high-volume autoinjector is configured to subcutaneously administer the formulation from a pre-filled syringe having a volume of about 3 mL to about 15 mL. In one embodiment, the pre-filled syringe is equipped with a needle having a gauge of about 20 to about 33. 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 / sec to about 0.10 mL / sec. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to a subject at a rate of about 0.10 mL / sec to about 0.20 mL / sec. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to a subject at a rate of about 0.20 mL / sec to about 0.30 mL / sec. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to a subject at a rate of about 0.30 mL / sec to about 0.40 mL / sec. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to a subject at a rate of about 0.40 mL / sec to about 0.50 mL / sec. In one embodiment, the high-volume autoinjector is configured to administer the formulation subcutaneously to a subject at a rate of about 0.50 mL / sec to about 0.60 mL / sec. In one embodiment, the high volume autoinjector is configured to administer the formulation subcutaneously to a subject at a rate of about 0.60 mL / second to about 0.70 mL / second.In one embodiment, the high-volume autoinjector is configured to subcutaneously administer the formulation to a subject at a rate of about 0.70 mL / sec to about 0.80 mL / sec. In one embodiment, the high-volume autoinjector is configured to subcutaneously administer the formulation to a subject at a rate of about 0.80 mL / sec to about 0.90 mL / sec. In one embodiment, the high-volume autoinjector is configured to subcutaneously administer the formulation to a subject at a rate of about 0.90 mL / sec to about 1.00 mL / sec. In one embodiment, the high-volume autoinjector is configured to subcutaneously administer the formulation to a subject with an application force of about 10 N to about 200 N. In one embodiment, the high-volume autoinjector is configured to subcutaneously administer the formulation to a subject with an application force of about 10 N to about 45 N. In one embodiment, the high-volume autoinjector is configured to subcutaneously administer the formulation to a subject with an application 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. [Brief explanation of the drawings]

[0006] The following detailed description of embodiments of hyaluronidase enzyme formulations for high volume administration will be better understood when read in conjunction with the accompanying drawings of exemplary embodiments. [Figure 1] 1 is a chart of applied force (N) (mean±SEM) during injection of Ig-120 and Ig-120+rHuPH20. [Figure 2] 1 is a chart of the individual applied forces (N) during injection of Ig-120 and Ig-120+rHuPH20. [Figure 3] 1 is a chart of the mean (±SEM) reflux leak and individual weights. [Figure 4] 10 is a chart of individual swelling volumes (cm3) following SC injection of Ig-120 and Ig-120+rHuPH20—caliper measurements. [Figure 5] 10 is a chart of individual swelling areas (cm2) following SC injection of Ig-120 and Ig-120+rHuPH20—caliper measurements. [Figure 6]1 is a chart of individual swelling heights (mm) following SC injection of Ig-120 and Ig-120+rHuPH20—caliper measurements. [Figure 7A] Composite 3D images of minipigs treated with Ig-120. [Figure 7B] 3D composite images of minipigs treated with Ig-120+rHuPH20. [Figure 8] Chart of individual bleb volumes (cm3) after SC injection of Ig-120 and Ig-120 + rHuPH20 - 3D imaging. [Figure 9] Chart of individual bleb area (cm2) after SC injection of Ig-120 and Ig-120 + rHuPH20 - 3D imaging. [Figure 10] Chart of individual bleb heights (mm) after SC injection of Ig-120 and Ig-120+rHuPH20—3D imaging. [Figure 11] 1 is a chart of the change in surface temperature: from pre-injection to post-injection. [Figure 12] 1 is a chart of the qualitative assessment of erythema after injection. [Figure 13] 1 is a chart of the qualitative assessment of swelling size after injection. [Figure 14] 1 is a chart of the qualitative assessment of induration (hardness) after injection. [Figure 15A] 1 shows a Certificate of Analysis for Ig-120 and rHuPH20 used in Examples 2 to 4 of the present disclosure. 1 shows a Certificate of Analysis for Ig-120. [Figure 15B] 1A-1C are Certificates of Analysis for Ig-120 and rHuPH20 used in Examples 2 to 4 of the present disclosure. 1B are Certificates of Analysis for rHuPH20. [Figure 16A] Photographs of minipig AID#1107 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 16B]Photographs of minipig AID#1107 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 17A] Photographs of minipig AID#1114 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 17B] Photographs of minipig AID#1114 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 18A] Photographs of minipig AID#1181 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 18B] Photographs of minipig AID#1181 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 19A] Photographs of minipig AID#1184 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 19B] Photographs of minipig AID#1184 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 20A] Photographs of minipig AID#1185 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 20B] Photographs of minipig AID#1185 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 21A] Photographs of minipig AID#1188 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 21B]Photographs of minipig AID#1188 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 22] 1 is a chart of applied force (N) (mean±SEM) during injection of Ig-120 and Ig-120+rHuPH20. [Figure 23] 1 is a chart of the individual applied forces (N) during injection of Ig-120 and Ig-120+rHuPH20. [Figure 24] 1 is a chart of the mean reflux leak (mg±SEM) and individual weights. [Figure 25] 10 is a chart of individual swelling volumes (cm3) following SC injection of Ig-120 and Ig-120+rHuPH20—caliper measurements. [Figure 26] 10 is a chart of individual swelling areas (cm2) following SC injection of Ig-120 and Ig-120+rHuPH20—caliper measurements. [Figure 27] 1 is a chart of individual swelling heights (mm) following SC injection of Ig-120 and Ig-120+rHuPH20—caliper measurements. [Figure 28A] Composite 3D images of minipigs treated with Ig-120. [Figure 28B] 3D composite images of minipigs treated with Ig-120+rHuPH20. [Figure 29] Chart of individual bleb volumes (cm3) after SC injection of Ig-120 and Ig-120 + rHuPH20 - 3D imaging. [Figure 30] Chart of individual bleb area (cm2) after SC injection of Ig-120 and Ig-120 + rHuPH20 - 3D imaging. [Figure 31] Chart of individual bleb heights (mm) after SC injection of Ig-120 and Ig-120+rHuPH20—3D imaging. [Figure 32] 1 is a chart of the change in surface temperature: from pre-injection to post-injection. [Figure 33]1 is a chart of the qualitative assessment of erythema after injection. [Figure 34] 1 is a chart of the qualitative assessment of swelling size after injection. [Figure 35] 1 is a chart of the qualitative assessment of induration (hardness) after injection. [Figure 36A] Photographs of minipig AID#1359 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 36B] Photographs of minipig AID#1359 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 37] Photographs of the injection site of minipig AID#1361 before and at different intervals after the 10 mL Ig-120 injection procedure are provided. [Figure 38] Photographs of the injection site of minipig AID#1361 are provided before and at different intervals after the 10 mL Ig-120+rHuPH20 injection procedure. [Figure 39A] Photographs of minipig AID#1362 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 39B] Photographs of minipig AID#1362 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 40A] Photographs of minipig AID#1363 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 40B] Photographs of minipig AID#1363 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 41A] Photographs of minipig AID#1396 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 41B] Photographs of minipig AID#1396 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 42A] Photographs of minipig AID#1405 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 42B] Photographs of minipig AID#1405 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 43] 1 is a chart of applied force (N) (mean±SEM) during injection of Ig-120 and Ig-120+rHuPH20. [Figure 44] 1 is a chart of the individual applied forces (N) during injection of Ig-120 and Ig-120+rHuPH20. [Figure 45A] 1 is a chart of the mean reflux leak (mg±SEM) and individual weights. [Figure 45B] 10 is a chart of individual swelling volumes (cm3) following SC injection of Ig-120 and Ig-120+rHuPH20—caliper measurements. [Figure 46] 10 is a chart of individual swelling areas (cm2) following SC injection of Ig-120 and Ig-120+rHuPH20—caliper measurements. [Figure 47] 1 is a chart of individual swelling heights (mm) following SC injection of Ig-120 and Ig-120+rHuPH20—caliper measurements. [Figure 48] This is a chart of bleb volume over time (T0 to T15 to T30). [Figure 49] This is a chart of bleb area over time (T0-T15-T30). [Figure 50] This is a chart of bleb height over time (T0~T15~T30). [Figure 51A] Composite 3D images of minipigs treated with Ig-120. [Figure 51B]3D composite images of minipigs treated with Ig-120+rHuPH20. [Figure 52] Chart of individual bleb volumes (cm3) after SC injection of Ig-120 and Ig-120 + rHuPH20 - 3D imaging. [Figure 53] Chart of individual bleb area (cm2) after SC injection of Ig-120 and Ig-120 + rHuPH20 - 3D imaging. [Figure 54] Chart of individual bleb heights (mm) after SC injection of Ig-120 and Ig-120+rHuPH20—3D imaging. [Figure 55] 1 is a chart of the change in surface temperature: from pre-injection to post-injection. [Figure 56] 1 is a chart of the qualitative assessment of erythema after injection. [Figure 57] 1 is a chart of the qualitative assessment of swelling size after injection. [Figure 58] 1 is a chart of the qualitative assessment of induration (hardness) after injection. [Figure 59A] Photographs of minipig AID#1535 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 59B] Photographs of minipig AID#1535 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 60A] Photographs of minipig AID#1536 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 60B] Photographs of minipig AID#1536 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 61A] Photographs of minipig AID#1537 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 61B] Photographs of minipig AID#1537 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 62A] Photographs of minipig AID#1539 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 62B] Photographs of minipig AID#1539 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 63A] Photographs of minipig AID#1542 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 63B] Photographs of minipig AID#1542 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 64A] Photographs of minipig AID#1543 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 64B] Photographs of minipig AID#1543 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 65] 1 is a chart showing the injection times (mean ± SEM) for individual animals calculated by video analysis for each configuration of the high volume autoinjector (HVAI). [Figure 66] 1 is a chart showing the mean reflux leak (mg±SEM) and individual weights. [Figure 67] 1 is a chart showing the individual swelling volumes (mL) following SC injection of Ig-120 and Ig-120+rHuPH20 as determined using caliper measurements. [Figure 68]1 is a chart showing swelling (bleb) volume over time at T0, T15, and T30. [Figure 69] 1 is a chart showing individual swelling areas (cm 2 ) following SC injection of Ig-120 and Ig-120+rHuPH20 as determined using caliper measurements. [Figure 70] 1 is a chart showing swelling area over time at time points T0, T15, and T30. [Figure 71] 1 is a chart showing individual swollen bleb heights (mm) following SC injection of Ig-120 and Ig-120+rHuPH20 as determined using caliper measurements. [Figure 72] 1 is a chart showing swelling height over time at time points T0, T15, and T30. [Figure 73A] Composite 3D images (colorimetric surface contour maps) of blebs after each injection for Ig-120 and Ig-120+rHuPH20 administered with an HVAI and a 23G needle (Figure 73A), and with an HVAI and a 25G needle (Figure 73B). [Figure 73B] Composite 3D images (colorimetric surface contour maps) of blebs after each injection for Ig-120 and Ig-120+rHuPH20 administered with an HVAI and a 23G needle (Figure 73A), and with an HVAI and a 25G needle (Figure 73B). [Figure 74] 1 is a chart of individual swelling volumes (mL) following SC injection of Ig-120 and Ig-120+rHuPH20 as determined using 3D imaging. [Figure 75] 10 is a chart of individual swollen bleb area (cm 2 ) following SC injection of Ig-120 and Ig-120+rHuPH20 as determined using 3D imaging. [Figure 76] 1 is a chart of individual swollen bleb heights (mm) following SC injection of Ig-120 and Ig-120+rHuPH20 as determined using 3D imaging. [Figure 77] 1 is a chart of the change in skin temperature from pre-injection to post-injection. [Figure 78] 1 is a chart showing the qualitative assessment of erythema after injection. [Figure 79] 1 is a chart showing the qualitative assessment of swelling size after injection. [Figure 80] 1 is a chart showing the qualitative assessment of induration (hardness) after injection. [Figure 81A] Photographs of minipig AID#1865 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 81B] Photographs of minipig AID#1865 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 82A] Photographs of minipig AID#1866 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 82B] Photographs of minipig AID#1866 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 83A] Photographs of minipig AID#1867 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 83B] Photographs of minipig AID#1867 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 84A] Photographs of minipig AID#1869 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 84B] Photographs of minipig AID#1869 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 85A] Photographs of minipig AID#1870 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 85B] Photographs of minipig AID#1870 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 86A] Photographs of minipig AID#1926 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120 injection are provided. [Figure 86B] Photographs of minipig AID#1926 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after Ig-120+rHuPH20 injection are provided. [Figure 87] 1 is a Certificate of Analysis of rHuPH20 used in Example 4 of the present disclosure. [Figure 88A] 1 is a graph of applied force (N) (mean±SEM) during injection of GAMMAGARD LIQUID (GAMMAGARD LIQUID, GGL) and GGL plus Enhanze Drug Product (Enhanze Drug Product, EDP). [Figure 88B] 1 is a graph of the individual applied forces (N) during injection of GGL+EDP. [Figure 89] 1 is a graph of the mean injection time (seconds ± SEM) for 25G Terumo needles versus 25G BD needles. [Figure 90] 1 is a graph of the mean reflux leak (mg±SEM) and individual weights. [Figure 91] Graph of individual swelling volumes (mL) after SC injection of GGL and GGL+EDP—caliper measurements (T0). [Figure 92] Graph of individual swelling area (cm2) after SC injection of GGL and GGL+EDP - caliper measurement (T0). [Figure 93] Graph of individual swelling heights (mm) after SC injection of GGL and GGL+EDP—Caliper measurements (T0). [Figure 94] Graph of mean bleb volume over time (T0-T15-T30) - caliper measurements. [Figure 95]Graph of mean bleb volume over time (T0-T15-T30) - caliper measurements. [Figure 96] Graph of mean bleb area over time (T0-T15-T30) - caliper measurements. [Figure 97] Provides composite 3D images (T0~T15~T30) of GGL-25G-Terumo. [Figure 98] Provides a composite of 3D images (T0~T15~T30) of GGL+EDP-25G-Terumo. [Figure 99] Provides synthesis of 3D images (T0~T15~T30) of GGL+EDP-25G-BD. [Figure 100] Provides synthesis of 3D images (T0~T15~T30) of GGL+EDP-23G-BD. [Figure 101] Graph of individual bleb volumes (cm3) after SC injection of GGL and GGL+EDP—3D imaging. [Figure 102] Graph of individual bleb area (cm2) after SC injection of GGL and GGL+EDP—3D imaging. [Figure 103] Graph of individual bleb height (mm) after SC injection of GGL and GGL+EDP—3D imaging. [Figure 104] Graph of mean bleb volume over time (T0-T15-T30) - 3D imaging. [Figure 105] Graph of mean bleb area over time (T0-T15-T30) - 3D imaging. [Figure 106] Graph of mean bleb height over time (T0-T15-T30) - 3D imaging. [Figure 107] 1 is a graph of the qualitative assessment of erythema after injection. [Figure 108] Graph of qualitative assessment of erythema after injection (0-120 min). [Figure 109] 1 is a graph of the qualitative assessment of swelling size after injection. [Figure 110] Graph of qualitative scoring of swelling after injection (0-120 min). [Figure 111] 1 is a graph of the qualitative assessment of induration (hardness) after injection. [Figure 112] Graph of qualitative assessment of induration after injection (0-120 min). [Figure 113A] Photographs of minipig AID#2662 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL injection using a 25G Terumo needle are provided. [Figure 113B] Photographs of minipig AID#2662 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL+EDP injection using a 25G Terumo needle are provided. [Figure 114A] Photographs of minipig AID#2663 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL+EDP injection using a 25G BD needle are provided. [Figure 114B] Photographs of minipig AID#2663 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL+EDP injection using a 25G BD needle are provided. [Figure 115A] Photographs of minipig AID#2665 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL injection using a 25G Terumo needle are provided. [Figure 115B] Photographs of minipig AID#2665 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL+EDP injection using a 23G BD needle are provided. [Figure 116A] Photographs of minipig AID#2666 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL+EDP injection using a 25G BD needle are provided. [Figure 116B] Photographs of minipig AID#2666 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site are provided after GGL+EDP injection using a 23G BD needle. [Figure 117A]Photographs of minipig AID#2195 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL injection using a 25G Terumo needle are provided. [Figure 117B] Photographs of minipig AID#2195 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL+EDP injection using a 25G BD needle are provided. [Figure 118A] Photographs of minipig AID#2273 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL+EDP injection using a 25G Terumo needle are provided. [Figure 118B] Photographs of minipig AID#2273 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL+EDP injection using a 23G BD needle are provided. [Figure 119A] Photographs of minipig AID#2195 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL injection using a 25G Terumo needle are provided. [Figure 119B] Photographs of minipig AID#2195 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL+EDP injection using a 25G Terumo needle are provided. [Figure 120A] Photographs of minipig AID#2265 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL+EDP injection using a 25G BD needle are provided. [Figure 120B] Photographs of minipig AID#2265 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL+EDP injection using a 25G Terumo needle are provided. [Figure 121A] Photographs of minipig AID#2272 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL injection using a 25G Terumo needle are provided. [Figure 121B]Photographs of minipig AID#2272 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL+EDP injection using a 23G BD needle are provided. [Figure 122A] Photographs of minipig AID#2275 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL+EDP injection using a 25G BD needle are provided. [Figure 122B] Photographs of minipig AID#2275 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL+EDP injection using a 23G BD needle are provided. [Figure 123A] Photographs of minipig AID#2279 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL injection using a 25G Terumo needle are provided. [Figure 123B] Photographs of minipig AID#2279 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site are provided after GGL+EDP injection using a 25G BD needle. [Figure 124A] Photographs of minipig AID#2282 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL+EDP injection using a 25G BD needle are provided. [Figure 124B] Photographs of minipig AID#2282 are provided before and at different intervals after the 10 mL injection procedure. Images of the injection site after GGL+EDP injection using a 23G BD needle are provided. [Figure 125]Schematic for the human study in Example 6. Note: Sentinel subjects in each cohort will receive doses at least 24 hours apart, with dosing for the remaining subjects in that cohort beginning at least 24 hours after the last sentinel subject's dose. *If Cohort B does not tolerate 10 mL / 30 sec with a syringe pump, Cohort C will be added, evaluating 10 mL / 45 sec with a syringe pump on the same schedule as Days 5-8. **If Cohort B tolerates 10 mL / 30 sec with a syringe pump at Injection Visit 1 but does not tolerate 10 mL / 30 sec with an HVAI at Injection Visit 2, Cohort C will be evaluated using a syringe pump at 10 mL / 45 sec on the same schedule as Days 5-8. If Cohort C tolerates 10 mL / 45 sec with a syringe pump, the HVAI dose for Cohort B is 10 mL / 45 sec. ***If 10 mL / 30 seconds is tolerated using the HVAI (Injection Visit 2 / Cohort B), then the volume for Cohort A at Injection Visit 2 will be increased to 10 mL / 30 seconds (or highest tolerated volume / rate combination). [Figure 126] 1 is a diagram of an exemplary high volume autoinjector (HVAI). In this embodiment, the tip cap shown on the syringe is discarded before filling the syringe with drug. [Figure 127] 1 provides patient demographics in Example 6. [Figure 128] The administration groups and methods in Example 6 are provided. [Figure 129] The duration of injections for each cohort in Example 6 is provided. [Figure 130] Pain scores from Example 6 are provided. [Figure 131] Pain scores from Example 6 are provided. [Figure 132] Pain scores from Example 6 are provided. [Figure 133] Draize score / erythema from Example 6 is provided. [Figure 134] Draize score / erythema from Example 6 is provided. [Figure 135]Draize score / edema from Example 6 is provided. [Figure 136] Draize score / edema from Example 6 is provided. [Figure 137] The Draize score / hardening from Example 6 is provided. [Figure 138] The Draize score / hardening from Example 6 is provided. [Figure 139] Adverse events from Example 6 are provided. [Figure 140A] Example 6 provides a summary of applied force data from Cohort A (5 mL / 30 seconds). Using the Hagen-Poiseuille equation, these results predict that a doubling of flow rate will also result in a doubling of pressure (and force). Thus, the predicted applied force for Cohort B (25G-Terumo needle) was approximately 40.8 N. [Figure 140B] Example 6 provides a summary of applied force data from Cohort A (5 mL / 30 seconds). Using the Hagen-Poiseuille equation, these results predict that a doubling of flow rate will also result in a doubling of pressure (and force). Thus, the predicted applied force for Cohort B (25G-Terumo needle) was approximately 40.8 N. [Figure 141A] Example 6 provides a summary of applied force data from Cohort B (10 mL / 30 seconds). The predicted applied force (AF) was approximately twice as high in Cohort B compared to Cohort A. Comparison of clinical and non-clinical AF values ​​allowed prediction of HVAI performance using various needle gauges. [Figure 141B] Example 6 provides a summary of applied force data from Cohort B (10 mL / 30 seconds). The predicted applied force (AF) was approximately twice as high in Cohort B compared to Cohort A. Comparison of clinical and non-clinical AF values ​​allowed prediction of HVAI performance using various needle gauges. [Figure 142] Provide a comparison of applicability between preclinical and clinical trials. [Figure 143]A human clinical trial of HVAI injection has been completed, showing that it was well tolerated. [Figure 144] 1 shows rapid time to resolution for human clinical trial HVAI injections. [Figure 145] A modified Draize score for erythema, swelling, and induration due to HVAI injection is provided. [Figure 146A] Data are provided demonstrating that modified Draize scores for erythema, swelling, and induration were low and resolved rapidly (scores ≦1). [Figure 146B] Data are provided demonstrating that modified Draize scores for erythema, swelling, and induration were low and resolved rapidly (scores ≦1). [Figure 147] Data are provided using a numerical rating scale (NRS, 0-10 scale) demonstrating that subjects had minimal pain with injection and rapid resolution of pain. [Figure 148] Data are provided using a numerical rating scale (NRS, 0-10 scale) demonstrating that subjects had minimal pain with injection and rapid resolution of pain. [Figure 149A] Data are provided using a numerical rating scale (NRS, 0-10 scale) demonstrating that subjects had minimal pain with injection and rapid resolution of pain. [Figure 149B] Data are provided using a numerical rating scale (NRS, 0-10 scale) demonstrating that subjects had minimal pain with injection and rapid resolution of pain. [Figure 150] FIG. 1 is an illustrative rendering of a two-step patient-friendly 10 mL HVAI concept based on a staked needle PFS primary container. [Figure 151] Figure 1 shows a summary of swelling and induration scores for a minipig administered 10 mL IgG (120 mg / mL) with 2,000 U / mL rHuPH20 at a rate of 30 mL / min. As shown, swelling and induction were both "very slight" within 30 minutes after HVAI injection. Swelling and induration rapidly resolved after delivery. Injection times were approximately 30 seconds for the 25G-BD and 19 seconds for the 25G-Terumo. [Figure 152] Summary of swelling and hardening scores for minipigs administered 10 mL IgG (100 mg / mL) with 4,000 U / mL rHuPH20 via HVAI within 30 seconds. [Figure 153] Summary of swelling and hardening scores for minipigs administered IgG-rHuPH20 (120 mg / mL to 2,000 U / mL) to IgG-rHuPH20 (100 mg / mL to 4,000 U / mL) via HVAI. [Fig. 154] FIG. 1 is an exploded view of a button-activated autoinjector according to a first exemplary embodiment of the present invention. [Figure 155] FIG. 155 is a perspective view of the button-activated autoinjector of FIG. 154. [Figure 156] FIG. 155 is a cross-sectional view of the button-activated autoinjector of FIG. 154. [Figure 157] FIG. 155 is a partial cross-sectional view of the button-activated autoinjector of FIG. 154 in a locked configuration. [Figure 158] FIG. 155 is a partial cross-sectional view of the button-activated autoinjector of FIG. 154 in an unlocked configuration. [Figure 159] FIG. 155 is a partial cross-sectional view of the button-activated autoinjector of FIG. 154 in an ejection configuration. [Figure 160A] FIG. 155 is a cross-sectional view of the latch of the button-activated autoinjector of FIG. 154; [Figure 160B] FIG. 155 is a cross-sectional view of the latch of the button-activated autoinjector of FIG. 154; [Figure 161] FIG. 155 is a perspective view of the button-activated autoinjector of FIG. 154 in an ejection configuration. [Figure 162A] FIG. 155 is a cross-sectional view of a button of the button-activated autoinjector of FIG. 154. [Figure 162B] FIG. 155 is a perspective view of a button of the button-activated autoinjector of FIG. 154. [Figure 163A] FIG. 10 is an exploded view of a button-activated autoinjector according to a second exemplary embodiment of the present invention. [Figure 163B]FIG. 1 is a perspective view of a button-activated autoinjector according to a second exemplary embodiment of the present invention. [Figure 163C] FIG. 4 is a cross-sectional view of a container support according to a second exemplary embodiment of the present invention. [Figure 164A] FIG. 10 is an exploded view of a button-activated autoinjector according to a third exemplary embodiment of the present invention. [Figure 164B] FIG. 10 is a perspective view of a button-activated autoinjector according to a third exemplary embodiment of the present invention. [Figure 164C] FIG. 10 is a cross-sectional view of a container support according to a third exemplary embodiment of the present invention. [Figure 165] FIG. 10 is a perspective view of a button-activated autoinjector according to a fourth exemplary embodiment of the present invention. [Figure 166] FIG. 10 is a perspective view of a button-activated autoinjector coupled with a tubing set according to a fifth exemplary embodiment of the present invention. [Figure 167A] FIG. 10 is a perspective view of a button-activated autoinjector according to a sixth exemplary embodiment of the present invention. [Figure 167B] FIG. 10 is an exploded view of a button-activated autoinjector according to a sixth exemplary embodiment of the present invention. [Figure 168] FIG. 10 is a cross-sectional view of a button-activated autoinjector according to a seventh exemplary embodiment of the present invention. [Figure 169] FIG. 10 is a partial cross-sectional view of a button-activated autoinjector according to a seventh exemplary embodiment of the present invention in a locked configuration. [Figure 170] FIG. 10 is a partial cross-sectional view of a button-activated autoinjector according to a seventh exemplary embodiment of the present invention in an ejection configuration. [Figure 171] Graph of individual animal injection time data (mean±SEM). [Fig. 172] Graph of reflux leakage data (mean±SEM) for individual animals. [Figure 173] An example of how needles were selected for human clinical trials in Example 6 is provided. DETAILED DESCRIPTION OF THE INVENTION

[0007] definition 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 belongs. All patents and publications mentioned herein are incorporated by reference in their entirety.

[0008] As used herein, the terms "administer," "administration," or "administering" refer to (1) providing, giving, administering, and / or prescribing, either by or under the direction of a medical professional or their authorized representative, in accordance with this disclosure, and / or (2) placing, taking, or consuming, in accordance with this disclosure, by a subject, e.g., a mammal, including a human.

[0009] As used herein, the terms "co-administration," "co-administering," "administered in combination with," "administering in combination with," "concurrently," and "simultaneously" encompass the administration of two or more active pharmaceutical ingredients to a subject such that both active pharmaceutical ingredients and / or their metabolites are present in the subject at the same time. Co-administration includes concurrent administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present. In some embodiments, concurrent administration in separate compositions and administration in a composition in which both agents are present are preferred.

[0010] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or combination of compounds described herein that is sufficient to achieve the intended application, including, but not limited to, the treatment of a disease. A therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease state being treated (e.g., the subject's weight, age, and sex), the severity of the disease state, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art. The term also applies to a dose that will induce a specific response in target cells (e.g., reduced platelet adhesion and / or cell migration). The specific dose will vary depending on the subject to which the dose is administered, the particular compound selected, the administration regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which the compound is delivered.

[0011] As used herein, the term "therapeutic benefit" encompasses therapeutic benefit and / or prophylactic benefit. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0012] As used herein, the terms "treat," "treatment," and / or "treating" can refer to the management of a disease, disorder, or condition, or a symptom thereof, with the intent to cure, ameliorate, stabilize, and / or control the disease, disorder, condition, or symptom thereof. More specifically, with respect to the control of a disease, disorder, or condition, "control" can include the absence of condition progression as assessed by response to the methods described herein; such response can be complete (e.g., placing the disease in remission) or partial (e.g., reducing or ameliorating any symptoms associated with the condition). As used herein, the terms "prevent," "preventing," and / or "prevention" can refer to reducing the risk of developing a disease, disorder, or condition.

[0013] As used herein, soluble hyaluronidase refers to a form of hyaluronidase that is not GPI-anchored, but is soluble under physiological conditions and secreted upon expression. Soluble hyaluronidase includes any that is secreted from cells upon expression and exists in a soluble form. Human PH20 hyaluronidase does not occur as a soluble hyaluronidase. It is known in the art that removal of all or part of the GPI anchor results in a soluble form. Such soluble hyaluronidases include, but are not limited to, bacterial soluble hyaluronidase, non-human soluble hyaluronidases, such as bovine PH20 and ovine PH20, human soluble PH20, and variants thereof. Because glycosylation is important for the catalytic activity and stability of hyaluronidase, soluble forms of PH20 are generally produced using protein expression systems that promote correct N-glycosylation to ensure the polypeptide retains activity. Such cells include, for example, Chinese Hamster Ovary (CHO) cells (eg, DG44 CHO cells).

[0014] As used herein, the term "rHuPH20" refers to a soluble hyaluronidase composition produced upon expression in mammalian cells, such as CHO cells or other cells that provide glycosylation, of a nucleic acid encoding residues 36-482 of SEQ ID NO:1. For expression in the cells, the encoding nucleic acid is linked to a native (residues 1-35 of SEQ ID NO:1) or heterologous signal sequence for transport and secretion of the encoded polypeptide. The resulting secreted soluble glycoprotein is a heterogeneous mixture of polypeptides, including polypeptides terminating at residues 479, 480, 481, and 482 and consisting of residues 36-479, 36-480, 36-481, and 36-482 with respect to SEQ ID NO:1. Shorter C-terminal truncations may also be included in varying amounts. Typically, rHuPH20 is produced in cells that promote correct N-glycosylation to retain activity, such as CHO cells (e.g., DG44 CHO cells). In some embodiments, one of the most abundant species 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 upon expression in mammalian cells and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to residues 36-482 of SEQ ID NO: 1.

[0015] As used herein, "combination therapy" refers to therapy in which a subject is given two or more therapeutic agents, such as at least two or at least three therapeutic agents, to treat a single disease.

[0016] As used herein, "hyaluronidase activity" refers to the ability to enzymatically catalyze the cleavage of hyaluronic acid. The United States Pharmacopeia (USP) XXII assay for hyaluronidase indirectly determines hyaluronidase activity by measuring the amount of high molecular weight hyaluronic acid, or hyaluronan (HA) substrate, remaining after reacting the enzyme with HA at 37°C for 30 minutes (USP XXII-NF XVII (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 the low turbidity assay, which indirectly measures the cleavage of hyaluronic acid by hyaluronidase by detecting the insoluble precipitate formed when uncleaved hyaluronic acid binds to serum albumin, and the biotinylated hyaluronic acid assay, which indirectly measures the cleavage of hyaluronic acid by detecting the remaining biotinylated hyaluronic acid non-covalently bound to microtiter plate wells using streptavidin-horseradish peroxidase complex and a chromogenic substrate.Reference standards can be used, for example, to generate a standard curve to determine the activity of the hyaluronidase being tested in units.

[0017] A "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" or "physiologically compatible" carrier or carrier medium is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inactive ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable 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, can also be incorporated into the compositions and methods described.

[0018] As used herein, "specific activity" refers to units of activity per mg of protein. A milligram of hyaluronidase is M -1 cm -1 is defined by the absorbance of the solution at 280 nm, assuming a molar extinction coefficient of approximately 1.7, in units of 1.

[0019] As used herein, "neutral activity" refers to the ability of a PH20 polypeptide to enzymatically catalyze the cleavage of hyaluronic acid at neutral pH (e.g., pH 7.0 or about pH 8.0).

[0020] As used herein, a "GPI anchor attachment signal sequence" is a C-terminal sequence of amino acids that directs the addition of a preformed GPI anchor to a polypeptide within the lumen of the ER. GPI anchor attachment signal sequences are present in precursor polypeptides of GPI-anchored polypeptides, such as GPI-anchored PH20 polypeptides. C-terminal GPI anchor attachment signal sequences typically contain a predominantly 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 GPI anchor attachment site. GPI anchor attachment signal sequences can be identified by methods well known in the art, including, but not limited to, in silico methods and algorithms (e.g., 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), and the ExPASy proteomics tools site (e.g., worldwide website expasy.ch / tools / ).

[0021] As used herein, "sequence identity" refers to the relationship between polypeptides of nucleic acid molecules. Sequence identity can be assessed by aligning two sequences and counting the number of differences between the aligned portions and the sequence to which they are compared. Whether any two molecules have nucleotide or amino acid sequences that are at least 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% "identical" or "homologous" can be determined using known computer algorithms such as the "FASTA" program, e.g., Pearson et al. (1988) Proc. Natl. Acad. Sci. USA 85:2444 (other programs include the GCG program package (Devereux, J., et al., Nucleic Acids Research 12(I):387(1984)), BLASTP, BLASTN, FASTA (Altschul, S. F., et al., J. Mol. Biol. 215:403(1990)); Guide to Huge Computers, Martin J. Bishop, ed., Academic Press, San Diego, 1994, and Carrillo et al. (1988) SIAM J Applied Math 48:1073) using default parameters. 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 Genetics Computer Group (UWG) "Gap" program (Madison, WI).Percent homology or identity of proteins 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). Briefly, the GAP program defines similarity as the number of aligned symbols (i.e., nucleotides or amino acids) that are similar, divided by the total number of symbols in the shorter of the two sequences. Default parameters for the GAP program can include: (1) a unary comparison matrix (containing a value of 1 for identity and a value of 0 for non-identity), and (2) a sparse matrix (as described in Schwartz and Dayhoff, eds., ATLAS OF PROTEIN SEQUENCE AND STRUCTURE, National Biomedical Research Foundation, pp. 353-358 (1979)) similar to that used by Gribskov et al. (1986) Nucl. Acids. Res. 14:6745 weighted comparison matrix; (2) a penalty of 3.0 for each gap and an additional penalty of 0.10 for each symbol in each gap; and (3) no penalty for end gaps.

[0022] Thus, as used herein, the terms "identity" or "homology" represent a comparison between a test polypeptide and a reference polypeptide or polynucleotide.

[0023] As used herein, the term "at least 90% identical" refers to a percent identity of 90 to 99.99 with a reference nucleic acid or amino acid sequence of a polypeptide. Identity at a level of 90% or greater indicates, for illustrative purposes, the fact that a test polypeptide of 100 amino acids in length is being compared to the reference polypeptide. 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. Similar comparisons can be made between test and reference polynucleotides. Such differences can be represented as point mutations randomly distributed throughout the entire length of the polypeptide, or they can be clustered at one or more positions over a range of lengths up to the maximum allowable limit (e.g., 10 / 100 amino acid difference (approximately 90% identity)). Differences are defined as nucleic acid or amino acid substitutions, insertions, or deletions. At levels of homology or identity greater than about 85-90%, the results are independent of the program and gap parameter settings, and such high levels of identity can often be easily assessed by manual alignment without relying on software.

[0024] As used herein, "aligned sequences" refers to the use of homology (similarity and / or identity) to align corresponding positions in a sequence of nucleotides or amino acids. Typically, two or more sequences related by 50% or more identity are aligned. A set of aligned sequences refers to two or more sequences aligned at corresponding positions, and may include aligned sequences derived from RNAs such as ESTs and other cDNAs aligned with genomic DNA sequences.

[0025] As used herein, "denaturing conditions" or "denaturation conditions" refers to any condition or agent that, when exposed to a protein, acts or affects the degradation or denaturation of the protein, generally as a result of the loss or partial loss of the tertiary or secondary structure of the protein. Denaturing conditions can result in effects such as loss or reduction of activity, loss or reduction of solubility, aggregation and / or crystallization.

[0026] As used herein, "resistance to denaturing conditions" refers to any reduced or eliminated 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. Thus, resistance to denaturation means that a protein exhibits decreased aggregation or crystallization, increased solubility, or increased or enhanced activity (e.g., hyaluronidase activity) when exposed to denaturing conditions compared to a reference protein (e.g., an unmodified enzyme).

[0027] As used herein, "stability of a modified PH20 hyaluronidase" means that it is resistant to degradation caused by denaturing conditions or denaturing agents.

[0028] For example, when ranges are used herein to describe physical or chemical properties such as molecular weight or chemical formula, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The use of the term "about" when referring to a number or numerical range means that the stated number or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary. Variations are typically 0% to 15%, 0% to 10%, 0% to 5%, etc., of the stated number or numerical range.

[0029] As used herein, the term "about" means that a quantity, size, formulation, parameter, shape, and other quantity and characteristic is not exact and need not be exact, but may be approximate and / or larger or smaller, if desired, to reflect tolerances, conversion factors, rounding, measurement error, etc., and other factors known to those of ordinary skill in the art. In general, a quantity, size, formulation, parameter, shape, or other quantity or characteristic is "about" or "approximately" whether or not expressly described as such. The term "about" generally refers to a particular numerical value that is within an acceptable error range as determined by one of ordinary skill in the art, which depends in part on how the numerical value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean a range of ±20%, ±10%, or ±5% of the given numerical value.

[0030] The transitional phrases "comprising," "consisting essentially of," and "consisting of," when used in the appended claims, in original and amended form, define the scope of the claim with respect to whether additional, unrecited claim elements or steps, if any, are excluded from the scope of the claim. The term "comprising" is intended to be inclusive or open-ended and does not exclude any additional, unrecited elements, methods, steps, or materials. The term "consisting of" excludes any elements, steps, or materials other than those specified in the claim, and in the latter case, also excludes impurities normally associated with the particular material. The term "consisting essentially of" limits the scope of the claim to the specified elements, steps, or materials, and to those that do not materially affect the basic and novel characteristics of the claimed invention. All compounds, compositions, formulations, and methods described herein that embody the present invention can, in alternative embodiments, be more specifically defined by any of the transitional terms "comprising," "consisting essentially of," and "consisting of." The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes embodiments such as, for example, any composition, method, or process embodiment that "consists of" or "consists essentially of" the recited features.

[0031] The present disclosure generally relates to automatic or manual trigger devices used to deliver high volumes of injectable fluids, such as medications (e.g., 2 ml, 3 ml, 5 ml, 10 ml or more doses), for penetration below the skin surface (e.g., subcutaneous and intramuscular injection). Devices that deliver high volumes of medication are prone to configuration limitations, such as spring force limitations and syringe barrel breakage, as the medication delivery volume increases. Due to current configurations of the overall device design and limitations of biological uptake factors that limit injection speed and volume, injection devices are held in place for long periods of time, often leading to the use of other delivery methods, such as on-body delivery systems worn by the patient during injection.

[0032] Increasingly, more and more biologics are being administered at home. However, the high doses and resulting volume of drug that must be delivered for many biologics often preclude self-administration due to the long time required to hold the delivery device in place. While ultra-concentrated proteins can be used to reduce injection volumes, the resulting drug often has a much higher viscosity than traditional biologics. Powerful injectors can enable the delivery of these ultra-concentrated proteins. However, typical handheld injector designs only allow for the injection of up to 2.25 mL of viscous drug in 30 seconds.

[0033] The development of enzymes that locally degrade hyaluronan (HA) in the subcutaneous (SC) space, thereby temporarily removing the barrier to fluid flow, may reduce the traditional limitations of biological uptake factors that limit injection speed and volume. Thus, higher volumes of viscous drugs may be delivered. Therefore, there is a need to provide a handheld device that can deliver high doses (e.g., 3 mL, 5 mL, 10 mL, 20 mL, and up to 50 mL) of viscous drugs with delivery times suitable for handheld devices.

[0034] Drug delivery technologies for high-dose viscous drugs are currently based on proprietary recombinant human hyaluronidase PH20 enzymes (e.g., rHuPH20; Halozyme, Inc.), which facilitate SC delivery of co-administered therapeutics. rHuPH20 acts by degrading HA, thus reducing resistance to bulk fluid flow in the SC space and enabling high-volume SC drug delivery, dispersion, and absorption. Co-administration of rHuPH20 with injectable therapeutics has been shown to overcome the administration time and volume barriers associated with existing SC therapeutic formulations and reduce the burden on patients and healthcare providers compared to intravenous formulations. rHuPH20 has myriad applications in the current field of injectable therapeutics by increasing the dispersion and absorption of other injected drugs, such as anti-cancer therapies (e.g., trastuzumab and rituximab), immunodeficiency treatments, subcutaneous urography to improve absorption of radiopaque agents, and fluid delivery for rehydration.

[0035] Button-activated autoinjector or injector Referring in detail to the drawings, wherein like reference numerals refer to like elements throughout, FIGS. 154-170 show a button-activated autoinjector or injector, generally designated 10, in accordance with a first exemplary embodiment of the present invention.

[0036] 154, there is shown an injector 10 as described in more detail below. The injector 10 may include a button 24, a latch 34, a spring 42, a ram 38, a housing 12, a container support 46, a stopper 18, a primary container 14, a flange 20, and a plug 54.

[0037] Referring to FIG. 155, an injector 10 is shown having a housing 12 configured to allow a user to grip or handle the injector 10. The housing 12 may be shaped to fit in a user's hand for one-handed operation. The housing 12 may have a generally oval cross-section to aid in positioning the injector 10 in the user's hand. The housing 12 may further include a ridge extending along the longitudinal axis L of the housing (as shown in FIG. 155) to aid in aligning or positioning the injector 10 in the user's hand. The housing 12 may substantially house the components shown in FIGS. 156-160B.

[0038] A primary container 14 containing an injectable fluid may be at least partially retained within the housing 12. As used herein, a fluid may include a medication, drug, biologic, solution, gel, suspension, or other substance that can be delivered via a syringe or needle, and such terms may be used interchangeably as set forth in the specification and claims. The primary container 14 may be a prefilled syringe. In one embodiment, the primary container 14 is one of a prefilled cartridge, a prefilled staked-needle syringe, a vial, or other container that contains an injectable fluid. The primary container 14 has a distal portion and a proximal portion opposite the distal portion. The primary container 14 may include a container portion 16 that defines a fluid chamber that contains the medication. In one embodiment, the container portion 16 of the primary container 14 has a maximum volume of approximately 5 mL. In one embodiment, container portion 16 of primary container 14 has a maximum volume selected from about 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.

[0039] As shown in FIG. 156 , the primary container 14 may further include a stopper 18 movable within the fluid chamber relative to the primary container 14. Prior to use or actuation of the injector 10, the stopper 18 may be positioned at the distal end of the container portion 16. The stopper 18 may be a plunger that seals the medicament within the container portion 16. The stopper 18 may be made from a rubber material. In one embodiment, the stopper 18 is made from plastic. In one embodiment, the stopper 18 is made from butyl rubber, polyisoprene, polytetrafluoroethylene, high-density polyethylene, or other thermoset elastomer. As shown in FIGS. 155 and 156 , a flange 20 may extend outward from the distal portion of the primary container 14. In one embodiment, the flange 20 is Luer. In one embodiment, the flange 20 is Luer-Lock. In another embodiment, the flange 20 may be matable with a needle 19 that is in fluid communication with the medicament within the container portion 16. In some embodiments, needle 19 can be a regular wall needle. In some embodiments, needle 19 can be a thin wall needle. Needle 19 can be a 21-30 gauge needle. In one embodiment, flange 20 can be matable with tubing set 21 (as shown in FIG. 166) that is in fluid communication with the medication in container portion 16. In one embodiment, as shown in FIGS. 167A and 167B, a staking needle 27 is pre-attached and extends from the distal portion of primary container 14. In one embodiment, a double-hub pen needle is attached to the medication cartridge with the needle piercing the septum of the cartridge to deliver fluid. In one embodiment, a primary container with a septum is inserted into a fixed needle hub.

[0040] The needle 19 may be a 20 gauge needle, the needle 19 may be a 21 gauge needle, the needle 19 may be a 22 gauge needle, the needle 19 may be a 23 gauge needle, the needle 19 may be a 24 gauge needle, the needle 19 may be a 25 gauge needle, the needle 19 may be a 26 gauge needle, the needle 19 may be a 27 gauge needle, the needle 19 may be a 28 gauge needle, the needle 19 may be a 29 gauge needle, the needle 19 may be a 30 gauge needle, and the needle 19 may be a 31 gauge needle.

[0041] Needle 19 is a) It may have a length selected from 1 / 8 inch, 3 / 16 inch, 1 / 4 inch, 5 / 16, 3 / 8 inch, 7 / 16 inch, 1 / 2 inch, 9 / 16 inch, 5 / 8 inch, 11 / 16 inch, 3 / 4 inch, 13 / 16 inch, 7 / 8 inch, 15 / 16 inch, 1 inch, 1 1 / 8 inch, 1 3 / 16 inch, 1 1 / 4 inch, 1 5 / 16, 1 3 / 8 inch, 1 7 / 16 inch, and 1 1 / 2 inch.

[0042] The housing 12 may house at least a portion of the primary container 14. In one embodiment, the housing 12 houses only a proximal portion of the primary container 14. In one embodiment, the housing 12 may house the entire primary container 14. The portion of the housing 12 that receives the primary container 14 may have generally the same shape as the proximal portion of the primary container 14 to prevent rotation of the primary container 14 relative to the housing 12. The primary container 14 may be prevented from moving relative to the housing 12, as described in more detail below.

[0043] The primary container 14 comprises: a) Selected from luer fit cyclic olefin copolymer (COC) syringes, glass stake needle syringes, polymer stake needle syringes, and glass cartridge syringes.

[0044] The primary container 14 comprises: a) 3mL~5mL, 3mL~10mL, 3mL~15mL, 3mL~20mL, 3mL~25mL, 3mL~30mL, 3mL~35mL, 3mL~40mL, 3mL~45mL, 3mL~50mL, 5mL~10mL, 5mL~15mL, 5mL~20mL, 5mL ~25mL, 5mL~30mL, 5mL~35mL, 5mL~40mL;5mL~45mL, 5mL~50mL, 10mL~15mL;10mL~20mL;10mL~25mL;10mL~30mL;10mL~35mL;10mL~40mL, 10mL~50mL; b) Approximately 3 mL to 5 mL, approximately 3 mL to 10 mL, approximately 3 mL to 15 mL, approximately 3 mL to 20 mL, approximately 3 mL to 25 mL, approximately 3 mL to 30 mL, approximately 3 mL to 35 mL, approximately 3 mL to 40 mL, approximately 3 mL to 45 mL, approximately 3 mL to 50 mL, approximately 5 mL to 10 mL, approximately 5 mL to 15 mL, approximately 5 mL to 20 mL, approximately 5 mL to 25 mL, approximately 5 mL to 30 mL, approximately 5 mL to 35 mL, approximately 5 mL to 40 mL; approximately 5 mL to 45 mL, approximately 5 mL to 50 mL, approximately 10 mL to 15 mL; approximately 10 mL to 20 mL; approximately 10 mL to 25 mL; approximately 10 mL to 30 mL; approximately 10 mL to 35 mL; approximately 10 mL to 40 mL, approximately 10 mL to 50 mL; 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 d) may be sized and shaped to hold a volume corresponding to a volume selected from 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.

[0045] The injector 10 may be configured to deliver all or a portion of a predetermined amount of the medicament in the primary container 14. The predetermined amount of medicament may correspond to the volume contained in the primary container 14. In one embodiment, the injector 10 may release a first portion of the volume (the initial volume), followed by a second step of releasing the remaining portion of the volume (the deliverable volume). In one embodiment, the medicament contained in the primary container 14 may be a) 3mL~5mL, 3mL~10mL, 3mL~15mL, 3mL~20mL, 3mL~25mL, 3mL~30mL, 3mL~35mL, 3mL~40mL, 3mL~45mL, 3mL~50mL, 5mL~10mL, 5mL~15mL, 5mL~2 0mL, 5mL~25mL, 5mL~30mL, 5mL~35mL, 5mL~40mL;5mL~45mL, 5mL~50mL, 10mL~15mL;10mL~20mL;10mL~25mL;10mL~30mL;10mL~35mL;10mL~40 mL, 10mL to 50mL; b) Approx. 3mL to approx. 5mL, approx. 3mL to approx. 10mL, approx. 3mL to approx. 15mL, approx. 3mL to approx. 20mL, approx. 3mL to approx. 25mL, approx. mL~50mL, 5mL~10mL, 5mL~15mL, 5mL~20mL, 5mL~25mL, 5mL~30mL, 5mL~35mL, 5mL~40mL; 5mL~45mL, 5mL~50mL, 10mL~10mL 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; 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 20 mL.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 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, Corresponding to a volume selected from 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, and at least 50 mL.

[0046] The flow rate of the injector 10 is highly dependent on the viscosity and volume of the drug. However, the injector 10 may deliver the entire amount of drug at a rate of approximately 0.08-0.75 mL / sec. For example, this may provide a target delivery rate range of 13-120 seconds for a 10 mL dose volume. The injector 10 may deliver 10 mL of drug at a rate of 0.33 mL / sec. In one embodiment, the injector 10 includes: 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, 2.75 mL / 10 seconds, 3 mL / 10 seconds; 3.25mL / 10 seconds, 3.5mL / 10 seconds, 3.75mL / 10 seconds, 4mL / 10 seconds, 4.25mL / 10 seconds, 4.5mL / 10 seconds, 4.75 mL / 10 seconds, 5mL / 10 seconds; b) 2mL / 30 seconds, 2.5mL / 30 seconds, 3mL / 30 seconds, 3.5mL / 30 seconds, 4mL / 30 seconds, 4.5m c) deliver the full deliverable volume of medication at rates of 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.

[0047] In one embodiment, the viscosity of the agent is: a) 5 centipoise (cP), 6 cP, 7 cP, 8 cP, 9 cP, 10 cP, 11 cP, 12 cP, 13 cP, 14 cP, 15 cP, 16 cP, 17 cP, 18 cP, 19 cP, 20 cP, 21 cP, 22 cP, 23 cP, 24 cP, 25 cP, 26 cP, 27 cP, 28 cP, 29 cP , 30;b) Approximately 5 cP to approximately 7 cP, approximately 5 cP to approximately 9 cP, approximately 5 cP to approximately 11 cP, approximately 5 cP to approximately 13 cP, approximately 5 cP to approximately 15 cP, approximately 5 cP to approximately 17 cP, approximately 5 cP to approximately 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 2 0 cP, about 10 cP to about 25 cP, about 10 cP to about 30 cP, c) at least about 5 cP, at least about 6 cP, at least about 7 cP, at least about 8 cP, at least about 9 cP, at least about 10 cP, at least about 11 cP, at least about 12 cP, at least about 13 cP, at least about 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 28 cP, at least about 29 cP, at least about 30; and d) may be selected from at least about 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, at least 16 cP, at least 17 cP, at least 18 cP, at least 19 cP, at least 20 cP, at least 21 cP, at least 22 cP, at least 23 cP, at least 24 cP, at least 25 cP, at least 26 cP, at least 27 cP, at least 28 cP, at least 29 cP, at least 30 cP.

[0048] The user's experience can be improved if the injector 10 can deliver the entire amount of medication as quickly as possible. Faster delivery may result in less pain and discomfort for the patient. The injector 10 can deliver the entire deliverable volume of medication in 5 seconds. The injector 10 can deliver the entire deliverable volume of medication in 10 seconds. The injector 10 can deliver the entire deliverable volume of medication in 15 seconds. The injector 10 can deliver the entire deliverable volume of medication in 20 seconds. The injector 10 can deliver the entire deliverable volume of medication in 25 seconds. The injector 10 can deliver the entire deliverable volume of medication in 30 seconds. The injector 10 can deliver the entire deliverable volume of medication in 35 seconds. The injector 10 can deliver the entire deliverable volume of medication in 40 seconds. The injector 10 can deliver the entire deliverable volume of medication in 45 seconds. The injector 10 can deliver the entire deliverable volume of medication in 50 seconds. The injector 10 can deliver the entire deliverable volume of drug in 55 seconds. The injector 10 can deliver the entire deliverable volume of drug in 60 seconds. The injector 10 can deliver the entire deliverable volume of drug in 70 seconds. The injector 10 can deliver the entire deliverable volume of drug in 80 seconds. The injector 10 can deliver the entire deliverable volume of drug in 90 seconds. The injector 10 can deliver the entire deliverable volume of drug in 100 seconds. The injector 10 can deliver the entire deliverable volume of drug in 110 seconds. The injector 10 can deliver the entire deliverable volume of drug in 120 seconds.

[0049] Any number of indicia may be displayed on the injector 10. For example, a symbol 23 (as shown in FIG. 155) may be displayed on the housing 12, or an indicator regarding the status of the injector 10 may be displayed on the button 24 (as shown in FIG. 155). With reference to FIGS. 155 and 161, the housing 12 may include a cutout 13 extending therethrough to allow viewing of an indicator on the button 24 disposed within the housing 12. The cutout 13 may be located in a proximal portion of the housing 12. The cutout 13 may be generally oval-shaped. The cutout 13 may expose a portion of the button 24, including the indicia. The button 24 may be at least partially received within the proximal portion of the housing 12. The button 24 may include a lock indicator 15 thereon to indicate a locked state of the button and / or to indicate that the injector 10 is in a locked configuration. The lock indicator 15 may be stamped, etched, printed, or molded into the button 24. In one embodiment, the lock indicator 15 is a decal secured to the button 24 with an adhesive. In one embodiment, the lock indicator 15 is applied onto the button 24 by spray painting, powder coating, silk screening, laser marking, pad printing, or heat staking. The lock indicator 15 can be a lock graphic that indicates that the injector 10 is in a locked configuration. The lock indicator 15 can be any combination of shapes and / or words.

[0050] The button 24 can further include a rotation indicator 17 to indicate the direction in which the button 24 can move about the longitudinal axis L. The rotation indicator 17 can be engraved on the button 24. In one embodiment, the rotation indicator 17 is a decal secured to the button 24 with an adhesive. In one embodiment, the rotation indicator 17 is applied to the button 24 by spray painting, powder coating, silk screening, laser marking, pad printing, or heat staking. The rotation indicator 17 can be an arrow indicating the direction in which the button 24 must be rotated relative to the housing 12 to transition from the locked configuration to the unlocked configuration. The rotation indicator 17 can be any combination of shapes and / or words. In one embodiment, the button includes indicia for partial dosing of medication, such as an initial dose, at the location of the lock indicator 15. The partial dose indicator can be engraved, etched, printed, or molded into the button 24. In one embodiment, the partial dose indicator is a decal secured to the button 24 with an adhesive. In one embodiment, the partial dose indicator is applied onto the button 24 by spray painting, powder coating, silk screening, laser marking, pad printing, or heat staking.

[0051] To release a drug from the primary container 14, the injector 10 undergoes a series of sequential movements that result in a trigger event. The trigger event is initiated by a user moving the button 24 relative to the housing 12. Referring to FIGS. 156-160B, the injector 10 may further include a trigger mechanism 22. The trigger mechanism 22 may include a button 24 located in a proximal portion of the housing 12, a latch 34, a ram 38, and a spring 42. The button 24 may be coupled to the housing 12 so as to be rotatable about its longitudinal axis L. The button 24 may be rotatable between an unlocked configuration and a locked configuration, which may be indicated to the user by indicia visible through the cutout 13. Rotation of the button 24 between the locked and unlocked configurations will not breach the sterility barrier of the primary container 14. This may allow the user to rotate the button 24 back to the locked configuration for later use.

[0052] In the locked configuration, the button 24 may be prevented from moving distally along the longitudinal axis L of the housing 12 by a rim along the inner surface of the housing 12. For certain applications (i.e., laboratory testing), it may be necessary to remove the button 24. In one embodiment, the button 24 may be moved proximally along the longitudinal axis L of the housing 12. The button 24 may include a through-hole 59 extending through its proximal end, which may be disassembled using appropriate equipment. In one embodiment, the button 24 is removable by inserting a disassembly tool (not shown) into the through-hole 59, thereby releasing the button 24 from the rim. In the unlocked configuration, the button 24 may be movable distally along the longitudinal axis L of the housing 12 to initiate a trigger event. The button 24 may be generally cylindrical in shape. The proximal end of the button 24 may be closed, and the distal end of the button 24 may be open. The button 24 may have an internal cavity 28 defined therein. The button 24 may be the only feature of the injector 10 that is movable relative to the housing 12 prior to a trigger event. The outer surface of the button 24 may have one or more ridges extending along its length. In one embodiment, rotating the button 24 to the unlocked position causes the device to dispense the initial dose.

[0053] 156-160B, the button 24 may include a barrel 26 extending distally from the proximal end within the internal cavity 28. The barrel 26 may have a proximal side and a distal side. The barrel 26 may include a recess 30 extending radially inward on the barrel 26. The barrel 26 may be generally cylindrical on the distal side. The barrel 26 may be non-uniformly cylindrical on the proximal side. The barrel 26 may have a radius smaller than that of the button 24. The radius of the barrel 26 may be one-third the radius of the button 24. The barrel 26 may have a radius of 0.1 to 0.5 inches. The recess 30 may be located on the proximal side of the barrel 26. In one embodiment, the barrel 26 includes two recesses 30 on opposite sides of the barrel 26. The distal side of the barrel 26 may have a smaller diameter than the proximal side of the barrel 26. The barrel 26 may extend distally only a portion of the length of the button 24. In one embodiment, the barrel 26 extends distally substantially along the length of the button 24.

[0054] 160A-160B, trigger mechanism 22 may further include a latch 34 for facilitating a triggering event. Latch 34 may have a proximal end and a distal end. Latch 34 may have a generally cylindrical shape. Latch 34 may be disposed within housing 12. Latch 34 may be secured to housing 12. The proximal end of latch 34 may be disposed within button 24.

[0055] The latch 34 may further include a latch arm 32. The latch arm 32 may extend distally along the longitudinal axis L from a proximal end of the latch 34. The latch arm 32 may be coupled to the latch 34. The latch arm 32 may be biased radially inward. The latch arm 32 may be prevented from deflecting radially inward by the barrel 26 prior to a triggering event. The latch arm 32 may include a protrusion 36. The protrusion 36 may extend radially outward from the latch arm 32. The recess 30 may be configured to align with the latch arm 32 in the unlocked configuration. The latch arm 32 may be received within 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 may include two diametrically opposed latches.

[0056] 156-160B, the trigger mechanism 22 may further include a ram 38. The ram 38 may have a proximal side and a distal side opposite the proximal side. The ram 38 may be disposed within the latch 34. The ram 38 may be configured to engage the stopper 18 at its distal side. The ram 38 may have a generally cylindrical shape defining an internal cavity 40 therein. The spring 42 may be disposed within the internal cavity 40. In one embodiment, the spring 42 may be disposed outside the ram 38. The spring 42 may have a proximal end and a distal end opposite the proximal end. The proximal end of the spring 42 may engage with a collar 98 of the latch 34. The collar 98 may be generally cylindrical. The collar 98 may be sized to allow the barrel 26 to pass through. The radius of the collar 98 may be the same as that of the spring 42 to ensure that the collar 98 engages with the spring 42. The distal end of spring 42 may engage a ram collar 96 located within internal cavity 40 distally of ram 38. During a triggering event, spring 42 may bias ram 38 distally along longitudinal axis L relative to housing 12. In the exemplary embodiment, spring 42 comprises a compression spring, although other suitable energy sources may be used, such as an electric pump, an elastomeric or compressed gas spring, a compressed gas cylinder 43, a gas generator, or other suitable energy storage member. ram 38 may move stopper 18 distally along longitudinal axis L relative to primary container 14.

[0057] In some embodiments, a compressed gas cylinder 43 (not shown) is used in combination with or instead of the spring 42 as the energy source for the injector 10. The compressed gas cylinder 43 may be disposed at the proximal end of the injector 10. The compressed gas cylinder 43 may store energy therein, which may be selectively released when a 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 the ram 38 to move the ram 38 relative to the primary container 14, thereby releasing the medicament. In some embodiments, the compressed gas cylinder 43 includes a pin 45 that is movable relative to the compressed gas cylinder 43 and that may extend from its distal end upon actuation of the injector 10. The pin 45 may engage the ram 38 and move the ram 38 distally relative to the housing 12 upon actuation of the injector 10. The compressed gas cylinder 43 may increase the accuracy of medicament delivery by precisely controlling the force acting on the ram 38. The compressed gas cylinder 43 may reduce vibration and noise during use compared to alternative embodiments, such as the spring 42. In some embodiments, the injector 10 using the compressed gas cylinder 43 has a shorter length along the longitudinal axis L than the injector 10 using alternative embodiments of the energy source, such as the spring 42.

[0058] 156-160B, the ram 38 may include an opening 44 extending therethrough. The opening 44 may be located on a proximal side of the ram 38. The ram 38 may be prevented from moving distally relative to the housing 12 by the latch arm 32. The protrusion 36 may be engaged in the opening 44 to prevent the spring 42 from biasing the ram 38 distally.

[0059] 157 and 158 , in the unlocked configuration, distal movement of the button 24 along the longitudinal axis L relative to the housing 12 may cause the latch arm 32 to deflect radially inward into the recess 30 of the barrel 26, thereby initiating a triggering event. The radial deflection of the latch arm 32 may disengage the protrusion 36 from the opening 44. Disengagement of the latch arm 32 from the protrusion 36 may allow the spring 42 to bias the ram 38 distally along the longitudinal axis L relative to the housing 12. The ram 38 may move the stopper 18 distally along the longitudinal axis L relative to the primary container 14, expelling the medicament in the releasing configuration.

[0060] 156-160B, the spring 42 may be a compression spring. The spring 42 may have a diameter of 5 mm. The spring 42 may have a diameter of 6 mm. The spring 42 may have a diameter of 7 mm. The spring 42 may have a diameter of 8 mm. The spring 42 may have a diameter of 9 mm. The spring 42 may have a diameter of 10 mm. The spring 42 may have a diameter of 11 mm. The spring 42 may have a diameter of 12 mm. The spring 42 may have a diameter of 13 mm. The spring 42 may have a diameter of 14 mm. The spring 42 may have a diameter of 15 mm. The spring 42 may have a wire diameter of 0.75 mm. The spring 42 may have a wire diameter of 1 mm. The spring 42 may have a wire diameter of 1.25 mm. The spring 42 may have a wire diameter of 1.5 mm. The spring 42 may have a wire diameter of 1.75 mm. The spring 42 may have a wire diameter of 2 mm.

[0061] The spring can generate a force of 8 lbf. The spring can generate a force of 9 lbf. The spring can generate a force of 10 lbf. The spring can generate a force of 11 lbf. The spring can generate a force of 12 lbf. The spring can generate a force of 13 lbf. The spring can generate a force of 14 lbf. The spring can generate a force of 15 lbf. The spring can generate a force of 16 lbf. The spring can generate a force of 17 lbf. The spring can generate a force of 18 lbf. The spring can generate a force of 19 lbf. The spring can generate a force of 20 lbf. The spring can generate a force of 21 lbf. The spring can generate a force of 22 lbf. The spring can generate a force of 23 lbf. The spring can generate a force of 24 lbf. The spring can generate a force of 25 lbf. The spring can generate a force of 26 lbf. The spring can generate a force of 27 lbf. The spring can generate a force of 28 lbf. The spring can generate a force of 29 lbf. The spring can generate a force of 30 lbf. The spring can generate a force of 31 lbf. The spring can generate a force of 32 lbf. The spring can generate a force of 33 lbf. The spring can generate a force of 34 lbf. The spring can generate a force of 35 lbf. The spring can generate a force of 36 lbf. The spring can generate a force of 37 lbf. The spring can generate a force of 38 lbf. The spring can generate a force of 39 lbf. The spring can generate a force of 40 lbf.

[0062] The spring 42 may generate a maximum force of 15 lbf before a trigger event. The spring 42 may generate a maximum force of 17.5 lbf before a trigger event. The spring 42 may generate a maximum force of 20 lbf before a trigger event. The spring 42 may generate a maximum force of 22.5 lbf before a trigger event. The spring 42 may generate a maximum force of 25 lbf before a trigger event. The spring 42 may generate a maximum force of 27.5 lbf before a trigger event. The spring 42 may generate a maximum force of 30 lbf before a trigger event. The spring 42 may generate a maximum force of 32.5 lbf before a trigger event. The spring 42 may generate a maximum force of 35 lbf before a trigger event. The spring 42 may generate a maximum force of 37.5 lbf before a trigger event. The spring 42 may generate a maximum force of 40 lbf before a trigger event.

[0063] The spring 42 may generate a residual force of 8 lbf-force after dispensing the entire volume of fluid from the primary container. The spring 42 may generate a residual force of 10 lbf-force after dispensing the entire volume of fluid from the primary container. The spring 42 may generate a residual force of 12 lbf-force after dispensing the entire volume of fluid from the primary container. The spring 42 may generate a residual force of 14 lbf-force after dispensing the entire volume of fluid from the primary container. The spring 42 may generate a residual force of 16 lbf-force after dispensing the entire volume of fluid from the primary container. The spring 42 may generate a residual force of 18 lbf-force after dispensing the entire volume of fluid from the primary container. The spring 42 may generate a residual force of 20 lbf-force after dispensing the entire volume of fluid from the primary container. The spring 42 may generate a residual force of 22 lbf-force after dispensing the entire volume of fluid from the primary container. The spring 42 may generate a residual force of 24 lbf-force after dispensing the entire volume of fluid from the primary container. The spring 42 may generate a residual force of 26 lbf-force after dispensing the entire volume of fluid from the primary container. The spring 42 may generate a residual force of 28 lbf-force after dispensing the entire volume of fluid from the primary container. The spring 42 may generate a residual force of 30 lbf-force after dispensing the entire volume of fluid from the primary container. The spring 42 may generate a residual force of 32 lbf-force after dispensing the entire volume of fluid from the primary container. The spring 42 may generate a residual force of 34 lbf-force after dispensing the entire volume of fluid from the primary container. The spring 42 may generate a residual force of 36 lbf-force after dispensing the entire volume of fluid from the primary container. The spring 42 may generate a residual force of 38 lbf-force after dispensing the entire volume of fluid from the primary container. The spring 42 may generate a residual force of 40 lbf of force after expelling the entire volume of fluid from the primary container.

[0064] When the primary container 14 is receivable within the housing 12, it must be secured to the housing 12 to ensure that medicament is expelled as a result of a triggering event. If the primary container 14 rotates or moves distally as a result of a triggering event, delivery consistency may be compromised. With reference to FIGS. 156-160B , the injector 10 further includes a container support 46 coupled to the housing 12. The container support 46 may secure the primary container 14 to the housing 12. The container support 46 may prevent the primary container 14 from rotating about the longitudinal axis L relative to the housing 12. The container support 46 may axially support a proximal portion of the primary container 14 such that a distal portion of the primary container 14 is substantially unsupported axially. The container support 46 may extend distally along the longitudinal axis L to cover at least a portion of the primary container 14. In one embodiment, the container support 46 extends distally along the longitudinal axis L to cover the entire primary container 14. The container support 46 may include a window 66 (as shown in FIGS. 164A-164C and 165) that exposes at least a portion of the primary container 14.

[0065] 156-160B, the container support 46 includes an extension 48 extending proximally along the longitudinal axis L inside the housing 12. The extension 48 may engage a collar 50 at a proximal portion of the primary container 14. In some embodiments, the proximal end of the extension 48 may include a pad, cushion, rib, or other feature to attenuate the force exerted on the collar 50 during a triggering event to reduce the possibility of breakage. The extension 48 may engage the collar 50 with a distal portion of the latch 34, thereby securing the primary container 14 relative to the housing 12. The container support 46 may extend substantially the entire circumference of the collar 50 of the primary container 14. In one embodiment, the container support 46 extends only partially around the circumference of the collar 50 of the primary container 14. The container support 46 may be coupled to the housing 12 via a snap-fit ​​connection. In one embodiment, the container support 46 is threadably coupled to the housing 12.

[0066] 155, 156, and 161, flange 20 may be a luer lock disposed at the distal end of primary container 14. Flange 20 may be configured to mate with needle 19, thereby establishing fluid communication from primary container 14 to needle 19. Flange 20 may receive plug 54. Plug 54 may prevent medicament from flowing out of primary container 14. Plug 54 may be removed before needle 19 is coupled with the luer lock. Needle 19 may be threadably coupled to flange 20 to establish fluid communication therethrough. In one embodiment shown in FIG. 166, tubing set 21 is coupled with flange 20 to establish fluid communication therethrough. In some embodiments, housing 12 includes a safety cap (not shown) removably coupled to the distal end of housing 12. The safety cap may include a safety seal that contacts the housing 12 when the safety cap is mated with the housing 12 to prevent any contaminants (dirt, dust, liquids) from interacting with the needle 19 while the safety cap is mated with the housing 12. The needle 19 may be exposed when the safety cap is removed.

[0067] Friction between the button 24 and the housing 12 may provide adequate resistance to prevent accidental or unintended movement of the button 24. In one embodiment, as shown in FIGS. 168-170 , a button spring 56 is included to bias the button proximally relative to the housing to prevent accidental or unintended movement of the button 24. Referring to FIGS. 156-160B , the button 24 may be at least partially disposed within the housing 12. The button 24 may be biased proximally along the longitudinal axis L relative to the housing 12 by the button spring 56. The button spring 56 may have a proximal end and a distal end. The proximal end of the button spring 56 may be engaged with the button 24. The distal end of the button spring 56 may be engaged with the latch 34. The button spring 56 may generate a force of 1-5 lbf.

[0068] At any time prior to intended use, the injector 10 is preferably in a locked configuration to prevent unintended or accidental triggering events. Referring to FIG. 157, an embodiment of the injector 10 of the present disclosure is shown in the locked configuration. In the locked configuration, the button 24 may be prevented from moving along the longitudinal axis L relative to the housing 12. The button 24 may be rotatable only about the longitudinal axis L in the locked configuration. The latch arm 32 may be configured to align with a portion of the button 24 that does not include a recess 30 on its proximal end to ensure that a triggering event is not initiated. A button 24 that does not have a recess 30 aligned with the latch arm 32 may further prevent accidental ejection from dropping, misuse, or other handling. The barrel 26 may bias the latch arm 32 radially outward. In the locked configuration, the protrusion 36 of the latch arm 32 may engage with the opening 44 in the ram 38 to prevent the ram 38 from moving distally along the longitudinal axis L relative to the housing 12. In the locked configuration, the spring 42 may be in a compressed configuration. The spring 42 may be prevented from urging the ram 38 distally along the longitudinal axis L relative to the housing 12 by the protrusion 36 engaging with the opening 44 in the ram 38.

[0069] When the injector 10 is in use, it may be transitioned to an unlocked configuration to allow for a triggering event. Referring to FIG. 158, an embodiment of the injector 10 of the present disclosure is shown in the unlocked configuration. The injector 10 may be transitioned from the locked configuration to the unlocked configuration by rotating the button 24 about the longitudinal axis L. Rotating the button 24 to the unlocked configuration may cause the button 24 to move distally along the longitudinal axis L relative to the housing 12. Moving the button 24 distally along the longitudinal axis L relative to the housing 12 may prime the primary container 14 by removing any air within the container portion 16 prior to the triggering event. In the unlocked configuration, the spring 42 may be in a compressed configuration.

[0070] Rotation of button 24 90 degrees about longitudinal axis L may transition injector 10 from the locked configuration to the unlocked configuration. Rotation of button 24 between 0 degrees and 89 degrees about longitudinal axis L may not transition injector 10 from the locked configuration to the unlocked configuration. In one embodiment, rotation of button 24 45 degrees about longitudinal axis L transitions injector 10 from the locked configuration to the unlocked configuration. In one embodiment, rotation of button 24 180 degrees about longitudinal axis L transitions injector 10 from the locked configuration to the unlocked configuration. In one embodiment, rotation of button 24 between 90 degrees and 180 degrees about longitudinal axis L transitions injector 10 from the locked configuration to the unlocked configuration. In one embodiment, rotation of button 24 between 45 degrees and 180 degrees about longitudinal axis L transitions injector 10 from the locked configuration to the unlocked configuration.

[0071] In the unlocked configuration, the button 24 may be able to move proximally along the longitudinal axis L relative to the housing 12. The recess 30 of the barrel 26 may be aligned with the latch arm 32 in the unlocked configuration. When the button 24 moves proximally a predetermined distance along the longitudinal axis L relative to the housing 12, the latch arm 32 may be deflected radially inward into the recess 30, initiating a triggering event. The radially inward deflection of the latch arm 32 may disengage the protrusion 36 of the latch arm 32 from the opening 44 of the ram 38. Disengagement of the latch arm 32 from the opening 44 may allow the spring 42 to bias the ram 38 distally along the longitudinal axis L relative to the housing 12. Distal movement of the ram 38 along the longitudinal axis L relative to the housing 12 may move the stopper 18 through the container portion 16 of the primary container 14 and force the medicament through the flange 20. The container support 46, which engages the collar 50 of the primary container 14 relative to the latch 34, may prevent the primary container 14 from moving distally along the longitudinal axis L relative to the housing 12 during a triggering event.

[0072] Following a triggering event, the injector 10 may be disabled to prevent further actuations or triggering events. Referring to FIG. 159 , an embodiment of the injector 10 of the present disclosure is shown in the ejection configuration. The button 24 may be secured relative to the housing 12 in the ejection configuration. The biased latch arm 32 within the recess 30 may prevent the button spring 56 from biasing the button 24 distally along the longitudinal axis L relative to the housing 12. During a triggering event, the ram 38 may move distally along the longitudinal axis L relative to the housing 12 such that the ram 38 is fully disposed within the container portion 16 of the primary container 14 in the ejection configuration. In one embodiment, the ram 38 is partially disposed within the container portion 16 of the primary container 14 in the ejection configuration.

[0073] Referring to FIG. 161 , an embodiment of the injector 10 of the present disclosure is shown in the ejection configuration. The primary container 14 may be made of a transparent material. The primary container 14 may be made of glass. In one embodiment, the primary container 14 may be made of plastic. In the ejection configuration, the ram 38 may be visible through the primary container 14. The ram 38 and stopper 18 may be visible through the primary container 14.

[0074] 161, the button 24 may include a trigger indicator 52. The trigger indicator 52 may be engraved on the button 24. The trigger indicator 52 may be a decal secured to the button 24 with an adhesive. The trigger indicator 52 may be an arrow that indicates 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 shapes and / or words. The trigger indicator 52 may be visible within the cutout 13 when the injector 10 is in the ejection configuration.

[0075] Referring to FIG. 161 , the container support 46 may include a release mechanism. The release mechanism may allow a user to disassemble the injector 10 to replace and reset any of its components prior to a triggering event. The housing 12 may include an opening 62 extending therethrough. The container support 46 may include a catch 64 extending radially outward from the extension 48 through the opening 62 in the engaged configuration. The catch 64 may prevent the container support 46 from moving relative to the housing 12 in the engaged configuration. The catch 64 may allow the container support 46 to move relative to the housing 12 when the catch 64 is biased radially inward toward the disengaged configuration. The container support 46 may move along the longitudinal axis L in the disengaged configuration. As shown in FIGS. 164A-164C and 165 , the container support 46 may be removed and replaced with an alternative container support 46 embodiment. Removal of the container support 46 may allow for replacement of any of the components of the trigger mechanism 22 to accommodate different drug viscosities and volumes.

[0076] 160A-160B illustrate one embodiment of the button 24 of the present disclosure. The button 24 may include wings 58 projecting radially outward therefrom. The wings 58 may be located on a proximal portion of the button 24. The wings 58 may prevent the button 24 from rotating about the longitudinal axis L beyond a predetermined threshold. The inner surface of the housing 12 may include a bumper 60 (not shown) that engages with the wings 58 to prevent the wings 58 from passing therethrough as the button 24 rotates about the longitudinal axis L. The wings 58 and the bumper 60 may align when the injector 10 is in the locked and unlocked configurations. When the wings 58 engage the bumper 60 in the unlocked configuration, the inner surface of the housing 12, the latch arm 32, may align with the recess 30 in the barrel 26. In one embodiment, there are two wings. In one embodiment, a maximum torque of 1 in-lbs. to 15 in-lbs. is required to overcome bumper 60 and rotate from the locked position to the unlocked position.

[0077] Bumper 60 may allow button 24 to rotate 90° about longitudinal axis L before wings 58 engage bumper 60. In one embodiment, bumper 60 allows button 24 to rotate 45° about longitudinal axis L before wings 58 engage bumper 60. In one embodiment, bumper 60 allows button 24 to rotate 180° about longitudinal axis L before wings 58 engage bumper 60. In one embodiment, bumper 60 allows button 24 to rotate 1° to 180° about longitudinal axis L before wings 58 engage bumper 60.

[0078] 163A-163C, a second embodiment of the injector 10 is shown. The injector 10 may be similar to the embodiment of the injector 10 shown in FIGS. 154-161, except that the container support 46 may cover substantially the entire length of the primary container 14. In one embodiment, the container support 46 only partially covers the primary container 14.

[0079] As shown in FIGS. 163A-163C, the container support 46 may extend from a 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 that extends through the container support 46 to expose the primary container 14. The window 66 may be generally oval in shape. The window 66 may extend along substantially the entire length of the container support 46.

[0080] 164A-164C, a third embodiment of the injector 10 is shown. The injector 10 may be similar to the embodiment of the injector 10 shown in FIGS. 163A-163C, except that the container support 46 may have approximately the same thickness as the container portion 16 of the primary container 14. In one embodiment, the container support 46 has a thickness that is less than the thickness of the housing 12.

[0081] As shown in FIGS. 164A-164C , the container support 46 may extend from a proximal portion of the housing 12 to the flange 20. The container support 46 may generally have a thickness less than that of the housing 12. The container support 46 may include a window 66. The window 66 may be an opening that extends through the container support 46 to expose the primary container 14. The window 66 may be generally oval in shape. The window 66 may extend along substantially the entire length of the container support 46.

[0082] Referring to FIG. 165, a fourth embodiment of the injector 10 is shown. The injector 10 may be similar to the embodiment of the injector 10 shown in FIGS. 163A-163C, except that the container support 46 may have a cap 68 covering the container support 46. The cap 68 may have a thickness that is less than the thickness of the housing 12. In one embodiment, the cap 68 has a thickness that is approximately the same as the thickness of the housing 12.

[0083] Referring to FIG. 165, there is a cap 68 shown on the injector 10. The cap 68 may be removably coupled to the injector 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 opening. 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 injector 10 to stand vertically.

[0084] The cap 68 may be sized to receive the container support 46 through an opening in the proximal end. As shown in FIGS. 164A-164C, 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 near 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 couple the cap 68 and the container support 46. The cap 68 may cover the flange 20 of the primary container 14 to prevent damage or accidental removal of the plug 54 when the cap 68 is coupled to the container support 46.

[0085] Referring to FIG. 166, a fifth embodiment of the injector 10 is shown. The injector 10 may be similar to the embodiment of the injector 10 shown in FIGS. 154-161, except that for applications where the needle 19 may be insufficient or inappropriate for delivering the medicament, the flange 20 may be coupled with a tubing set 21. The plug 54 may be removed before the tubing set 21 is coupled with the luer lock. The tubing set 21 may be threadably coupled to the flange 20 to establish fluid communication therethrough.

[0086] 167A-167B, a sixth embodiment of the injector 10 is shown. The injector 10 may be similar to the embodiment of the injector 10 shown in FIGS. 154-161, except that the injector 10 may have a staking needle 27 pre-attached to and extending from a distal portion of the primary container 14. The staking needle 27 may be in fluid communication with the primary container 14, which contains the medicament.

[0087] 168-170, a seventh embodiment of the injector 10 is shown. The injector 10 may be similar to the embodiment of the injector 10 shown in FIGS. 154-161, except that a button spring 56 is included to bias the button 24 proximally to prevent an unintended or accidental triggering event. As discussed in more detail above, the button spring 56 may be disposed between the housing 12 and the latch 34 and engage the distal end of the latch 34 to bias the distal end of the button 24 proximally relative to the housing 12. As shown in FIG. 170, in the ejection configuration, the latch arm 32 may engage the recess 30 to prevent the button spring 56 from biasing the button 24 proximally relative to the housing.

[0088] Formulation for high-dose injection The present disclosure provides a formulation for high-dose injection containing a hyaluronidase enzyme. In one embodiment, the formulation is an aqueous formulation. In one embodiment, the formulation includes one or more pharmaceutically acceptable carriers.

[0089] Forms of soluble hyaluronidase Soluble hyaluronidases include any that are secreted from cells upon expression and exist in a soluble form. Such soluble hyaluronidases include, but are not limited to, bacterial soluble hyaluronidase, non-human soluble hyaluronidases, such as bovine PH20 and ovine PH20, human soluble PH20, and variants thereof. Because glycosylation is important for the catalytic activity and stability of hyaluronidases, soluble forms of PH20 are generally produced using protein expression systems that promote correct N-glycosylation to ensure that the polypeptide retains activity. Such cells include, for example, Chinese hamster ovary (CHO) cells (e.g., DG44 CHO cells).

[0090] Borhyaluronidase alfa is a recombinant human hyaluronidase PH-20 analog corresponding to amino acids 36-482 of human hyaluronidase PH-20. Borhyaluronidase alfa is produced in Chinese hamster ovary cells. Borhyaluronidase alfa is a glycoprotein consisting of 447 amino acid residues (molecular weight: 60,000-65,000). In one embodiment, a soluble PH20 product is a composition produced by expression of a nucleic acid encoding residues 36-482 in CHO cells, resulting in a mixture of polypeptides having C-termini at residues 477, 478, 479, 480, 481, and 482.

[0091] Soluble PH20 hyaluronidase is available and sold, for example, under the trademark ENHANZE® (CAS name for 36-482-Hyaluronic Acid Glucosaminidase PH20 (Human)). ENHANZE® is a mixture of polypeptides produced by expression of a nucleic acid encoding amino acids 36-482 (SEQ ID NO:2). The product is a mixture of polypeptides produced by expression of a nucleic acid 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). ENHANZE® technology provides a drug delivery technology that uses soluble hyaluronidase to facilitate the delivery of injectable drugs and fluids. When co-formulated with or administered with other drugs, ENHANZE® technology reduces the treatment burden on patients. This can allow for larger subcutaneous injection volumes with increased distribution and absorption of the co-administered therapeutic agents.

[0092] In one embodiment, one or more of N47, N131, N200, N219, N333, N358, or T440 in SEQ ID NOs:2-7 are glycosylation sites. In one embodiment, one or more of Q444, I445, F446, or Y447 in SEQ ID NOs: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 NOs:2-7 are disulfides.

[0093] rHuPH20 generally refers to a composition produced upon expression in cells, such as CHO cells, of a nucleic acid encoding residues 36-482 of SEQ ID NO:8 linked to a native or heterologous signal sequence (residues 1-35 of SEQ ID NO:8). rHuPH20 is produced in mammalian cells by expression of such a nucleic acid molecule encoding amino acids 1-482 (set forth in SEQ ID NO:8). Translational processing removes the 35 amino acid signal sequence. When produced in culture medium, heterogeneity exists at the C-terminus, such that the product designated rHuPH20 contains a mixture of species that may contain any one or more of polypeptides 36-480, 36-481, and 36-482 of SEQ ID NO:8, as well as several shorter polypeptides, in varying abundance. rHuPH20 and soluble hyaluronidase forms are produced in cells, such as CHO cells, that promote N-glycosylation, e.g., DG44 CHO cells. PH20 is a glycoprotein and, as is known in the art, requires glycosylation to maintain activity. See, e.g., U.S. Patent Nos. 8,927,249 and 9,284,543 (and International Application PCT / WO2010 / 077297), which describe the effects of glycosylation, partial glycosylation, and elimination of glycosylation on the activity of soluble forms of PH20. These patents and publications also describe and exemplify soluble C-terminally truncated forms of PH20.

[0094] Forms of soluble human PH20 Soluble hyaluronidases include bovine and ovine PH20, as well as recombinant and humanized forms thereof. Human PH20 naturally contains a GPI anchor and is present in association with sperm cells; it is not soluble. 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. Description and production of such soluble forms of PH20 are 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, each of which is incorporated herein by reference. Thus, soluble hyaluronidase includes forms of human PH20, which are neutral active hyaluronidases and require glycosylation for activity.

[0095] SEQ ID NO:1 sets forth the sequence of the precursor polypeptide, the mature PH20 polypeptide (residues 36-509); soluble forms also include those with amino acid truncations at the N-terminus, such as deletion of the first 1, 2, 3, or 4 residues, such that the resulting polypeptide has an N-terminus at residues 36, 37, 38, 39, or 40, and a C-terminus at residues 465-500, as well as variants thereof, including, but not limited to, variants discussed below, variants known in the art, and allelic variants.

[0096] The hyaluronidases for use in the compositions, combinations, and methods herein are soluble, neutrally active hyaluronidases, such as soluble C-terminal truncated forms of mature human PH20. Soluble forms with hyaluronidase activity include, but are not limited to, those cleaved at residues 465-500 of SEQ ID NO: 1 and secreted upon expression. Examples thereof include sequences 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, 36-489, 36-490, 36-491, 36-492, 36-493, 36-494, 36-495, 36-496, 36-497, 36-498, 36-499, 36-500, 36-501, 36-502, 36-503, 36-504, 36-505, 36-506, 36-507, 36-508, 36-509, 36-510, 36-511, 36-512, 36-513, 36-514, 36-515, 36-516, 36-517, 36-518, 36-519, 36-520, 36-521, 36-522, 36-523, 36-524, 36-525, 36-526, 36-527, 36-528, 36 and 36-500, as well as N-terminal truncated forms of each of the foregoing lacking 2 to 5 residues at the N-terminus, e.g., 37-368, 38-468, and any others that exhibit hyaluronidase activity at neutral pH, such as a pH in the range of 7.0 to 7.4.

[0097] Thus, such soluble forms include truncated forms of the mature form of human PH20 lacking all or a portion of the C-terminal GPI anchor, so long as the hyaluronidase is soluble and retains hyaluronidase activity. Soluble forms are secreted when expressed in mammalian cells and are encoded by a signal sequence, e.g., residues 1-35 of SEQ ID NO: 1, or a heterologous signal sequence that is cleaved by the cell to effect secretion. Soluble forms are forms that lack the signal peptide when expressed in cells. Soluble hyaluronidase also includes variants of soluble PH20 polypeptides that exhibit hyaluronidase activity. Variants include the PH20 polypeptides 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, 36-489, 36-490, 36-491, 36-492, 36-493, 36-494, 36-495, 36-496, 36-497, 36-498, 36-499, 36-500, 36-501, 36-502, 36-503, 36-504, 36-505, 36-506, 36-507, 36-508, 36-509, 36-601, 36-601, 36-602, 36-603, 36-604, 36-605, 36-606, 36-607, 36-608, 36-609, 36-701, 36-702, 36-703, 36-704, 36-705, 36-706, 36-707, 36-708, 36-7 488, 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. Amino acid variants include conservative and non-conservative insertions, deletions, or substitutions, including, for example, the modifications detailed in U.S. Pat. No. 11,041,149 and International Application PCT / WO2013 / 102144, alone or in combination. U.S. Pat. No. 11,041,149 and International Application PCT / WO2013 / 102144 describe systematic analyses and results that identify the effect of amino acid modifications at each residue in PH20, thereby providing a structure / function map of PH20, allowing one of skill in the art to identify substituted residues and the resulting alterations in properties and activities, such as to provide increased enzymatic activity, stability under denaturing conditions, and also residues whose substitution or deletion reduces or eliminates enzymatic activity.

[0098] It is understood that residues important or otherwise required for hyaluronidase activity, such as any of those listed above or known to those of skill in the art, generally remain unchanged and cannot be altered, except for possible conservative amino acid substitutions. These include, for example, active site residues. For example, amino acid residues 111, 113, and 176 of the human PH20 polypeptide (corresponding to residues in the mature PH20 polypeptide) or its soluble form generally remain unchanged and unaltered. Other residues that confer glycosylation and disulfide bond formation necessary for proper folding may also remain unchanged.

[0099] Soluble human PH20 hyaluronidase is GPI-anchored and can be made soluble by truncation at the C-terminus to remove all or part of the GPI anchor. Such truncation can remove all of the GPI anchor attachment sequence, or only a portion of the GPI anchor attachment sequence. However, the resulting polypeptide is soluble. If the soluble hyaluronidase retains a portion of the GPI anchor attachment signal sequence, one, two, three, four, five, six, seven, or more amino acid residues in the GPI anchor attachment signal sequence can be retained, as long as the polypeptide is soluble. Polypeptides that contain one or more amino acids of the GPI anchor are referred to as extended soluble hyaluronidases. One of skill in the art can determine whether a polypeptide is GPI-anchored using methods well known in the art. Such methods include, but are not limited to, using known algorithms to predict the presence and location of GPI anchor attachment signal sequences and ω sites, and performing solubility analyses before and after digestion with phosphatidylinositol-specific phospholipase C (PI-PLC) or D (PI-PLD).

[0100] For example, extended soluble hyaluronidases terminating at residues 495, 496, 497, 498, 499, and 500 with respect to SEQ ID NO: 1, such as those set forth 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 making a C-terminal truncation in any naturally occurring GPI-anchored hyaluronidase such that the resulting polypeptide is soluble and includes one or more amino acid residues from the GPI-anchor attachment signal sequence (see, e.g., U.S. Patent No. 8,927,249). These include hyaluronidases that are neutrally active, soluble, contain amino acid substitutions, and have at least 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95% or more sequence identity to any of SEQ ID NOs: 9-14.

[0101] Typically, soluble human hyaluronidases, such as soluble human PH20, e.g., PH20, and variants having at least 91%, 95%, or 98% sequence identity thereto, including, for example, those with deletions of one to five N-terminal residues, are used for use in the compositions, combinations, and methods herein. The hyaluronidases used in the regimens, combinations, compositions, and methods herein can be recombinantly produced or purified or partially purified from natural sources, such as, for example, from testis extracts. Methods for producing recombinant proteins, including recombinant hyaluronidase, are well known in the art.

[0102] Recombinant soluble forms of human PH20 have been generated and can be used in the compositions, combinations, and methods provided herein. For example, with respect to SEQ ID NO: 1, which sets forth the sequence of full-length precursor PH20, including the signal sequence (residues 1-35), soluble forms include those derived from the 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, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, , 499, or 500, or a C-terminally truncated polypeptide of human PH20 set forth in SEQ ID NO: 1, having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity when aligned to the unmodified sequence of soluble PH20, which is active at neutral pH and is soluble (secreted into the medium when expressed in mammalian cells). Soluble forms of human PH20 generally include those containing amino acids 36-464 set forth in SEQ ID NO: 1 and terminating at any of residues 465-500, and optionally containing one to three amino acid deletions 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. Thus, mature soluble polypeptides include polypeptides including amino acids 36-467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, and 500 of SEQ ID NO:1, inclusive.Exemplary soluble hyaluronidases are soluble human PH20 polypeptides that are 442, 443, 444, 445, 446, or 447 amino acids in length, such as those described above, and variants thereof that have, for example, at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto 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.

[0103] Because glycosylation is important for the catalytic activity and stability of hyaluronidase, soluble forms of PH20 are generally produced using protein expression systems that promote correct N-glycosylation to ensure that the polypeptide retains activity, such as Chinese hamster ovary (CHO) cells (e.g., DG44 CHO cells).

[0104] Compositions recombinantly produced from mammalian cells, such as CHO cells, are referred to as rHuPH20. It generally refers to compositions produced upon expression in cells, such as CHO cells, of a nucleic acid encoding residues 36-482 of SEQ ID NO:1 linked to a native (residues 1-35 of SEQ ID NO:1) or heterologous signal sequence. rHuPH20 is produced by expression of such a nucleic acid molecule encoding amino acids 1-482 (set forth in SEQ ID NO:1) or 36-482 with a heterologous signal sequence. Post-translational processing removes the 35 amino acid signal sequence, yielding a polypeptide or mixture of polypeptides, including those set forth 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). When produced in culture medium, heterogeneity exists at the C-terminus, resulting in a product designated rHuPH20 containing a mixture of species that may contain any one or more of SEQ ID NOS: 3 and 44-49 in varying abundance. Generally, soluble hyaluronidase, rHuPH20, is produced in cells that promote correct N-glycosylation to retain activity, such as CHO cells (e.g., DG44 CHO cells). Human soluble PH20 hyaluronidase requires glycosylation for activity. When recombinantly produced from a vector encoding residues 36-582, the most abundant species is a 446 amino acid polypeptide corresponding to residues 36-481 of SEQ ID NO: 1. The specific distribution of polypeptides obtained may depend on the particular 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.

[0105] Glycosylation of hyaluronidase Glycosylation, including N- and O-linked glycosylation, of some hyaluronidases, including soluble PH20 hyaluronidase, can be important for their catalytic activity and stability. For some hyaluronidases, removal of N-linked glycosylation can result in near-complete inactivation of hyaluronidase activity. For such hyaluronidases, the presence of N-linked glycans can be important for generating active enzymes.

[0106] N-linked oligosaccharides are classified into several major types (oligomannose, complex, hybrid, and sulfated), all of which contain a (Man)3-GlcNAc-GlcNAc-core linked through the amide nitrogen of an Asn residue within the -Asn-Xaa-Thr / Ser- sequence (where Xaa is not Pro). Glycosylation at the -Asn-Xaa-Cys- site has been reported for coagulation protein C. In some cases, hyaluronidases, such as PH20 hyaluronidase, can contain both N-glycosidic and O-glycosidic linkages. For example, PH20 has both O-linked and N-linked oligosaccharides. There are six potential N-linked glycosylation sites at N82, N166, N235, N254, N368, and N393 in human PH20, as exemplified by SEQ ID NO: 1.

[0107] PH20 variant As discussed above, variants of PH20 are known to those of skill in the art or can be readily prepared given the skill and knowledge in the art. Variants include those with amino acid substitutions, insertions, and deletions. Variants of soluble PH20 polypeptides have been produced with altered properties, such as increased stability and / or activity. 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 structure / function maps of human PH20 detailing the effects of amino acid substitutions at every residue in the catalytic domain of PH20. These patents provide approximately 7,000 examples that identify and illustrate the effect of substituting each amino acid with 15 other amino acids on activity and stability. These patents and previous publications / patents describe virtually every variant of soluble PH20 polypeptides known in the art. Those skilled in the art can readily prepare soluble hyaluronidases and their variants and learn the properties of the resulting hyaluronidases.

[0108] Other variants are also known to those skilled in the art and can be used in the combinations, regimens, and methods described herein. See, for example, International Application Nos. PCT / WO2020 / 022791 and WO2020 / 197230, which are incorporated by reference and describe modified PH20 polypeptides. These polypeptides generally include variants of the PH20 polypeptide spanning residues 38-468, including substitutions, insertions, and deletions. Variants include, for example, one or more amino acid residue changes S343E, I344N, M345T, M348K, K349E, L353A, L354I, N356E, and I361T (see SEQ ID NO: 1), as well as approximately 15 amino acid variations and others including truncations at the N- and C-termini. Variants containing such and other modifications are described in SEQ ID NOs: 60-115 of International Application No. PCT / WO2020 / 022791. An example of such polypeptides is the polypeptide of SEQ ID NO: 99 therein, reproduced herein as SEQ ID NO: 15. International Application PCT / WO2021 / 150079 provides variant PH20 polypeptides that are described as having increased stability compared to unmodified PH20, such as that in rHuPH20. These variant polypeptides have been shown to have PH20 activity and are described as having use for subcutaneous co-administration with other agents.

[0109] In one embodiment, the variant of PH20 is a variant of human PH20 or rHuPH20 selected from any one of SEQ ID NOs: 16-47.

[0110] In one embodiment, the hyaluronidase enzyme is a human hyaluronidase enzyme. Exemplary human hyaluronidase enzymes include HYAL1, HYAL2, HYAL3, HYAL4, HYAL5 (also known as SPAM1 or PH20), and HYAL6 (also known as HYALP1). In one embodiment, the hyaluronidase enzyme is a recombinant hyaluronidase enzyme. In one embodiment, the hyaluronidase enzyme is a recombinant human hyaluronidase enzyme. In one embodiment, the hyaluronidase enzyme is a recombinant human hyaluronidase PH20 enzyme. Exemplary hyaluronidase enzymes that may be used in the present disclosure can be found in the following patents and patent applications, which are incorporated by reference in their entireties: U.S. Patent Application Publication No. 2022 / 0289864 (Alteogen), U.S. Patent No. 9,084,743 (Baxter), U.S. Patent No. 9,993,529 (Halozyme), U.S. Patent No. 8,795,654, U.S. Patent Application Publication No. 2009 / 0311237 (Greg Frost), U.S. Patent No. 9,284,543 (Halozyme), U.S. Patent No. 10,265,410 (Halozyme), U.S. Patent No. 10,137,104 (Halozyme), U.S. Patent Application Publication No. 2013 / 0022592, U.S. Patent Application Publication No. 2019 / 0284263 (Greg Frost), Frost), U.S. Patent No. 11,0653,09, WO 2017 / 185383, U.S. Patent No. 11,041,149 (Halozyme), U.S. Patent Application Publication No. 2010 / 0003238 (Greg Frost), U.S. Patent No. 8,343,487 (Halozyme), U.S. Patent No. 10,301,376 (Baxalta), U.S. Patent Application Publication No. 2013 / 0344048, U.S. Patent Application Publication No. 2021 / 0363270 (Alteogen), U.S. Patent Application Publication No. 2021 / 0155913 (Alteogen), WO 2021 / 150079 (Dassault Systems SolidWorks), and WO 2022 / 031093 (Toshiba TEC Kabushiki Kaisha).

[0111] In one embodiment, the hyaluronidase enzyme is from about 150 U / mL to about 1,000 kU / mL, from about 150 U / mL to about 900 kU / mL, from about 150 U / mL to about 800 kU / mL, from about 150 U / mL to about 700 kU / mL, from about 150 U / mL to about 600 kU / mL, from about 150 U / mL to about 500 kU / mL, from about 150 U / mL to about 400 kU / mL, or from about 150 U / mL to about 300 kU / mL. , 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 enzyme has an activity of about 10 kU / mL in a 5 mL formulation, or about 5 kU / mL in a 10 mL formulation. In one embodiment, the hyaluronidase enzyme 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 enzyme is a recombinant human hyaluronidase PH20 enzyme with an activity of about 120 kU / mL. In another embodiment, the hyaluronidase enzyme 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.

[0112] In one embodiment, the concentration of the hyaluronidase enzyme in the formulation is from about 10 U / mL to about 50,000 U / mL, from about 10 U / mL to about 45,000 U / mL, from about 10 U / mL to about 40,000 U / mL, from about 10 U / mL to about 35,000 U / mL, from about 10 U / mL to about 30,000 U / mL, from about 10 U / mL to about 25,000 U / mL, from about 10 U / mL to about 20,000 U / mL, from about 10 U / mL to about 15,000 U / mL, from about 10 U / mL to about 10,000 U / mL, or from about 100 U / mL to about 9,000 U / mL. mL, 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 2,000 U / mL. In one embodiment, the formulation comprises about 1,500 U / mL to about 10,000 U / mL of hyaluronidase enzyme. In one embodiment, the formulation contains about 1,500 U / mL to about 10,000 U / mL of recombinant human hyaluronidase PH20 enzyme. In one embodiment, the formulation contains about 2,000 U / mL of recombinant human hyaluronidase PH20 enzyme. In one embodiment, the formulation contains about 5,000 U / mL of recombinant human hyaluronidase PH20 enzyme. In another embodiment, the formulation contains at least 4,000 U / mL of recombinant human hyaluronidase PH20 enzyme. In another embodiment, the formulation contains at least 7,500 U / mL of recombinant human hyaluronidase PH20 enzyme. In another embodiment, the formulation contains at least 10,000 U / mL of recombinant human hyaluronidase PH20 enzyme. In one embodiment, the formulation contains about 4,000 U / mL of recombinant human hyaluronidase PH20 enzyme.

[0113] In one embodiment, the formulation comprises a hyaluronidase enzyme that allows for a high volume of the formulation to be injected at a high flow rate into a subject in need thereof. In one embodiment, the formulation comprises a hyaluronidase enzyme at a concentration and / or activity that allows for a high volume of the formulation to be injected at a high flow rate into a subject in need thereof.

[0114] In one embodiment, the formulation includes one or more pharmaceutically acceptable additives, including, but not limited to, carriers, excipients, fillers, preservatives, stabilizers, and antioxidants. The pharmaceutically acceptable additives can be any pharmaceutically acceptable additives known to those skilled in the art for injectable formulations. In one embodiment, the formulation includes histidine. In one embodiment, the formulation includes sodium chloride. In one embodiment, the formulation includes a polysorbate. In one embodiment, the polysorbate includes polysorbate 80. In one embodiment, the formulation comprises 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% polysorbate 80. In one embodiment, the formulation comprises an antioxidant. In one embodiment, the antioxidant comprises methionine. In one embodiment, the formulation comprises 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 of antioxidant. In one embodiment, the formulation comprises about 10 mM methionine. In one embodiment, the formulation comprises a carrier protein.

[0115] 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.

[0116] In one embodiment, the formulation comprises an active ingredient. The active ingredient can be any active ingredient for treating a disease or disorder in a subject in need thereof, provided that the active ingredient can be administered to a subject in need thereof via injection. In one embodiment, the active ingredient is selected from a small molecule, a peptide fragment, a biologic, a nanoparticle, an antibody, an antibody fragment, or a small molecule antiviral agent.

[0117] Treatment method In one aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject via injection a formulation comprising a hyaluronidase enzyme and a therapeutically effective amount of an active ingredient. The formulation is described elsewhere herein. In one embodiment, the hyaluronidase enzyme is a recombinant human hyaluronidase PH20 enzyme. 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 medical professional. In yet another embodiment, the formulation is administered to the subject by a layperson who is not a medical 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 from a pre-filled syringe using an HVAI. In another embodiment, the formulation is administered manually using a manually triggered injection device. In another embodiment, the formulation is administered from an on-body device.

[0118] In one embodiment, the formulation is administered to the abdomen or thigh of the subject. In one embodiment, the formulation is administered subcutaneously to the abdomen or thigh of the subject.

[0119] In one embodiment, the amount of a disclosed formulation administered to a subject depends on the subject, the severity of the disorder or condition being treated, the rate of administration, the nature of the compound, and / or the discretion of the prescribing physician. In one embodiment, an effective dosage of the active ingredient in a disclosed formulation ranges from about 0.001 to about 100 mg / kg of body weight / day, e.g., about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this amounts to about 0.05 to 7 g / day, e.g., about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower end of the aforementioned ranges are more than adequate, while in other cases, even larger doses can be used without causing adverse side effects, e.g., by dividing such larger doses into several smaller doses to be administered throughout the day.

[0120] In one embodiment, the disclosed formulations are administered to a subject in multiple doses. Administration can be about once, twice, three times, four times, five times, six times, or more than six times per day. Administration can be about once per month, once every two weeks, once per week, or once every other day. In one embodiment, the disclosed formulations are administered about once per day to about six times per day. In one embodiment, administration of the disclosed formulations continues for less than about seven days. In yet another embodiment, administration continues for more than about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous administration is achieved and maintained as long as necessary.

[0121] In one embodiment, the effective dosage of the active ingredient in the disclosed formulations ranges from 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.

[0122] In one embodiment, the formulation is administered using an HVAI equipped with a needle, hi one embodiment, the needle is 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. In one embodiment, the needle is a 27 gauge standard wall x ½ inch needle, a 27 gauge standard wall x 5 / 8 inch needle, a 27 gauge standard wall x ¾ inch needle, a 27 gauge standard wall x 1 inch needle, a 27 gauge thin wall x ½ inch needle, a 27 gauge thin wall x 5 / 8 inch needle, a 27 gauge thin wall x ¾ inch needle, a 27 gauge thin wall x 1 inch needle, a 25 gauge standard wall x ½ inch needle, a 25 gauge standard wall x 5 / 8 inch needle, a 25 gauge standard wall x ¾ inch needle, a 25 gauge standard wall x 1 inch needle, a 25 gauge thin wall x ½ inch needle, a 25 gauge thin wall x 5 / 8 inch needle, a 25 gauge thin wall x ¾ inch needle, a 25 gauge thin wall x 1 inch needle, a 23 gauge standard wall x ½ inch needle, The needles are 23 gauge standard wall x 5 / 8 inch needles, 23 gauge standard wall x 3 / 4 inch needles, or 23 gauge standard wall x 1 inch needles. In one embodiment, the needles are 25 gauge thin wall x 1 / 2 inch needles. In one embodiment, the needles are 25 gauge thin wall x 5 / 8 inch needles.

[0123] In one embodiment, a high volume of the formulation is administered to a subject. In one embodiment, a "high volume" is 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 is administered to a 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 35mL, about 3mL to about 40mL, about 3mL to about 45mL, about 3mL to about 50mL, about 5mL to about 10mL, about 5mL to about 15mL, about 5mL to about 20mL, about 5mL 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 is administered to a subject in a single dose.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 13.5 mL, at least about 14 mL, at least about 15 mL, at least about 16 mL, at least about 17 mL, at least about 18 mL, at least about 19 mL, at least about 20 mL, at least about 21 mL, at least about 22 mL, at least about 23 mL, at least about 24 mL, at least about 25 mL, at least about 26 mL, at least about 27 mL, at least about 28 mL, at least about 29 mL, at least about 30 mL, at least about 31 mL, at least about 32 mL, at least about 33 mL, at least about 34 mL, at least about 35 mL, at least about 36 mL, at least about 37 mL, at least about 38 mL, at least about 39 mL, at least about 40 mL, at least about 41 mL, at least about 42 mL, at least about 43 mL, at least about 44 mL, at least about 45 mL, at least about 46 mL, at least about 47 mL, at least about 48 mL, at least about 49 mL, at least about 50 mL, at least about 51 mL, at least about 52 mL, at least about 53 mL, at least about 54 mL, at least 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 is administered to a subject in a single dose. In one embodiment, 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 is administered to a subject in a single dose.

[0124] In one embodiment, 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 of the formulation is administered to a subject in a single dose. In one embodiment, more 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 of formulation is dispensed in about 10 seconds, about 12 seconds, about 16 seconds, about 18 seconds, about 20 seconds, The dose is administered to the subject in about 22 seconds, about 24 seconds, about 26 seconds, about 28 seconds, about 30 seconds, about 32 seconds, about 34 seconds, about 36 seconds, about 38 seconds, about 40 seconds, about 42 seconds, about 44 seconds, about 46 seconds, about 48 seconds, about 50 seconds, about 52 seconds, about 54 seconds, about 56 seconds, about 58 seconds, about 60 seconds, about 65 seconds, about 70 seconds, about 75 seconds, about 80 seconds, about 85 seconds, about 90 seconds, about 95 seconds, about 100 seconds, about 105 seconds, about 110 seconds, about 115 seconds, or about 120 seconds.

[0125] In one embodiment, about 5 mL of the formulation can be administered to a subject in 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.

[0126] In one embodiment, about 10 mL of the formulation can be administered to a subject in 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.

[0127] In one embodiment, about 10.5 mL of the formulation can be administered to a subject in 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.

[0128] In some embodiments, the rate at which a large volume of the formulation can be administered to a subject depends on the gauge of the needle used to inject the formulation. In one embodiment, the formulation is administered to a subject using an autoinjector and a 23-gauge needle. In one embodiment, about 10 mL of the formulation can be administered to a subject using an autoinjector and a 23-gauge needle in about 5 to about 45 seconds, about 5 to about 40 seconds, about 10 to about 40 seconds, about 10 to about 35 seconds, about 15 to about 35 seconds, about 15 to about 30 seconds, about 20 to about 30 seconds, about 15 to about 25 seconds, or about 20 seconds. In one embodiment, about 5.5 mL of the formulation can be administered to a subject using an autoinjector and a 23-gauge needle in about 5 seconds to about 45 seconds, about 5 seconds to about 40 seconds, about 10 seconds to about 40 seconds, about 10 seconds to about 35 seconds, about 15 seconds to about 35 seconds, about 15 seconds to about 30 seconds, about 15 seconds to about 25 seconds, or about 20 seconds. In one embodiment, about 5.5 mL of the formulation can be administered to a subject using an autoinjector and a 23-gauge needle in about 15 seconds to about 60 seconds, about 20 seconds to about 60 seconds, about 25 seconds to about 60 seconds, about 25 seconds to about 55 seconds, about 30 seconds to about 55 seconds, about 30 seconds to about 50 seconds, about 35 seconds to about 50 seconds, about 40 seconds to about 50 seconds, or about 45 seconds. In another embodiment, the formulation is administered to a subject using an autoinjector and a 25-gauge needle. In one embodiment, about 10 mL of the formulation can be administered to a subject using an autoinjector and a 25-gauge needle in 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 a subject using an autoinjector and a 23-gauge needle in about 5 to about 45 seconds, about 5 to about 40 seconds, about 10 to about 40 seconds, about 10 to about 35 seconds, about 15 to about 35 seconds, about 15 to about 30 seconds, about 15 to about 25 seconds, or about 20 seconds. In one embodiment, about 5.5 mL of the formulation can be administered to a subject using an autoinjector and a 25-gauge needle in about 15 seconds to about 60 seconds, about 20 seconds to about 60 seconds, about 25 seconds to about 60 seconds, about 25 seconds to about 55 seconds, about 30 seconds to about 55 seconds, about 30 seconds to about 50 seconds, about 35 seconds to about 50 seconds, about 40 seconds to about 50 seconds, or about 45 seconds.In another embodiment, the formulation is administered to a subject using an autoinjector and a 27-gauge needle. In one embodiment, about 10 mL of the formulation can be administered to a subject using an autoinjector and a 27-gauge needle in about 15 seconds to about 60 seconds, about 20 seconds to about 60 seconds, about 25 seconds to about 60 seconds, about 25 seconds to about 55 seconds, about 30 seconds to about 55 seconds, about 30 seconds to about 50 seconds, about 35 seconds to about 50 seconds, about 40 seconds to about 50 seconds, or about 45 seconds. In one embodiment, about 5.5 mL of the formulation can be administered to a subject using an autoinjector and a 27-gauge needle in about 15 seconds to about 60 seconds, about 20 seconds to about 60 seconds, about 25 seconds to about 60 seconds, about 25 seconds to about 55 seconds, about 30 seconds to about 55 seconds, about 30 seconds to about 50 seconds, about 35 seconds to about 50 seconds, about 40 seconds to about 50 seconds, or about 45 seconds.

[0129] In one embodiment, using a 23 gauge needle with an HVAI and the disclosed formulation provides an injection time that is about 40%, about 42%, about 44%, about 46%, about 48%, about 50%, about 52%, about 54%, about 56%, about 58%, or about 60% faster than using a 25 gauge needle with an HVAI.

[0130] In one embodiment, the device has a variable delivery rate that can deliver the formulation faster at the start of the injection and slower at the completion of the injection, hi another embodiment, the device has a variable delivery rate that delivers the formulation slower at the start of the injection and faster at the completion of the injection.

[0131] In one embodiment, the viscosity and volume of the disclosed formulations affect the time required to inject the formulation into a subject. However, the entire volume of the formulation can be delivered from the HVAI at a rate of about 0.08 to 1.0 mL / second. For example, this can 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 / second. In one embodiment, the HVAI delivers the entire deliverable volume of the formulation at a rate of 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, 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, or about 5 mL / 10 seconds. In one embodiment, the HVAI delivers the entire deliverable volume of the formulation at a rate of 2 mL / 30 seconds, 2.5 mL / 30 seconds, 3 mL / 30 seconds, 3.5 mL / 30 seconds, 4 mL / 30 seconds, 4.5 mL / 30 seconds, 5 mL / 30 seconds, 5.5 mL / 30 seconds, 6 mL / 30 seconds, 6.5 mL / 30 seconds, 7 mL / 30 seconds, 7.5 mL / 30 seconds, 8 mL / 30 seconds, 8.5 mL / 30 seconds, 9 mL / 30 seconds, 9.5 mL / 30 seconds, 10 mL / 30 seconds, or 10.5 mL / 30 seconds. In one embodiment, the total deliverable volume of the formulation is delivered at a rate of 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, 21 mL / min.

[0132] In one embodiment, the disclosed formulations have a flow rate of about 0.05 mL / sec, about 0.06 mL / sec, about 0.07 mL / sec, about 0.08 mL / sec, about 0.09 mL / sec, about 0.10 mL / sec, about 0.11 mL / sec, about 0.12 mL / sec, about 0.13 mL / sec, about 0.14 mL / sec, about 0.15 mL / sec, about 0.16 mL / sec, about 0.17 mL / sec, about 0.18 mL / sec, about 0.19 mL / sec, about 0.20 mL / sec, about 0.21 mL / sec, about 0.22 mL / sec, about 0.23 mL / sec, about 0.24 mL / sec, about 0.25 mL / sec, about 0.26 mL / sec, about 0.27 mL / sec, Approx. 0.28mL / sec, approx. 0.29mL / sec, approx. 0.30mL / sec, approx. 0.31mL / sec, approx. 0.32mL / sec, approx. 0.33mL / sec, approx. 0.34mL / sec, approx. 0.35mL / sec, approx. 0.36mL / sec, approx. 0.37mL / sec, approx. 0.38mL / sec, approx. 0.39mL / sec, approx. 0. 4mL / sec, about 0.41mL / sec, about 0.42mL / sec, about 0.43mL / sec, about 0.44mL / sec, about 0.45mL / sec, about 0.46mL / sec, about 0.47mL / sec, about 0.48mL / sec, about 0.49mL / sec, about 0.50mL / sec, about 0.51mL / sec, about 0.52mL / sec seconds, approx. 0.53 mL / sec, approx. 0.54 mL / sec, approx. 0.55 mL / sec, approx. 0.56 mL / sec, approx. 0.57 mL / sec, approx. 0.58 mL / sec, approx. 0.65mL / sec, approx. 0.66mL / sec, approx. 0.67mL / sec, 0.68mL / sec, approx. 0.69mL / sec, approx. 0.70mL / sec, approx. 0.71mL / sec, approx. 0.72mL / sec, approx. 0.73mL / sec, approx. 0.74mL / sec, approx. 0.75mL / sec, approx. 0.76mL / sec, approx. 0.77m L / sec, about 0.78 mL / sec, about 0.79 mL / sec, about 0.80 mL / sec, about 0.81 mL / sec, about 0.82 mL / sec, about 0.83 mL / sec, about 0.84 mL / sec, about 0.85 mL / sec, about 0.86 mL / sec, about 0.87 mL / sec, about 0.88 mL / sec, about 0.89 mL / sec, about 0.90 mL / sec, about 0.91 mL / sec, about 0.92 mL / sec, about 0.93 mL / sec, about 0.94 mL / sec, about 0.95 mL / sec, about 0.96 mL / sec, about 0.97 mL / sec, about 0.98 mL / sec, about 0.99 mL / sec, or about 1.0 mL / sec.

[0133] In one embodiment, the disclosed formulations are administered using a pre-filled syringe fitted with a 20-33 gauge needle at a rate of about 0.05 mL / sec, about 0.06 mL / sec, about 0.07 mL / sec, about 0.08 mL / sec, about 0.09 mL / sec, about 0.10 mL / sec, about 0.11 mL / sec, about 0.12 mL / sec, about 0.13 mL / sec, about 0.14 mL / sec, about 0.15 mL / sec, about 0.16 mL / sec, about 0.17 mL / sec, about 0.18 mL / sec, about 0.19 mL / sec, about 0.20 mL / sec, about 0.21 mL / sec, about 0.22 mL / sec, about 0.23 mL / sec, about 0.24 mL / sec, or about 0.25 mL / sec. L / sec, about 0.25mL / sec, about 0.26mL / sec, about 0.27mL / sec, about 0.28mL / sec, about 0.29mL / sec, about 0.30mL / sec, about 0.31mL / sec, about 0.32mL / sec, about 0.33mL / sec, about 0.34mL / sec, about 0.35mL / sec, about 0.36mL / sec, Approx. 0.37mL / sec, approx. 0.38mL / sec, approx. 0.39mL / sec, approx. 0.4mL / sec, approx. 0.41mL / sec, approx. 0.42mL / sec, approx. 0.43mL / sec, approx. 0.44mL / sec, approx. 0.45mL / sec, approx. 0.46mL / sec, approx. 0.47mL / sec, approx. 0.48mL / sec, approx. 0.49 mL / s, approx. 0.50mL / s, approx. 0.51mL / s, approx. 0.52mL / s, approx. 0.53mL / s, approx. 0.54mL / s, approx. 0.55mL / s, approx. 0.56mL / s, approx. 0.57mL / s, approx. 0.58mL / s, approx. 0.59mL / s, approx. 0.60mL / s, approx. 0.61mL / s , about 0.62mL / sec, about 0.63mL / sec, about 0.64mL / sec, about 0.65mL / sec, about 0.66mL / sec, about 0.67mL / sec, 0.68mL / sec, about 0.69mL / sec, about 0.70mL / sec, about 0.71mL / sec, about 0.72mL / sec, about 0.73mL / sec, about 0.7 4mL / sec, approx. 0.75mL / sec, approx. 0.76mL / sec, approx. 0.77mL / sec, approx. 0.78mL / sec, approx. 0.79mL / sec, approx. 0.80mL / sec, approx. 0.81mL / sec, approx. 0.82mL / sec, approx. 0.83mL / sec, approx. 0.84mL / sec, approx. 0.85mL / sec, approx. 0.86mL / sec 0.87mL / sec, 0.88mL / sec, 0.89mL / sec, 0.90mL / sec, 0.91mL / sec, 0.92mL / sec, 0.93mL / sec, 0.94mL / sec, 0.95mL / sec, 0.96mL / sec, 0.97mL / sec, 0.98mL / sec, 0.It is administered to the subject at a rate of 99 mL / sec, or approximately 1.0 mL / sec.

[0134] The formula for dispensing liquids is 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, approximately 0.27 mL / s. 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 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, and approximately 1.The solution is administered to the subject from a high volume autoinjector disclosed herein at a rate of 0 mL / sec.

[0135] In one embodiment, the disclosed formulation is contained in a pre-filled syringe with a needle having a gauge of 20 to 33, and the pre-filled syringe is contained in a high volume auto-injector disclosed herein, and the formulation is injected at a rate of about 0.05 mL / sec, about 0.06 mL / sec, about 0.07 mL / sec, about 0.08 mL / sec, about 0.09 mL / sec, about 0.10 mL / sec, about 0.11 mL / sec, about 0.12 mL / sec, about 0.13 mL / sec, about 0.14 mL / sec, about 0.15 mL / sec, about 0.16 mL / sec, about 0.17 mL / sec, about 0.18 mL / sec, about 0.19 mL / sec, about 0.20 mL / sec, about 0.21 mL / sec, about 0.22 mL / sec, about 0.23 mL / sec, about 0.24 mL / sec, about 0.25 mL / sec, about 0.26 mL / sec, about 0.27 mL / sec, about 0.28 mL / sec, about 0.29 mL / sec, about 10 mL / sec, about 11 mL / sec, about 12 mL / sec, about 13 mL / sec, about 14 mL / sec, about 15 mL / sec, about 16 mL / sec, about 17 mL / sec, about 18 mL / sec, about 19 mL / sec, about 20 mL / sec, about 21 mL / sec, about 22 mL / sec, about 23 mL / sec, about 24 mL / sec, about 25 mL / sec, about 26 mL / sec, about 27 mL / sec, about 28 mL / sec, about 29 mL / sec, about 30 mL / sec, about 31 mL / sec, about 32 mL / sec, about 33 mL / sec, about 34 mL / sec, .20mL / sec, approx. 0.21mL / sec, approx. 0.22mL / sec, approx. 0.23mL / sec, approx. 0.24mL / sec, approx. 0.25mL / sec, approx. 0.26mL / sec, approx. 0.27mL / sec, approx. 0.28mL / sec, approx. 0.29mL / sec, approx. 0.30mL / sec, approx. 0.31mL / sec, approx. 0.32mL / sec, approx. 0.33mL / sec, approx. 0.34mL / sec, approx. 0.35mL / sec, approx. 0.36mL / sec, approx. 0.37mL / sec, approx. 0.38mL / sec, approx. 0.39mL / sec, approx. 0.4mL / sec, approx. 0.41mL / sec, approx. 0.42mL / sec, approx. 0.43mL / sec, approx. 0.44mL / sec, approx. 0. 45mL / sec, approx. 0.46mL / sec, approx. 0.47mL / sec, approx. 0.48mL / sec, approx. 0.49mL / sec, approx. 0.50mL / sec, approx. 0.51mL / sec, approx. 0.52mL / sec, approx. 0.53mL / sec, approx. 0.54mL / sec, approx. 0.55mL / sec, approx. 0.56mL / sec, approx. 0.57mL / sec, about 0.58mL / sec, about 0.59mL / sec, about 0.60mL / sec, about 0.61mL / sec, about 0.62mL / sec, about 0.63mL / sec, about 0.64mL / sec, about 0.65mL / sec, about 0.66mL / sec, about 0.67mL / sec, 0.68mL / sec, about 0.69mL / sec, about 0. 70mL / sec, approx. 0.71mL / sec, approx. 0.72mL / sec, approx. 0.73mL / sec, approx. 0.74mL / sec, approx. 0.75mL / sec, approx. 0.76mL / sec, approx. 0.77mL / sec, approx. 0.78mL / sec, approx. 0.79mL / sec, approx. 0.80mL / sec, approx. 0.81mL / sec, approx. 0.82mL / sec 0.83mL / sec, 0.84mL / sec, 0.85mL / sec, 0.86mL / sec, 0.87mL / sec, 0.88mL / sec, 0.89mL / sec, 0.90mL / sec, 0.91mL / sec, 0.92mL / sec, 0.93mL / sec, 0.94mL / sec, 0.The fluid is administered to the subject at a rate of about 95 mL / second, about 0.96 mL / second, about 0.97 mL / second, about 0.98 mL / second, about 0.99 mL / second, or about 1.0 mL / second.

[0136] In one embodiment, about 3 mL to about 50 mL of the formulation is administered to a subject via subcutaneous administration, with the subcutaneous administration occurring at a rate of about 0.10 mL / sec to about 1.0 mL / sec. In one embodiment, about 3 mL to about 15 mL of the formulation is administered to a subject via subcutaneous administration, with the subcutaneous administration occurring at a rate of about 0.10 mL / sec to about 1.0 mL / sec. In one embodiment, the formulation is administered subcutaneously to a subject from a pre-filled syringe. In one embodiment, the pre-filled syringe is equipped with a needle having a gauge of about 20 to about 31. In one embodiment, the pre-filled syringe is equipped with a needle having a gauge of about 23, about 25, or about 27. In one embodiment, the formulation is administered to a subject from a pre-filled syringe using an HVAI as described elsewhere herein.

[0137] In one embodiment, about 5 mL of the formulation is administered to a subject at a rate of about 0.14 mL / second to about 0.21 mL / second. In one embodiment, about 5 mL of the formulation is administered to a subject from a pre-filled syringe using an HVAI at a rate of about 0.14 mL / second to about 0.21 mL / second. In one embodiment, about 5 mL of the formulation is administered to a subject at a rate of about 0.28 mL / second to about 0.42 mL / second. In one embodiment, about 5 mL of the formulation is administered to a subject from a pre-filled syringe using an HVAI at a rate of about 0.28 mL / second to about 0.42 mL / second. In one embodiment, about 10 mL of the formulation is administered to a subject at a rate of about 0.32 mL / second to about 0.42 mL / second. In one embodiment, about 10 mL of formulation is administered to a subject from a prefilled syringe at a rate of about 0.32 mL / second to about 0.42 mL / second using an HVAI. In one embodiment, about 10.5 mL of formulation is administered to a subject at a rate of about 0.40 mL / second to about 1.0 mL / second using an HVAI. In one embodiment, about 10.5 mL of formulation is administered to a subject from a prefilled syringe at a rate of about 0.40 mL / second to about 1.0 mL / second using an HVAI. In one embodiment, about 10.5 mL of formulation is administered to a subject at a rate of at least 0.7 mL / second. In one embodiment, about 10.5 mL of formulation is administered to a subject from a prefilled syringe at a rate of at least 0.7 mL / second using an HVAI.

[0138] 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 in 15 seconds using a needle having a gauge of 20-31. 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 in 15 seconds using a 27-gauge needle. In one embodiment, about 10.5 mL of the disclosed formulation can be administered to a subject within 15 seconds using a 27-gauge needle. In one embodiment, the needle is connected to a syringe, and the syringe is pre-filled with the disclosed formulation. In one embodiment, the pre-filled syringe is housed in an auto-injector. In one embodiment, the pre-filled syringe is housed in an HVAI as described elsewhere herein.

[0139] In one embodiment, about 3 mL to about 50 mL of a formulation disclosed herein can be delivered from a prefilled syringe using an HVAI to 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 The subject is administered a starting delivery force of 1 lbf to about 120 lbf, about 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, or about 25 lbf. In one embodiment, about 3 mL to about 50 mL of a formulation disclosed herein can be dispensed from a pre-filled syringe using an HVAI at about 1 lbf, about 2 lbf, about 3 lbf, about 4 lbf, 5 lbf, about 6 lbf, about 7 lbf, about 8 lbf, about 9 lbf, about 10 lbf, about 11 lbf, about 12 lbf, about 13 lbf, about 14 lbf, about 15 lbf, about 16 lbf, about 17 lbf, about 18lbf, about 19lbf, about 20lbf, about 21lbf, about 22lbf, about 23lbf, about 24lbf, about 25lbf, about 26lbf, about 27lbf, about 28lbf, about 29lbf , about 30lbf, about 31lbf, about 32lbf, about 33lbf, about 34lbf, about 35lbf, about 36lbf, about 37lbf, about 38lbf, about 39lbf, about 40lbf, about 41lb f, about 42lbf, about 43lbf, about 44lbf, about 45lbf, about 46lbf, about 47lbf, about 48lbf, about 49lbf, about 50lbf, about 51lbf, about 52lbf, about 53 lbf, approx. 54lbf, approx. 55lbf, approx. 56lbf, approx. 57lbf, approx. 58lbf, approx. 59lbf, approx. 60lbf, approx. 61lbf, approx. 62lbf, approx. 63lbf, approx. 64lbf, approx. 6 5 lbf, about 66 lbf, about 67 lbf, about 68 lbf, about 69 lbf, about 70 lbf, about 71 lbf, about 72 lbf, about 73 lbf, about 74 lbf, about 75 lbf, about 76 lbf, about 77 lbf, about 78 lbf, about 79 lbf, about 80 lbf, about 81 lbf, about 82 lbf, about 83 lbf, about 84 lbf, about 85 lbf, about 86 lbf, about 87 lbf, about 88 lbf,About 89 lbf, about 90 lbf, about 91 lbf, about 92 lbf, about 93 lbf, about 94 lbf, about 95 lbf, about 96 lbf, about 97 lbf, about 98 lbf, about 99 lbf, about 100 lbf, about 101 lbf, about 102 lbf, about 103 lbf, about 104 lbf, about 105 lbf, about 106 lbf, about 107 lbf, about 108 lbf, about 109 lbf, about 110 lbf, about 111 lbf, about 112 lbf, about 113 lbf, about 114 lbf, about 115 lbf, about 116 lbf, about 117 lbf, about 118 lbf, about 119lbf, about 120lbf, about 121lbf, about 122lbf, about 123lbf, about 124lbf, about 125lbf, about 126lbf, about 127lbf, about 128lbf, about 129lbf, about 130lbf, about 131lbf, about 132l bf, approx. 133lbf, approx. 134lbf, approx. 135lbf, approx. 136lbf, approx. 137lbf, approx. 138lbf, approx. f, about 147lbf, about 148lbf, about 149lbf, about 150lbf, about 151lbf, about 152lbf, about 153lbf, about 154lbf, about 155lbf, about 156lbf, about 157lbf, about 158lbf, about 159lbf, about 160lb f, approx. 161lbf, approx. 162lbf, approx. 163lbf, approx. 164lbf, approx. 165lbf, approx. 166lbf, approx. 167lbf, approx. 168lbf, approx. 169lbf, approx. , about 175 lbf, about 176 lbf, about 177 lbf, about 178 lbf, about 179 lbf, about 180 lbf, about 181 lbf, about 182 lbf, about 183 lbf, about 184 lbf, about 185 lbf, about 186 lbf, about 187 lbf, about 188 lbf, about 189 lbf, about 190 lbf, about 191 lbf, about 192 lbf, about 193 lbf, about 194 lbf, about 195 lbf, about 196 lbf, about 197 lbf, about 198 lbf, about 199 lbf, or about 200 lbf.

[0140] In one embodiment, the initial delivery force refers to the initial delivery force exerted on the tissue of a subject when administering a formulation from a prefilled syringe using an HVAI. In one embodiment, the initial delivery force refers to the initial delivery force exerted on the syringe stopper of the prefilled syringe in the HVAI when the disclosed formulation is delivered to a subject. In one embodiment, the initial delivery force refers to the initial delivery force exerted on the formulation when administering a formulation from a prefilled syringe using an HVAI. In one embodiment, the initial delivery force refers to the initial delivery force exerted on the prefilled syringe when administering a formulation from a prefilled syringe using an HVAI. In one embodiment, the initial delivery force refers to the initial delivery force generated by the HVAI device when administering a formulation from a prefilled syringe using an HVAI.

[0141] In one embodiment, about 3 mL to about 50 mL of a formulation disclosed herein can be delivered from a prefilled syringe using an HVAI to 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, or about 1 lbf to about 160 lbf. lbf, about 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. In one embodiment, about 3 mL to about 50 mL of a formulation disclosed herein can be dispensed from a pre-filled syringe using an HVAI at about 1 lbf, about 2 lbf, about 3 lbf, about 4 lbf, 5 lbf, about 6 lbf, about 7 lbf, about 8 lbf, about 9 lbf, about 10 lbf, about 11 lbf, about 12 lbf, about 13 lbf, about 14 lbf, about 15 lbf, about 16 lbf, about 17 lbf, about 18 lbf, about 20 lbf, about 21 lbf, about 22 lbf, about 23 lbf, about 24 lbf, about 25 lbf, about 26 lbf, about 27 lbf, about 28 lbf, about 29 lbf, about 30 lbf, about 31 lbf, about 32 lbf, about 33 lbf, about 34 lbf, about 35 lbf, about 36 lbf, about 37 lbf, about 38 lbf, about 39 lbf, about 40 lbf, about 41 lbf, about 42 lbf, about 43 lbf, about 44 lbf, about 45 lbf, about 46 lbf, about 47 lbf, about 48 lbf, about 49 lbf, about 50 lbf, about 51 lbf, about 52 lbf, about 53 lbf, about 54 lbf, about 55 lbf, about 56 lbf, about 57 lbf, about 58 lbf, about 59 lbf, about 60 lbf, about 61 lbf, about 62 lbf, approx. 18lbf, approx. 19lbf, approx. 20lbf, approx. 21lbf, approx. 22lbf, approx. 23lbf, approx. 24lbf, approx. 25lbf, approx. 26lbf, approx. 27lbf, approx. 28lbf , about 29lbf, about 30lbf, about 31lbf, about 32lbf, about 33lbf, about 34lbf, about 35lbf, about 36lbf, about 37lbf, about 38lbf, about 39lbf, about 4 0 lbf, about 41 lbf, about 42 lbf, about 43 lbf, about 44 lbf, about 45 lbf, about 46 lbf, about 47 lbf, about 48 lbf, about 49 lbf, about 50 lbf, about 51 lbf, about 52 lbf, about 53 lbf, about 54 lbf, about 55 lbf, about 56 lbf, about 57 lbf, about 58 lbf, about 59 lbf, about 60 lbf, about 61 lbf, about 62 lbf, about 63 lbf, about 64 lbf, about 65 lbf, about 66 lbf, about 67 lbf, about 68 lbf, about 69 lbf, about 70 lbf, about 71 lbf, about 72 lbf, about 73 lbf, about 74 lbf, about 75 lbf, about 76 lbf, about 77 lbf, about 78 lbf, about 79 lbf, about 80 lbf, about 81 lbf, about 82 lbf, about 83 lbf, about 84 lbf, about 85 lbf,About 86 lbf, about 87 lbf, about 88 lbf, about 89 lbf, about 90 lbf, about 91 lbf, about 92 lbf, about 93 lbf, about 94 lbf, about 95 lbf, about 96 lbf, about 97 lbf, about 98 lbf, about 99 lbf, about 100 lbf, about 101 lbf, about 102 lbf, about 103 lbf, about 104 lbf, about 105 lbf, about 106 lbf, about 107 lbf, about 108 lbf, about 109 lbf, about 110 lbf, about 111 lbf, about 112 lbf, about 113 lbf, about 114 lbf, about 115 lbf, about 116 lbf, about 117lbf, about 118lbf, about 119lbf, about 120lbf, about 121lbf, about 122lbf, about 123lbf, about 124lbf, about 125lbf, about 126lbf, about 127lbf, about 128lbf, about 129lbf, about 130lbf , 131lbf, 132lbf, 133lbf, 134lbf, 135lbf, 136lbf, 137lbf, 138lbf, 139lbf, 140lbf, 141lbf, 142lbf, 143lbf, 144lbf, 14 5 lbf, about 146 lbf, about 147 lbf, about 148 lbf, about 149 lbf, about 150 lbf, about 151 lbf, about 152 lbf, about 153 lbf, about 154 lbf, about 155 lbf, about 156 lbf, about 157 lbf, about 158 ​​lbf, about 159 lbf, about 160 lbf, about 161 lbf, about 162 lbf, about 163 lbf, about 164 lbf, about 165 lbf, about 166 lbf, about 167 lbf, about 168 lbf, about 169 lbf, about 170 lbf, about 171 lbf, about 172 lbf, about 173 lbf, about 1 The subject is administered a final delivery force of about 74 lbf, about 175 lbf, about 176 lbf, about 177 lbf, about 178 lbf, about 179 lbf, about 180 lbf, about 181 lbf, about 182 lbf, about 183 lbf, about 184 lbf, about 185 lbf, about 186 lbf, about 187 lbf, about 188 lbf, about 189 lbf, about 190 lbf, about 191 lbf, about 192 lbf, about 193 lbf, about 194 lbf, about 195 lbf, about 196 lbf, about 197 lbf, about 198 lbf, about 199 lbf, or about 200 lbf.

[0142] In one embodiment, the term "final delivery force" refers to the final delivery force exerted on the subject's tissue when administering the formulation from the prefilled syringe using an HVAI. In one embodiment, the term "final delivery force" refers to the final delivery force exerted on the syringe stopper of the prefilled syringe in the HVAI when the disclosed formulation is delivered to the subject. In one embodiment, the term "final delivery force" refers to the final delivery force exerted on the formulation when administering the formulation from the prefilled syringe using an HVAI. In one embodiment, the term "delivery end force" refers to the final delivery force exerted on the prefilled syringe when administering the formulation from the prefilled syringe using an HVAI. In one embodiment, the term "delivery end force" refers to the final delivery force generated by the HVAI device when administering the formulation from the prefilled syringe using an HVAI.

[0143] In one embodiment, about 3 mL to about 50 mL of a formulation disclosed herein is administered to a subject using an HVAI from a pre-filled syringe at a starting 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 a formulation disclosed herein is administered to a subject using an HVAI from a pre-filled syringe at a starting 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, about 3 mL to about 50 mL of a formulation disclosed herein is delivered from a pre-filled syringe using an HVAI at about 50 psi, about 51 psi, about 52 psi, about 53 psi, about 54 psi, about 55 psi, about 56 psi, about 57 psi, about 58 psi, about 59 psi, about 60 psi, about 61 psi, about 62 psi, about 63 psi, about 64 psi, about 65 psi, about 66 psi, about 67 psi, about 68 psi, 69psi, 70psi, 71psi, 72psi, 73psi, 74psi, 75psi, 76psi, 77psi, 78psi, 79psi, 80psi, 81psi, 82 psi, about 83psi, about 84psi, about 85psi, about 86psi, about 87psi, about 88psi, about 89psi, about 90psi, about 91psi, about 92psi, about 93psi, about 94psi, about 95psi,96psi, 97psi, 98psi, 99psi, 100psi, 101psi, 102psi, 103psi, 104psi, 105psi, 106psi, 107psi, 108psi, 109ps i, about 110psi, about 111psi, about 112psi, about 113psi, about 114psi, about 115psi, about 116psi, about 117psi, about 118psi, about 119psi, about 120psi, about 121psi, about 122psi, about 123psi, about 124psi, about 125psi, about 126psi, about 127psi, about 128psi, about 129psi, about 130psi, about 131psi, about 132psi, about 133psi, about 134psi, about 135psi, about 13 6psi, about 137psi, about 138psi, about 139psi, about 140psi, about 141psi, about 142psi, about 143psi, about 144psi, about 145psi, about 146psi, about 147psi, about 148psi, about 149ps i, about 150psi, about 151psi, about 152psi, about 153psi, about 154psi, about 155psi, about 156psi, about 157psi, about 158psi, about 159psi, about 160psi, about 161psi, about 162psi, 163psi, 164psi, 165psi, 166psi, 167psi, 168psi, 169psi, 170psi, 171psi, 172psi, 173psi, 174psi, 175psi, 17 The subject is administered at a starting pressure of about 6 psi, about 177 psi, about 178 psi, about 179 psi, about 180 psi, about 181 psi, about 182 psi, about 183 psi, about 184 psi, about 185 psi, about 186 psi, about 187 psi, about 188 psi, about 189 psi, about 190 psi, about 191 psi, about 192 psi, about 193 psi, about 194 psi, about 195 psi, about 196 psi, about 197 psi, about 198 psi, about 199 psi, or about 200 psi.

[0144] In one embodiment, the starting pressure refers to the starting pressure exerted on the tissue of a subject when administering a formulation from a pre-filled syringe using an HVAI. In one embodiment, the starting pressure refers to the starting pressure exerted on the syringe stopper of the pre-filled syringe in the HVAI when the disclosed formulation is delivered to a subject. In one embodiment, the starting pressure refers to the starting pressure exerted on the formulation when administering a formulation from a pre-filled syringe using an HVAI. In one embodiment, the starting pressure refers to the starting pressure exerted on the pre-filled syringe when administering a formulation from a pre-filled syringe using an HVAI. In one embodiment, the starting pressure refers to the starting pressure generated by the HVAI device when administering a formulation from a pre-filled syringe using an HVAI.

[0145] In one embodiment, about 3 mL to about 50 mL of a 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. In one embodiment, about 3 mL to about 50 mL of a 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, about 3 mL to about 50 mL of a formulation disclosed herein is delivered from a pre-filled syringe using an HVAI at about 20 psi, about 21 psi, about 22 psi, about 23 psi, about 24 psi, about 25 psi, about 26 psi, about 27 psi, about 28 psi, about 29 psi, about 30 psi, about 31 psi, about 32 psi, about 33 psi, about 34 psi, about 35 psi, about 36 psi, about 37 psi, about 38 psi, about 39 psi, about 40 psi, about 41 psi, about 42 psi, about 43 psi, about 44 psi, about The inhaler is administered to a subject at a final pressure of 45 psi, about 46 psi, about 47 psi, about 48 psi, about 49 psi, about 50 psi, about 51 psi, about 52 psi, about 53 psi, about 54 psi, about 55 psi, about 56 psi, about 57 psi, about 58 psi, about 59 psi, about 60 psi, about 61 psi, about 62 psi, about 63 psi, about 64 psi, about 65 psi, about 66 psi, about 67 psi, about 68 psi, about 69 psi, about 70 psi, about 71 psi, about 72 psi, about 73 psi, about 74 psi, or about 75 psi.

[0146] In one embodiment, the end pressure refers to the end pressure exerted on the tissue of a subject when using an HVAI to administer the disclosed formulation from a pre-filled syringe.In one embodiment, the end pressure refers to the end pressure exerted on the syringe stopper of the pre-filled syringe in the HVAI when the disclosed formulation is delivered to a subject.In one embodiment, the end pressure refers to the end pressure exerted on the formulation when using an HVAI to administer the formulation from a pre-filled syringe.In one embodiment, the end pressure refers to the end pressure exerted on the pre-filled syringe when using an HVAI to administer the formulation from a pre-filled syringe.In one embodiment, the end pressure refers to the end pressure generated by the HVAI device when using an HVAI to administer the formulation from a pre-filled syringe.

[0147] In one embodiment, administration of the formulation to a subject requires less application force compared to a similar formulation that does not include the hyaluronidase enzyme.

[0148] In one embodiment, about 3 mL to about 50 mL of a formulation disclosed herein is administered with an applied 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 at a rate of about 0.05 mL / sec to about 1.0 mL / sec.

[0149] In one embodiment, about 5 mL of the formulation is administered to a subject at a rate of about 0.14 mL / second to about 0.21 mL / second with an application force of about 10 N to about 45 N. In one embodiment, about 5 mL of the formulation is administered to a subject using a 25-gauge needle at a rate of about 0.14 mL / second to about 0.21 mL / second with an application force of about 10 N to about 45 N. In one embodiment, about 5 mL of the formulation is administered to a subject using a 25-gauge needle at a rate of about 0.14 mL / second to about 0.21 mL / second with an application force of about 15 N to about 25 N. In one embodiment, about 5 mL of the formulation is administered to a subject using a 25-gauge needle at a rate of about 0.14 mL / second to about 0.21 mL / second with an application force of about 22 N to about 40 N. In one embodiment, about 10 mL of the formulation is administered to a subject at a rate of about 0.32 mL / sec to about 0.42 mL / sec with an applied force of about 25 N to about 50 N.

[0150] In one embodiment, the force applied when a formulation is administered to a subject at a particular rate depends on the gauge of the needle used to deliver the formulation to the subject. In one embodiment, the force applied when a formulation is administered to a subject at a particular rate depends on the gauge of the needle used to deliver the formulation to the subject and the inner diameter of the needle used to deliver the formulation to the subject. Thus, in one embodiment, use of a 25-gauge needle with a larger inner diameter (i.e., a thin-walled needle such as a Terumo needle) requires less force to administer the disclosed formulation to a subject at a particular rate than use of a 25-gauge needle with a smaller inner diameter (e.g., a BD needle). In one embodiment, about 5 mL of the formulation is administered to a subject at a rate of about 0.14 mL / sec to about 0.21 mL / sec using a 25-gauge needle with an applied force of about 15 N to about 25 N, and the needle is a thin-walled needle (e.g., a Terumo needle). In another embodiment, about 5 mL of the formulation is administered to a subject at a rate of about 0.14 mL / sec to about 0.21 mL / sec using a 25 gauge needle with an application force of about 22 N to about 40 N, and the needle is not a thin-walled needle (e.g., a BD needle).

[0151] In one embodiment, about 10 mL of the formulation is administered to a subject using a 25 gauge needle at a rate of about 0.32 mL / sec to about 0.42 mL / sec with an applied force of about 25 N to about 50 N.

[0152] In one embodiment, about 5 mL of the formulation is administered to a subject at a rate of about 0.14 mL / second to about 0.21 mL / second 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, 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 administered to a subject at a rate of about 0.14 mL / second to about 0.21 mL / second using a 25 gauge needle 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, 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.

[0153] In one embodiment, about 10 mL of the formulation is administered to a subject at a rate of about 0.32 mL / sec to about 0.42 mL / sec 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 administered to a subject at a rate of about 0.32 mL / second to about 0.42 mL / second using a 25 gauge needle 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.

[0154] The HVAI may deliver the entire deliverable volume of the formulation in 5 seconds, 10 seconds, 15 seconds, 20 seconds, 25 seconds, 30 seconds, 35 seconds, 40 seconds, 45 seconds, 50 seconds, 55 seconds, 60 seconds, 70 seconds, 80 seconds, 90 seconds, 100 seconds, 110 seconds, or 120 seconds.

[0155] In one embodiment, the hyaluronidase enzyme allows the formulation to be administered to a subject more quickly than a comparable formulation without the hyaluronidase enzyme. In one embodiment, a disclosed formulation can be administered about 20%, about 22%, about 24%, about 26%, about 28%, about 30%, about 32%, about 34%, about 36%, about 38%, about 40%, about 42%, about 44%, about 46%, or about 48% faster than a comparable formulation without hyaluronidase, when both are administered using the same HVAI equipped with a 23-gauge needle. In one embodiment, a disclosed formulation can be administered about 2%, about 4%, about 6%, about 8%, about 10%, about 12%, about 14%, about 16%, about 18%, or about 20% faster than a comparable formulation without hyaluronidase, when both are administered using the same HVAI equipped with a 25-gauge needle.

[0156] In one embodiment, injection of a high volume of the disclosed formulation in a subject leads to fewer side effects in the subject compared to the same subject receiving the same volume of a comparable formulation without the hyaluronidase enzyme. In one embodiment, injection of a high volume as disclosed elsewhere herein with the disclosed formulation has reduced reflux leakage compared to a similar formulation without the hyaluronidase enzyme. In one embodiment, reflux leakage is reduced by about 54%, about 56%, about 58%, about 60%, about 62%, about 64%, about 66%, about 68%, about 70%, about 72%, about 74%, about 76%, or about 78% compared to a similar formulation without hyaluronidase when a high volume of the disclosed formulation is administered to a subject using an HVAI equipped with a 23-gauge needle. In one embodiment, reflux leakage is reduced by about 62%, about 64%, about 68%, about 70%, about 72%, about 74%, about 76%, about 78%, about 80%, about 82%, about 84%, or about 86% when a high volume of the disclosed formulation is administered to a subject using an HVAI equipped with a 25 gauge needle, compared to a similar formulation without hyaluronidase.

[0157] In one embodiment, swelling (bleb) volume is reduced after injection of the disclosed formulation into a subject compared to a similar formulation without the hyaluronidase enzyme. In one embodiment, swelling height is reduced after injection of the disclosed formulation compared to a similar formulation without the hyaluronidase enzyme. In one embodiment, swelling size is reduced after injection of the disclosed formulation compared to a similar formulation without the hyaluronidase enzyme. In one embodiment, swelling area is reduced after injection of the disclosed formulation compared to a similar formulation without the hyaluronidase enzyme. In one embodiment, swelling hardening after the first injection of the disclosed formulation is minimized compared to a similar formulation without the hyaluronidase enzyme. In one embodiment, swelling dissipates more rapidly when the disclosed formulation is injected compared to a similar formulation without the hyaluronidase enzyme. In one embodiment, the disclosed formulation allows for more consistent delivery from injection to injection (i.e., reduced time to delivery, bleb swelling volume, height, and hardening) compared to a similar formulation without the hyaluronidase enzyme. In one embodiment, the disclosed formulations allow for faster delivery of the full dose from an HVAI than a comparable formulation that does not contain hyaluronidase, which results in less pain and discomfort for the subject.

[0158] Disclosure clause.

[0159] Clause 1. A method for treating a disease or disorder in a subject in need thereof, comprising administering to the subject via subcutaneous administration about 3 mL to about 50 mL of a formulation comprising a hyaluronidase enzyme and a therapeutically effective amount of an active ingredient.

[0160] Clause 2. The method of clause 1, wherein the hyaluronidase enzyme is a recombinant human hyaluronidase enzyme.

[0161] Clause 3. The method of clause 1, wherein the hyaluronidase enzyme is a recombinant human hyaluronidase PH20 enzyme.

[0162] Clause 4. The method of Clause 1, wherein the hyaluronidase enzyme has an activity of about 150 U / mL to about 150 kU / mL.

[0163] Clause 5. The method according to clauses 1 to 4, wherein the concentration of the hyaluronidase enzyme in the formulation is from about 500 U / mL to about 5,000 U / mL.

[0164] Clause 6. The method of any one of clauses 1 to 5, wherein the concentration of the hyaluronidase enzyme in the formulation is from about 1,500 U / mL to about 10,000 U / mL.

[0165] Clause 7. The method of any one of clauses 1 to 6, wherein the active ingredient is a small molecule, a peptide fragment, a biologic, or a nanoparticle.

[0166] Clause 8. The method of any one of clauses 1 to 7, wherein the active ingredient is an antibody, antibody fragment, or small molecule antiviral drug.

[0167] Clause 9. The method of any one of clauses 1 to 8, comprising administering about 10 mL to about 20 mL of the formulation to the subject.

[0168] Clause 10. The method of any one of clauses 1-8, 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.

[0169] Clause 11. The method of any one of clauses 1 to 10, comprising administering the formulation using a high volume autoinjector.

[0170] Clause 12. The method of any one of clauses 1 to 11, wherein the formulation is in a pre-filled syringe.

[0171] Clause 13. The method of 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 formulation.

[0172] Clause 14. The method of clause 12 or 13, wherein the prefilled syringe is equipped with a needle having a gauge of about 20 to about 27.

[0173] Clause 15. The method of any one of clauses 12-14, wherein the prefilled 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.

[0174] Clause 16. The method of any one of clauses 1 to 15, comprising administering the formulation at a rate of about 0.08 to about 0.75 mL / second.

[0175] Clause 17. The method of any one of clauses 1 to 16, wherein the formulation has a viscosity of from about 1 cP to about 50 cP.

[0176] Clause 18. The method of any one of clauses 1 to 17, wherein the administration takes a time period of about 20 seconds to about 40 seconds.

[0177] Clause 19. The method of any one of clauses 1 to 18, wherein the administration takes a time period of about 26 seconds to about 30 seconds.

[0178] Clause 20. The method of any one of clauses 1 to 19, wherein administration of the formulation is faster than a similar formulation that does not contain the hyaluronidase enzyme.

[0179] Clause 21. The method of any one of clauses 1 to 20, wherein administration of the formulation produces fewer side effects in the subject compared to a similar formulation that does not contain the hyaluronidase enzyme.

[0180] Clause 22. The method of any one of clauses 1 to 21, wherein administration of the formulation causes less pain and discomfort in the subject compared to a similar formulation that does not contain the hyaluronidase enzyme.

[0181] Clause 23. The method of any one of clauses 1 to 22, wherein administration of the formulation results in less reflux leakage at the injection site compared to a similar formulation that does not contain the hyaluronidase enzyme.

[0182] Clause 24. The method of clause 23, wherein reflux leakage at the injection site is reduced by about 85% to about 30% compared to a similar formulation that does not contain the hyaluronidase enzyme.

[0183] Clause 25. The method of any one of clauses 1 to 24, wherein administration of the formulation results in less swelling volume and / or swelling height at the injection site compared to a similar formulation that does not contain the hyaluronidase enzyme.

[0184] Clause 26. The method of clause 25, wherein the formulation results in about 35% to about 5% less swelling and / or swelling height at the injection site compared to a similar formulation that does not include the hyaluronidase enzyme.

[0185] Clause 27. The method of any one of clauses 1 to 26, wherein administration of the formulation results in smaller bleb swelling size, less bleb hardening, and / or more rapid bleb resolution compared to a similar formulation that does not contain a hyaluronidase enzyme.

[0186] Clause 28. The method of any one of clauses 1 to 27, wherein the subject is a human.

[0187] Clause 29. The method of any one of clauses 1 to 28, wherein the subject self-administers the formulation.

[0188] Clause 30. The method of any one of clauses 1 to 28, wherein a healthcare provider or caregiver administers the formulation to the subject.

[0189] Clause 31. The method of any one of clauses 1 to 30, wherein the subcutaneous administration is a single injection.

[0190] Clause 32. The method of any one of clauses 1 to 30, wherein the subcutaneous administration comprises two or more injections.

[0191] Clause 33. The method of any one of clauses 1 to 30, wherein the subcutaneous administration is delivered via an on-body device.

[0192] Clause 101. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject via subcutaneous administration about 3 mL to about 50 mL of a formulation comprising a therapeutically effective amount of an active ingredient selected from a small molecule, a peptide fragment, a biologic, a nanoparticle, an antibody, an antibody fragment, and a small molecule antiviral, wherein the subcutaneous administration occurs via a high volume autoinjector with a starting delivery force of about 5 lbf to about 50 lbf, a finishing delivery force of about 5 lbf to about 20 lbf, a starting pressure of about 50 psi to about 200 psi, and / or a finishing pressure of about 20 psi to about 75 psi.

[0193] Clause 102. The method of claim 101, wherein the formulation further comprises a hyaluronidase enzyme.

[0194] Clause 103. The method of claim 102, wherein the hyaluronidase enzyme is a recombinant human hyaluronidase enzyme.

[0195] Clause 104. The method of claim 102 or 103, wherein the hyaluronidase enzyme is a recombinant human hyaluronidase PH20 enzyme.

[0196] Clause 105. The method of any one of claims 102 to 104, wherein the hyaluronidase enzyme has an activity of about 150 U / mL to about 150 kU / mL.

[0197] Clause 106. The method of any one of claims 102 to 104, wherein the hyaluronidase enzyme has an activity of from about 500 U / mL to about 5,000 U / mL.

[0198] Clause 107. The method of any one of claims 102-104, wherein the hyaluronidase enzyme has an activity of from about 1,500 U / mL to about 10,000 U / mL.

[0199] Clause 108. The method of any one of claims 101 to 107, wherein the active ingredient is a small molecule, a peptide fragment, a biologic, or a nanoparticle.

[0200] Clause 109. The method of any one of claims 101 to 108, wherein the active ingredient is an antibody, an antibody fragment, or a small molecule antiviral drug.

[0201] Clause 110. The method of any one of claims 101 to 109, comprising administering about 10 mL to about 20 mL of the formulation to the subject.

[0202] Clause 111. The method of any one of claims 101 to 110, comprising administering to the subject about 3 mL to about 15 mL of the formulation.

[0203] Item 112. 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, 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, 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, approximately 13.6 mL, approximately 13.7 mL L, 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 16.7 mL, approximately 16.8 mL, approximately 16.9mL, about 17mL, about 17.1mL, about 17.2mL, about 17.3mL, about 17.4mL, about 17.5mL, about 17.6mL, about 17.7mL, about 17.8mL, about 17.9mL, about 1 8mL, about 18.1mL, about 18.2mL, about 18.3mL, about 18.4mL, about 18.5mL, about 18.6mL, about 18.7mL, about 18.8mL, about 18.9mL, about 19mL, about 1 9.1mL, 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, 20.2mL, 20.3mL, 20.4mL, 20.5mL, 20.6mL, 20.7mL, 20.8mL, 20.9mL, 21mL, 21.1mL, 21.2m L, about 21.3mL, about 21.4mL, about 21.5mL, about 21.6mL, about 21.7mL, about 21.8mL, about 21.9mL, about 22mL, about 22.1mL, about 22.2mL, about 22. 3mL, about 22.4mL, about 22.5mL, about 22.6mL, about 22.7mL, about 22.8mL, about 22.9mL, about 23mL, about 23.1mL, about 23.2mL, about 23.3mL, about 2 112. The method of any one of claims 101 to 111, comprising administering to a subject 3.4 mL, about 23.5 mL, about 23.6 mL, about 23.7 mL, about 23.8 mL, about 23.9 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.

[0204] Clause 113. The method of any one of claims 101 to 112, comprising administering the formulation using a high volume autoinjector.

[0205] Clause 114. The method of any one of claims 101-113, comprising administering the formulation using a high volume autoinjector at a starting delivery force of about 3 lbf to about 50 lbf.

[0206] Clause 115. The method of any one of claims 101-114, comprising administering the formulation using a high volume autoinjector at a final delivery force of about 5 lbf to about 20 lbf.

[0207] Clause 116. The method of any one of claims 101-115, comprising administering the formulation using a high volume autoinjector at a starting pressure of about 50 psi to about 200 psi.

[0208] Clause 117. The method of any one of claims 101-116, comprising administering the formulation using a high volume autoinjector at an end pressure of about 20 psi to about 75 psi.

[0209] Clause 118. The method according to any one of claims 101 to 117, wherein the formulation is in a pre-filled syringe.

[0210] Item 119. Premium Scale, 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 0.9mL, 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 0.5mL, 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 0.7mL, 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 18.8mL, approximately 18.9mL, approximately 19m L, 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 2 0.1mL, approx. 20.2mL, approx. 20.3mL, approx. 20.4mL, approx. 20.5mL, approx. 20.6mL, approx. 20.7mL, approx. 20.8mL, approx. 20.9mL, approx. 21mL, approx. 21.1m L, 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 2 2.2mL, about 22.3mL, about 22.4mL, about 22.5mL, about 22.6mL, about 22.7mL, about 22.8mL, about 22.9mL, about 23mL, about 23.1mL, about 23.2m 119. The method of claim 118, wherein the container contains about 23.3 mL, about 23.4 mL, about 23.5 mL, about 23.6 mL, about 23.7 mL, about 23.8 mL, about 23.9 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 of the formulation.

[0211] Clause 120. The method of claim 118 or 119, wherein the prefilled syringe is equipped with a needle having a gauge of about 20 to about 33.

[0212] Clause 121. The method of any one of claims 118-120, wherein the prefilled 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.

[0213] Clause 122. The method of any one of claims 101 to 121, comprising administering the formulation at a rate of about 0.08 to about 1.00 mL / second.

[0214] Clause 123. The method of any one of claims 101 to 122, comprising administering the formulation at a rate of at least about 0.08 to about 1.0 mL / sec.

[0215] Clause 124. The method of any one of claims 101 to 122, comprising administering the formulation at a rate of at least about 0.08 to about 1.00 mL / second or faster.

[0216] Clause 125. The method of any one of claims 101 to 124, wherein administration takes from about 10 seconds to about 40 seconds.

[0217] Clause 126. The method of any one of claims 101 to 124, wherein administration takes a time period of at least about 10 seconds to about 40 seconds.

[0218] Clause 127. The method of any one of claims 101 to 124, wherein administration takes at least about 10 seconds to about 40 seconds or less.

[0219] Clause 128. The method of any one of claims 101 to 124, wherein administration takes from about 15 seconds to about 30 seconds.

[0220] Clause 129. The method of any one of claims 101 to 124, wherein administration takes at least about 15 seconds to about 30 seconds.

[0221] Clause 130. The method of any one of claims 101 to 124, wherein administration takes at least about 15 seconds to about 30 seconds or less.

[0222] Clause 131. The method of any one of claims 101-124, comprising administering about 5 mL of the formulation at a rate of about 0.14 mL / second to about 0.21 mL / second.

[0223] Clause 132. The method of any one of claims 101-124, comprising administering about 10 mL of the formulation at a rate of about 0.32 mL / sec to about 0.42 mL / sec.

[0224] Clause 133. The method of any one of claims 101 to 132, wherein the formulation has a viscosity of from about 1 cP to about 50 cP.

[0225] Clause 134. The method of any one of claims 101 to 132, wherein administration of the formulation requires less application force compared to a similar formulation that does not contain the hyaluronidase enzyme.

[0226] Clause 135. The method of any one of claims 101 to 134, comprising administering about 5 mL of the formulation at a rate of about 0.14 mL / sec to about 0.21 mL / sec with an applied force of about 10 N to about 45 N.

[0227] Clause 136. The method of claim 135, comprising administering the formulation to the subject using a pre-filled syringe equipped with a 25 gauge needle.

[0228] Clause 137. The method of any one of claims 101 to 134, comprising administering about 10 mL of the formulation to the subject at a rate of about 0.32 mL / sec to about 0.42 mL / sec with an applied force of about 25 N to about 50 N.

[0229] Clause 138. The method of claim 137, comprising administering the formulation to the subject using a pre-filled syringe equipped with a 25 gauge needle.

[0230] Clause 139. The method of any one of claims 102 to 138, wherein administration of the formulation is faster than a similar formulation that does not contain the hyaluronidase enzyme.

[0231] Clause 140. The method of any one of claims 102 to 139, wherein administration of the formulation produces fewer side effects in the subject compared to a similar formulation that does not contain the hyaluronidase enzyme.

[0232] Clause 141. The method of any one of claims 102 to 140, wherein administration of the formulation causes less pain and discomfort in the subject compared to a similar formulation that does not contain the hyaluronidase enzyme.

[0233] Clause 142. The method of any one of claims 102 to 141, wherein administration of the formulation results in less reflux leakage at the injection site compared to a similar formulation that does not contain the hyaluronidase enzyme.

[0234] Clause 143. The method of claim 142, wherein reflux leakage at the injection site is reduced by about 85% to about 30% compared to a similar formulation that does not contain the hyaluronidase enzyme.

[0235] Clause 144. The method of any one of claims 102 to 143, wherein administration of the formulation results in less swelling volume and / or swelling height at the injection site compared to a similar formulation that does not contain the hyaluronidase enzyme.

[0236] Clause 145. The method of claim 144, wherein the formulation results in about 35% to about 5% less swelling and / or swelling height at the injection site compared to a similar formulation that does not contain the hyaluronidase enzyme.

[0237] Clause 146. The method of any one of claims 102 to 145, wherein administration of the formulation results in smaller bleb swelling size, less bleb hardening, and / or more rapid bleb resolution compared to a similar formulation that does not contain the hyaluronidase enzyme.

[0238] Clause 147. The method of any one of claims 101 to 146, wherein administration of the formulation results in a more consistent delivery time compared to a similar formulation that does not contain the hyaluronidase enzyme.

[0239] Clause 148. The method of any one of claims 101 to 147, wherein the subject is a human.

[0240] Clause 149. The method of any one of claims 101 to 148, wherein administering comprises the subject self-administering the formulation.

[0241] Clause 150. The method of any one of claims 101 to 149, wherein administering comprises administering the formulation to the subject by a healthcare provider or caregiver.

[0242] Clause 151. The method of any one of claims 101 to 150, wherein the subcutaneous administration comprises a single injection.

[0243] Clause 152. The method of any one of claims 101 to 150, wherein the subcutaneous administration comprises two or more injections.

[0244] Clause 153. The method of any one of claims 101 to 152, wherein the subcutaneous administration is delivered via an on-body device.

[0245] Clause 154. A pharmaceutical kit comprising a high volume autoinjector and about 3 mL to about 50 mL of a formulation comprising a therapeutically effective amount of an active ingredient selected from a small molecule, a peptide fragment, a biologic, a nanoparticle, an antibody, an antibody fragment, and a small molecule antiviral agent.

[0246] Clause 155. The pharmaceutical kit of claim 154, wherein the formulation further comprises a hyaluronidase enzyme.

[0247] Clause 156. The pharmaceutical kit of claim 154, further comprising instructions for administering the hyaluronidase enzyme to a subject in need thereof.

[0248] Clause 157. The pharmaceutical kit of claim 154, further comprising instructions for administering the hyaluronidase enzyme to a subject in need thereof, either simultaneously or sequentially with a formulation comprising the active ingredient.

[0249] Clause 158. The pharmaceutical kit of any one of claims 154-157, wherein the high volume autoinjector is configured to administer the formulation subcutaneously to the subject at a rate of about 0.05 mL / sec to about 1.0 mL / sec.

[0250] Clause 159. The pharmaceutical kit of claim 158, wherein the high volume autoinjector is configured to administer the formulation subcutaneously from a prefilled syringe having a volume of about 3 mL to about 15 mL.

[0251] Clause 160. The pharmaceutical kit of claim 159, wherein the prefilled syringe is equipped with a needle having a gauge of about 20 to about 33.

[0252] Clause 161. The pharmaceutical kit of any one of claims 154-160, wherein the high volume autoinjector is configured to administer the formulation subcutaneously to a subject at a rate of about 0.05 mL / sec to about 0.10 mL / sec.

[0253] Clause 162. The pharmaceutical kit of any one of claims 154-160, wherein the high volume autoinjector is configured to administer the formulation subcutaneously to a subject at a rate of about 0.10 mL / sec to about 0.20 mL / sec.

[0254] Clause 163. The pharmaceutical kit of any one of claims 154-160, wherein the high volume autoinjector is configured to administer the formulation subcutaneously to a subject at a rate of about 0.20 mL / sec to about 0.30 mL / sec.

[0255] Clause 164. The pharmaceutical kit of any one of claims 154 to 160, wherein the high volume autoinjector is configured to administer the formulation subcutaneously to a subject at a rate of about 0.30 mL / sec to about 0.40 mL / sec.

[0256] Clause 165. The pharmaceutical kit of any one of claims 154 to 160, wherein the high volume autoinjector is configured to administer the formulation subcutaneously to a subject at a rate of about 0.40 mL / sec to about 0.50 mL / sec.

[0257] Clause 166. The pharmaceutical kit of any one of claims 154-160, wherein the high volume autoinjector is configured to administer the formulation subcutaneously to a subject at a rate of about 0.50 mL / sec to about 0.60 mL / sec.

[0258] Clause 167. The pharmaceutical kit of any one of claims 154-160, wherein the high volume autoinjector is configured to administer the formulation subcutaneously to a subject at a rate of about 0.60 mL / sec to about 0.70 mL / sec.

[0259] Clause 168. The pharmaceutical kit of any one of claims 154 to 160, wherein the high volume autoinjector is configured to administer the formulation subcutaneously to a subject at a rate of about 0.70 mL / sec to about 0.80 mL / sec.

[0260] Clause 169. The pharmaceutical kit of any one of claims 154 to 160, wherein the high volume autoinjector is configured to administer the formulation subcutaneously to a subject at a rate of about 0.80 mL / sec to about 0.90 mL / sec.

[0261] Clause 170. The pharmaceutical kit of any one of claims 154-160, wherein the high volume autoinjector is configured to administer the formulation subcutaneously to a subject at a rate of about 0.90 mL / sec to about 1.00 mL / sec.

[0262] Clause 171. The pharmaceutical kit of any one of claims 154 to 170, wherein the high volume autoinjector is configured to administer the formulation subcutaneously to a subject with an applied force of about 10 N to about 200 N.

[0263] Clause 172. The pharmaceutical kit of any one of claims 154-171, 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 45 N.

[0264] Clause 173. The pharmaceutical kit of any one of claims 154-171, wherein the high volume autoinjector is configured to administer the formulation subcutaneously to the subject with an applied force of about 25N to about 50N.

[0265] Clause 174. The pharmaceutical kit of any one of claims 154 to 173, wherein the high volume autoinjector is configured for self-administration of the formulation by a subject. [Example]

[0266] Example 1: Evaluation of a 10 mL Subcutaneous Vertical Injection Using a 25G Needle for the Development of an Autoinjector overview This study investigated the delivery of a 120 mg / mL formulated Ig solution using a simulated autoinjector. Test solutions were delivered with and without rHuPH20 at a concentration of 2,000 U / mL. All injections were performed using a handheld device that held the needle in place, thereby inserting it vertically into the subcutaneous space at an injection depth of 7.5 mm. The test solution volume was 10 mL and was delivered in 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 load cell to the end of the syringe flange. Additionally, reflux leakage was collected after injection and quantified by weight. Post-injection swelling was measured using calipers and 3D imaging. After injection, three independent raters assessed the injection site over time (at times T=0, 15, 30 min, 2 h, and 24 h) for erythema, swelling size, and induration to assess the time to resolution of swelling after injection.

[0267] Introduction Current auto-injectors (AIs) are limited to extremely small volumes (typically ≤2.25 mL), limiting their usefulness for delivering larger volumes. For larger volumes, high flow rates are required to make AIs practical. Currently, the recommended amount of time the device can be held in place during self-administration to prevent injection fatigue and potential interruptions is 30 seconds.

[0268] rHuPH20 has been shown to facilitate subcutaneous (SC) administration of fluids and drugs by transiently and locally depolymerizing hyaluronan (HA) in the extracellular matrix (ECM). HA depolymerization subsequently reduces tissue backpressure in the SC space, allowing for rapid, large-volume administration of drugs. Previous studies have shown that rHuPH20 can facilitate the delivery of large volumes to the SC space at high flow rates using an infusion set.

[0269] The minipig model was chosen due to its high similarity to the human subcutaneous space. Previous studies using the minipig model demonstrated the applicability of the model for use in preclinical (Kang et al., 2013) and autoinjector testing (Shi et al., 2021).

[0270] In summary, the objective of this study was to determine whether rHuPH20 could enhance the development of high-volume AIs capable of delivering clinically relevant volumes at high flow rates to the SC space, using minipigs as an animal model. Specifically, this study evaluated the delivery of an Ig solution formulated at 120 mg / mL through a 25G needle when injected perpendicularly into the SC space using a handheld simulated autoinjector device.

[0271] Test Materials and Methods Test substance Human gamma globulin (Ig-120: 12% solution) Lot number: 1032-17 Description: Lyophilized powder to be reconstituted at 120mg / mL Manufacture date: September 21, 2020 Formula: 10mM histidine, 130mM sodium chloride, pH 6.5 Storage conditions: 2~8℃ Supplier: BioMed Supply Formulated by: Halozyme Product Development

[0272] Recombinant Human Hyaluronidase rHuPH20 Lot number: 462-022 Description: Colorless and transparent solution Concentration: 10mg / mL Manufacture date: December 30, 2014 Re-examination date: February 2023 Enzyme activity: 1,229,456U / mL Storage:≦70℃ Formula: 10mM histidine, 130mM sodium chloride, pH 6.5 Handling conditions: Standard laboratory precautions Supplier: Halozyme Therapeutics, Inc.

[0273] formulation Preparation of test solutions The two test solutions administered in this study were Ig-120 alone and Ig-120 + rHuPH20. These were prepared by adding rHuPH20 from a concentrated stock to a previously prepared Ig solution at 120 mg / mL. The final concentration of rHuPH20 in the test solutions was 2,000 U / mL.

[0274] Ig-120 was allowed to thaw overnight at 2-8°C. The following day, test solutions were prepared by adding rHuPH20 to the Ig-120 solution at room temperature. A concentrated stock of rHuPH20 was used for test article 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. 75 mL of each test solution was then aliquoted into individual 100 mL glass vials and stored at 4°C until used for syringe filling the day before testing.

[0275] The Ig-120 + rHuPH20 solutions were tested for rHuPH20 activity prior to the start of testing using a low turbidity assay. The activity of the Ig-120 + rHuPH20 test solutions 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, subsequent test and stored at 2-8°C.

[0276] At the end of the study, dose retention samples obtained during the study procedure, as well as the Ig-120 + rHuPH20 stock used for syringe filling and maintained continuously at 2-8°C since formulation, were tested for rHuPH20 activity. The activity of the Ig-120 + rHuPH20 test solutions was considered within acceptable limits. These values ​​are summarized in Tables 1 and 2.

[0277] [Table 1]

[0278] [Table 2]

[0279] Animal Description Species: Pig (Sus scrofa domestica) Lineage: Yucatan miniature Gender: Female Age: >3 months Weight: 12-16kg upon receipt Amount: 6 Supplier: Premier BioSource (Ramona, CA)

[0280] breeding The animals were received by the facility on September 2, 2022, and were allowed to acclimate before the start of the study. The animals were group-housed in steel enclosures with water automatically provided ad libitum. The animals were fed twice daily (AM and PM) except on test days (PM only). The indoor environment was maintained at a temperature of approximately 17-27°C and a relative humidity of 40-70%. A 12-hour light / 12-hour dark time cycle was maintained. Animals were allowed to acclimate to the facility for a minimum of 3 days before the start of the study.

[0281] Test materials

[0282] [Table 3]

[0283] Experimental design In this study, two 10 mL injections were administered into the abdomen of Yucatan minipigs. One side of the abdomen received a test solution of Ig-120 alone. The other opposite side of the animal received a second test solution of Ig-120 plus rHuPH20. All test solutions containing rHuPH20 were formulated at 2000 U / mL. The location of the injection site was randomized between the left and right sides of the animal. A needle was attached to the mock autoinjector device handle, and the needle was inserted perpendicularly into the SC space. The treatments for each animal are summarized in Table 4.

[0284] [Table 4]

[0285] Quantitative endpoints included the force applied to the syringe barrel during injection, measurement of the volume, area, and height of the post-injection swelling (bleb) via digital caliper measurements, and changes in skin temperature before and after injection collected via an infrared thermometer. Additionally, post-injection reflux leakage of the test substance was collected from the injection site over a 30-second period after removal of the needle using an eye spear to absorb any leakage and quantified by weight. The volume of the injection site bleb was also determined using a 3D camera. Further post-injection qualitative injection site evaluations for erythema, swelling, and induration were performed immediately after injection (T0), as well as 15 minutes (T15), 30 minutes (T30), 2 hours (T2h), and approximately 24 hours (T24h) after injection. Qualitative injection site evaluations were performed with the animals under anesthesia at T0, T15, T30, and T24h, while the animals were conscious and hand-held by an animal technician during the T2 evaluation. Standard photographs were taken both before injection and at T0, T15, T30, T2h, and T24h post-injection. After euthanasia, 12mm punch biopsies were obtained from the injection site and fixed in 10% formalin. In summary, the study endpoints were as follows: Applied force during injection Measurement of reflux leakage after injection Measurement of bleb size (length / width / height) after injection (vernier caliper) Measurement of bleb size (volume, height, area) using 3D imaging Assessment of blebs for erythema, swelling size, and induration at times T0, T15, T30, T2h, and T24h Measurement of injection site temperature (before and after injection) Evaluation of the injection site by histological methods (24 hours after injection)

[0286] Test Procedure Prior to the start of testing, animals were evaluated for general health and body weights were collected. The day before testing, test material (approximately 17 mL) was drawn into a 20 mL syringe, capped, and stored at 2-8°C. On the day of testing, syringes were removed from 2-8°C and allowed to come to room temperature for at least 30 minutes but not more than 4 hours. Dose retentates collected during testing procedures were kept at room temperature until returned to product development.

[0287] Animals were anesthetized with isoflurane gas, placed supine on a foam wedge placed on a heated operating table, and maintained under isoflurane gas for the entire procedure. The abdominal area was cleansed with Nolvasan, followed by wiping the injection site with gauze containing 70% isopropanol and wiping it dry with sterile gauze.

[0288] Injection sites were located in the left and right abdominal regions of the animals, approximately 5 cm cranial to the midline from the inguinal fold and approximately 3 cm toward the midline. Each injection site was marked with a permanent marker and then photographed with a standard camera and a 3D camera before needle insertion. Skin temperature at the injection site was recorded before the start of the injection using an infrared thermometer. The first injection for each animal was a control solution (Ig-120 alone). The second injection on the opposite side of the animal was a test solution containing rHuPH20 (Ig-120 + rHuPH20).

[0289] Assembly of the mock device The mock device was prepared by attaching a capped 25G x 1 inch Leur-lok needle to the male end of a 21-inch extension set. The extension set was then fed through the inside of the mock device, firmly securing the needle in place at the end of the device. Assembly of the mock device was completed by screwing the device cap onto the end of the device. The length of the needle protruding from the end of the mock device was confirmed to be 7.5 mm ± 0.5 mm. The needle remained capped until immediately prior to vertical needle insertion. The syringe containing the test solution was uncapped and attached to the female end of the extension set, and the hardware was then used to prime the needle tip with the test solution. The syringe was then placed into the syringe pump. A load cell was then attached to the end of the syringe plunger. After the load cell was zeroed, the applied force reading was initiated. The pump block was positioned adjacent to the syringe plunger-load cell end with minimal contact force and then locked into place. The needle was inserted perpendicularly into the marked injection site and held in place by hand at a predetermined depth of approximately 7.5 mm. After the load cell reading was confirmed, the syringe pump was started to begin injecting the test substance at a specified flow rate of 20 mL / min. Upon completion of the injection, the needle was removed, the pressure on the syringe pump block was released, and data collection of the applied force was stopped. Backflow leakage of the test solution was then absorbed into a tared eye spear over the injection site for 30 seconds. The weight of the eye spear was recorded using an analytical balance with an accuracy of 0.1 mg. The edges of the bleb at the injection site were marked with a permanent marker, and the length, width, and height were measured and recorded using digital calipers, and then photographed with a standard camera and a 3D camera immediately after injection. The injection sites were then qualitatively scored by three independent assessors for the appearance and severity of erythema, swelling / bleb size, and hardness (induration) using a 5-point scoring system (modified Draize test) based on the 1992 OECD guidelines for staging skin reactions (Tables 5, 6, and 7). The assessors were blinded to each other's scores. After the first injection, the procedure was repeated on the other side of the animal using the other test solution (Ig-120 + rHuPH20).

[0290] [Table 5]

[0291] [Table 6]

[0292] [Table 7]

[0293] Qualitative scores for erythema, swelling, and induration were collected again by all three assessors at 15 minutes, 30 minutes, 2 hours, and approximately 24 hours after injection. Photographs were collected at each of these time points using a standard camera. After the final assessment, animals were humanely euthanized using a ready-to-use solution of pentobarbital sodium and phenytoin sodium (Euthasol®).

[0294] Computational and Statistical Methods Applicability assessment The applied force, measured via a load cell attached to the end of the syringe plunger, was recorded using SensorVUE software (Loadstar Sensors) and the average applied force over the entire injection period was calculated.

[0295] Assessment of local swelling volume and area using caliper measurements and 3D imaging 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 bleb formed after injection. Length and width are defined as measurements from end to end of the bleb along their longest axis (i.e., diameter). These values ​​were recorded manually, and the volume was calculated using the equation Vol = (2 / 3) for half an ellipsoid. * π * A * B * The thickness was determined using the formula A=length / 2, B=width / 2, and C=height.

[0296] 3D imaging was applied as a longitudinal method to measure post-injection swelling. By obtaining high-precision pre- and post-injection 3D images, the distance between two aligned surfaces could be determined. A camera captured images using a factory-calibrated bifocal imaging system to measure the distance between the surfaces. Surface alignment was performed using a multipoint method utilizing common landmarks between the pre- and post-injection images. Using proprietary software, the volume, area, and height of the post-injection swelling were calculated for each injection.

[0297] Caliper measurements and 3D imaging measurements will yield different values ​​for volume, area, and bleb height. This difference is a result of differences in bleb size measurements. 3D measurements calculate bleb height based on the apex of the bleb to the original skin location, while bleb height from caliper measurements measures from the apex of the bleb to the height of the bleb edge. Due to the curvature of the skin, this may result in an overall increase in bleb height for caliper measurements compared to 3D measurements, resulting in larger bleb volume and height. However, the measurements are consistent with each other and therefore do not show any substantial differences.

[0298] Results and Discussion Quantitative measurements before and after injection The applied force was measured during injection. Once the injection was completed, any backflow leakage of the test solution was collected for 30 seconds and weighed. In addition, the size of the swollen bleb was measured using both calipers and 3D imaging using the methods described above. Temperature readings before and after injection were also taken to calculate the temperature change at the injection site.

[0299] Assessment of applied force during injection: Applied force was measured during SC injection by attaching a miniature load cell to the end of a 20 cc syringe barrel. The load cell provided electronically recorded force data throughout the injection via a DI-100U load cell interface at a data acquisition rate of 2 Hz. The applied force and flow rate for each test solution are summarized in Table 8 and Figure 1. The applied force during injection for individual animals at each flow rate is shown in Figure 2.

[0300] [Table 8]

[0301] Assessment of Post-Injection Reflux Leakage: The amount of reflux leakage for each injection was measured by collecting post-injection fluid at the site using a surgical eye spear. Prior to collection, the weight of each eye spear was tared on an analytical balance. Post-injection reflux leakage from the injection site was collected at 30-second intervals. The eye spear was then immediately weighed and the weight recorded. The analytical balance had an accuracy of 0.1 mg. Reflux leakage for Ig-120 alone and Ig-120 + rHuPH20 is shown in Table 9, and individual animal data are shown in Figure 3 with mean ± SEM.

[0302] [Table 9] n=(5 / group)

[0303] Assessment of post-injection bleb volume, area, and height (caliper measurements): Swelling at the local injection site was marked and measured using digital calipers. The bleb volume, dispersion area, and swelling height for each bleb were determined as described above and are summarized in Table 10 for Ig-120 and Ig-120 + rHuPH20. Individual post-injection bleb volume, area, and height values ​​are shown in Figures 4-6.

[0304] [Table 10]

[0305] The swelling volume, area, and height of the Ig-120+rHuPH20 injection were found to be reduced by 37%, 13%, and 29%, respectively, compared to the Ig-120 injection alone.

[0306] Assessment of post-injection bleb shape, volume, area, and height (3D imaging): Pre- and post-injection photographs were taken using a 3D imaging system. This technique allows point-to-point alignment of these two images through multipoint surface registration. The distance between any two points is then represented using a colorimetric surface contour map. Areas with no difference between the two images are displayed in gray. If the post-injection image is higher than the pre-injection image, the area is displayed in a shade of blue. If the post-injection image is lower than the pre-injection image, the distance is displayed in a shade of orange. Color intensity is proportional to the amount of distance measured between the images and the ranges set for positive and negative measurements. Height measurements outside the range are shown in white (>6 mm). Bleb volume and height measurements include out-of-range areas.

[0307] For each animal, a pre-injection 3D image of the injection site was taken, followed by a second image immediately after injection, and these images were mapped to each other using multipoint registration. These registered pre- and post-injection images were then used to calculate bleb volume, height, circumference, length, and width for each bleb using proprietary software. Colorimetric surface contour maps of each post-injection bleb for Ig-120 and Ig-120 + rHuPH20 are shown in Figures 7A-7B.

[0308] The bleb volume, area, and height calculated from 3D images after injection of Ig-120 and Ig-120 + rHuPH20 are summarized in Table 11. The bleb volume, area, and height after each injection are shown graphically in Figures 8-10.

[0309] [Table 11]

[0310] The swelling volume and height after injection were found to be reduced with Ig-120 + rHuPH20 injection compared with Ig-120 alone. Because the swelling area was similar with both injections, the difference in volume appears to be primarily the result of reduced bleb height with Ig-120 + rHuPH20 injection.

[0311] Assessment of temperature change after injection: The temperature at the injection site was measured immediately prior to needle insertion using an infrared thermometer. It was then remeasured at the end of injection to determine if any significant changes in temperature could occur as a result of the flow rate. The temperature changes are summarized in Figure 34. Although the variability in surface temperature was greater than with Ig-120 alone, the mean change in surface temperature between the two test solutions was not significantly different.

[0312] Qualitative assessment of local injection sites After completion of the 5 mL injection, qualitative assessment of erythema, swelling size, and hardness by three different assessors was performed as described above.

[0313] Qualitative assessment of post-injection erythema: Erythema was mild for both test solutions. It was most frequently observed at T15 post-injection but rapidly resolved in all cases, being substantially reduced by T30 and nearly completely resolved by T2h. The scores for erythema (mean ± SEM) by three raters for each test solution are shown in Figure 12 and summarized in Table 12.

[0314] [Table 12]

[0315] Qualitative assessment of swelling size after injection: Scoring by three assessors of swelling size (mean±SEM) over time for each test solution is shown in FIG. 13 and summarized in Table 13.

[0316] [Table 13]

[0317] Injection of Ig-120 + rHuPH20 appeared to reduce bleb swelling size more rapidly over time, approaching resolution (≦1) by T2h, whereas injection of Ig-120 alone was still significant (approximately 3) at T2h.

[0318] Qualitative assessment of post-injection hardness (hardness): Post-injection bleb hardness (hardness) was also assessed by an independent assessor. The scoring over time for hardness (mean ± SEM) for each test solution is shown in Figure 14 and summarized in Table 14.

[0319] [Table 14]

[0320] It was determined that post-injection swelling stiffness was reduced at T0 for Ig-120 + rHuPH20 compared to Ig-120 alone. Additionally, stiffness resolved rapidly with Ig-120 + rHuPH20 injection compared to Ig-120 alone, and was nearly completely resolved by T2h (≦1). In contrast, stiffness of post-injection blebs from Ig-120 alone injections was still significant at T2h.

[0321] The injection sites were photographed before and after the 10 mL injection procedure. Photographs are shown in Figures 16A-21B. Note that at the 2-hour time point (T2h), photographs were taken of animals in an unanesthetized state while being hand-held by an animal technician. Due to increased stress on the animals, this resulted in some flushing of the skin in some animals. Additionally, the injection site may have had some increased tension (skin stretching) at the time of photography. Therefore, qualitative scoring is considered a more accurate assessment of the injection site at the 2-hour time point.

[0322] Summary and Conclusion The test solution of Ig-120+rHuPH20 required approximately 9% less application force for delivery compared to Ig-120 alone.

[0323] Reflux leakage for Ig-120+rHuPH20 injection was reduced by approximately 43% compared to Ig120 alone.

[0324] Post-injection swelling volume, area, and bleb height were reduced by injection of Ig120+rHuPH20 compared to Ig-120 alone (approximately 37%, 13%, and 29%, respectively).

[0325] Qualitative assessment of swelling size and hardening over time after injection showed that Ig-120 + rHuPH20 reduced swelling compared to Ig-120 alone and dissipated more rapidly than Ig-120 alone, with most swelling dissipating within 30 minutes.

[0326] Example 2: Evaluation of a 10 mL Subcutaneous Vertical Injection Using a 23G Needle for the Development of an Autoinjector overview This study investigated the delivery of a 120 mg / mL formulated Ig solution using a simulated autoinjector. Test solutions were delivered with and without rHuPH20 at a concentration of 2,000 U / mL. All injections were performed using a handheld device that held the needle in place so that it could be inserted vertically into the subcutaneous space at an injection depth of 7.5 mm. The test solution volume was 10 mL and was delivered in 30 seconds using a 20 cc syringe and a 23G needle. The force applied to the syringe barrel was measured throughout the injection by attaching a load cell to the end of the syringe flange. Additionally, reflux leakage was collected after injection and quantified by weight. Post-injection swelling was measured using calipers and 3D imaging. After injection, three independent raters assessed the injection site over time (at times T=0, 15, 30 min, 2 h, and 24 h) for erythema, swelling size, and induration to assess the time to resolution of swelling after injection.

[0327] Introduction Current autoinjectors (AIs) are limited to extremely small volumes (typically ≤2.25 mL), limiting their usefulness for delivering larger volumes. For larger volumes, high flow rates are required to make AIs practical. Currently, the recommended amount of time the device can be held in place during self-administration to prevent injection device fatigue and potential interruptions is 30 seconds.

[0328] rHuPH20 has been shown to facilitate SC administration of fluids and drugs by transiently and locally depolymerizing hyaluronan (HA) in the extracellular matrix (ECM). HA depolymerization subsequently reduces tissue backpressure in the SC space, allowing for rapid, large-volume administration of drugs. Previous studies have shown that rHuPH20 can facilitate the delivery of large volumes to the SC space at high flow rates using an infusion set.

[0329] The minipig model was chosen due to its high similarity to the human subcutaneous space. Previous studies using the minipig model demonstrated the applicability of the model for use in preclinical (Kang et al., 2013) and autoinjector testing (Shi et al., 2021).

[0330] In summary, the purpose of this study was to determine whether rHuPH20 could enhance the development of high-volume AIs capable of delivering clinically relevant volumes to the SC space at high flow rates, using minipigs as an animal model. In this study, the use of a larger, vertically positioned 23G needle was investigated for all injections using a handheld simulated autoinjector device.

[0331] Test Materials and Methods Test substance Human gamma globulin (Ig-120: 12% solution) Lot number: 1032-17 Description: Lyophilized powder to be reconstituted at 120mg / mL Manufacture date: September 21, 2020 Formula: 10mM histidine, 130mM sodium chloride, pH 6.5 Storage conditions: 2~8℃ Supplier: BioMed Supply Formulated by: Halozyme Product Development

[0332] Recombinant Human Hyaluronidase rHuPH20 (ENHANZE™ Pharmaceuticals) Lot number: 462-022 Description: Colorless and transparent solution Concentration: 10mg / mL Manufacture date: December 30, 2014 Re-examination date: February 2023 Enzyme activity: 1,229,456U / mL Storage:≦70℃ Formula: 10mM histidine, 130mM sodium chloride, pH 6.5 Handling conditions: Standard laboratory precautions Supplier: Halozyme Therapeutics, Inc.

[0333] Ig dilution buffer Description: Colorless, transparent liquid Formula: 20mM histidine, 130mM sodium chloride, 0.05% PS80, pH 6.3 Batch / Lot: 01032-3 Storage conditions: 2~8℃ Handling conditions: Standard laboratory precautions Supplier: Halozyme Therapeutics, Inc.

[0334] formulation Preparation of test solutions The two test solutions administered in this study were Ig-120 alone and Ig-120 + rHuPH20. These were prepared by adding rHuPH20 from a concentrated stock to a previously prepared Ig solution at 120 mg / mL. The final concentration of rHuPH20 in the test solutions was 2,000 U / mL.

[0335] Ig-120 was allowed to thaw overnight at 2-8°C. The next day, test solutions were prepared by adding rHuPH20 to the Ig-120 solution at room temperature. A concentrated stock of rHuPH20 was used for test article 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 used for syringe filling the day before testing.

[0336] The Ig-120 + rHuPH20 solution was tested for rHuPH20 activity prior to the start of the study using a low turbidity 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, stored at 2-8°C, and tested for enzyme activity prior to the start of the study.

[0337] At the end of the study, dose retention samples obtained during the study procedure were tested for rHuPH20 activity. The activity of the Ig-120 + rHuPH20 test solutions was considered to be within acceptable limits. These values ​​are summarized in Tables 15 and 16.

[0338] [Table 15]

[0339] [Table 16]

[0340] Animal Description Species: Pig (Sus scrofa domestica) Lineage: Yucatan miniature Gender: Female Age: >3 months Weight: 12-16kg upon receipt Amount: 6 Supplier: Premier BioSource (Ramona, CA)

[0341] breeding Animals were received at the facility and allowed to acclimate before the start of the study. Animals were group-housed in steel enclosures with water automatically provided ad libitum. Animals were fed twice daily (AM and PM) except on test days (PM only). The indoor environment was set to maintain a temperature of approximately 17-27°C, a relative humidity of 40-70%, and a 12-hour light / 12-hour dark time cycle. Animals were allowed to acclimate to the facility for a minimum of 3 days before the start of the study.

[0342] Test materials

[0343] [Table 17]

[0344] Experimental design In this study, two 10 mL injections were administered into the abdomen of Yucatan minipigs. One side of the abdomen received a test solution of Ig-120 alone. The other opposite side of the animal received a second test solution of Ig-120 plus rHuPH20. All test solutions containing rHuPH20 were formulated at 2000 U / mL. The location of the injection site was randomized by injecting each test solution three times into the left and right sides of the animals. A needle was attached to the mock autoinjector device handle and inserted perpendicularly into the SC space. The treatments and treatment descriptions for each animal are summarized in Table 18.

[0345] [Table 18]

[0346] Quantitative endpoints included in this study were measurements of the force applied to the syringe barrel during injection, the volume, area, and height of the swelling (bleb) after injection, and changes in skin temperature before and after injection, which were collected via an infrared thermometer. Additionally, post-injection reflux leakage of the test substance was collected from the injection site over a 30-second period after removal of the needle using an eye piercer to absorb any leakage and quantified by weight. The volume of the bleb at the injection site was determined by digital caliper measurements (length, width, and height) and 3D camera imaging. Further post-injection qualitative injection site evaluations for erythema, swelling, and induration were performed immediately after injection (T0), as well as 15 minutes (T15), 30 minutes (T30), 2 hours (T2h), and approximately 24 hours (T24h) after injection. Qualitative evaluation of the injection site was performed with the animals under anesthesia at time points TO, T15, T30, and T24 h, while the T2 evaluation was performed while the animals were conscious and held by hand by an animal technician. Standard photographs were taken both pre-injection and post-injection at time points TO, T15, T30, T2, and T24 h. After euthanasia, 12 mm punch biopsies were obtained from the injection site and fixed in 10% formalin. In summary, the study endpoints were as follows: Applied force during injection Measurement of reflux leakage after injection Measurement of bleb size (length / width / height) after injection (vernier caliper) Measurement of bleb size (volume, height, area) using 3D imaging Assessment of blebs for erythema, swelling size, and induration at times T0, T15, T30, T2h, and T24h Measurement of temperature at the injection site both before and after injection

[0347] Test Procedure Prior to the start of testing, animals were evaluated for general health and body weights were collected. The day before testing, test material (approximately 17 mL) was drawn into a 20 mL syringe, capped, and stored at 2-8°C. On the day of testing, syringes were removed from 2-8°C and allowed to come to room temperature for at least 30 minutes but not more than 2 hours. Dose retentates collected during the testing procedure were stored on ice until returned to product development for enzyme testing later in the testing procedure.

[0348] Animals were anesthetized with isoflurane gas, placed supine on a foam wedge placed on a heated operating table, and maintained under isoflurane gas for the entire procedure. The abdominal area was cleansed with Nolvasan, followed by wiping the injection site with gauze containing 70% isopropanol and wiping it dry with sterile gauze.

[0349] Injection sites were located in the left and right abdominal regions of the animals, approximately 6 cm cranial to the midline from the inguinal fold and approximately 3 cm toward the midline. Each injection site was marked with a permanent marker and then photographed with a standard camera and a 3D camera before needle insertion. Skin temperature at the injection site was recorded before the start of the injection using an infrared thermometer. The first injection for each animal was a control solution (Ig-120 alone). The second injection on the opposite side of the animal was a test solution containing rHuPH20 (Ig-120 + rHuPH20).

[0350] Assembly of the mock device The simulated device was prepared by attaching a capped 23G x 1 inch Luer-lok needle to the male end of a 21 inch extension set. The extension set was then fed through the inside of the simulated device, firmly securing the needle in place at the end of the device. The device with the attached needle was then inserted into the platform. The length of the needle protruding from the end of the simulated 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 prior to perpendicular needle insertion. A 20 cc syringe containing the test solution was uncapped and attached to the female end of the extension set. The hardware was then primed with the test solution to the tip of the needle, and the syringe was placed into the syringe pump. A load cell was then attached to the end of the syringe plunger. The applied force reading was initiated, and the load cell was zeroed. The pump block was positioned adjacent to the syringe plunger-load cell end with minimal contact force and then locked into place. After ensuring that the applied force reading was recorded, the syringe pump was started to begin injecting the test substance at the specified flow rate of 20 mL / min. Upon completion of the injection, the needle was removed, the pressure on the syringe pump block was released, and data collection of applied force was stopped. Backflow leakage of the test solution was then absorbed into a tared eye spear for 30 seconds by suctioning the injection site. The weight of the eye spear was recorded using an analytical balance with an accuracy of 0.1 mg. The edges of the bleb at the injection site were marked with a permanent marker, and the length, width, and height were measured and recorded using digital calipers. The injection site was then photographed with a standard camera and a 3D camera, and the injection site was then qualitatively scored by three independent evaluators for the appearance and severity of erythema, swelling / bleb size, and hardness (induration) using a 5-point scoring system (modified Draize test) based on the 1992 OECD guidelines for staging skin reactions (Tables 18, 19, and 20). The assessors were blinded to each other's scores. After the first injection, the procedure was repeated on the other side of the animal using the other test solution (Ig-120+rHuPH20).

[0351] [Table 19]

[0352] [Table 20]

[0353] [Table 21]

[0354] Qualitative scores for erythema, swelling, and induration were collected again by all three assessors at 15 minutes, 30 minutes, 2 hours, and approximately 24 hours after injection. Photographs were collected at each of these time points using a standard camera. After the final assessment, animals were humanely euthanized using a ready-to-use solution of pentobarbital sodium and phenytoin sodium (Euthasol®).

[0355] Computational and Statistical Methods Applicability assessment The applied force, measured via a load cell attached to the end of the syringe plunger, was recorded using SensorVUE software (Loadstar Sensors) and the average applied force over the entire injection period was calculated.

[0356] Assessment of local swelling volume and area using caliper measurements and 3D imaging 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 bleb formed after injection. Length and width are defined as measurements from end to end of the bleb along their longest axis (i.e., diameter). These values ​​were recorded manually, and the volume was calculated using the equation Vol = (2 / 3) for half an ellipsoid. * π * A * B * The thickness was determined using the formula A=length / 2, B=width / 2, and C=height.

[0357] 3D imaging was applied as a longitudinal method to measure post-injection swelling. By obtaining high-precision pre- and post-injection 3D images, the distance between two aligned surfaces could be determined. A camera captured images using a factory-calibrated bifocal imaging system to measure the distance between the surfaces. Surface alignment was performed using a multipoint method utilizing common landmarks between the pre- and post-injection images. Using proprietary software, the volume, area, and height of the post-injection swelling were calculated for each injection.

[0358] Caliper measurements and 3D imaging measurements will yield different values ​​for volume, area, and bleb height. This difference is a result of differences in bleb size measurements. 3D measurements calculate bleb height based on the apex of the bleb to the original skin location, while bleb height from caliper measurements measures from the apex of the bleb to the height of the bleb edge. Due to the curvature of the skin, this can result in an overall increase in bleb height for caliper measurements compared to 3D measurements, resulting in larger bleb volume and height. However, the measurements are consistent with each other and therefore differ only by methodology.

[0359] Results and Discussion Quantitative measurements before and after injection Quantitative measurements included applied force, reflux leakage, bleb size (length, width, and height), and pre- and post-injection temperature (as above).

[0360] Assessment of applied force during injection: Applied force was measured during SC injection by attaching a miniature load cell to the end of a 20 cc syringe barrel. The load cell provided electronically recorded force data throughout the injection via a DI-100U load cell interface at a data acquisition rate of 2 Hz.

[0361] The applied forces and flow rates for each test solution are summarized in Table 21 and Figure 22. The applied forces during injection for individual animals at each flow rate are shown in Figure 23.

[0362] [Table 22] n=(5 / group)

[0363] Assessment of Post-Injection Reflux Leakage: The amount of reflux leakage for each injection was measured by collecting post-injection fluid at the site using a surgical eye spear. Prior to collection, the weight of each eye spear was tared on an analytical balance. Post-injection reflux leakage from the injection site was collected at 30-second intervals. The eye spear was then immediately weighed and the weight recorded. The analytical balance had an accuracy of 0.1 mg. Reflux leakage for Ig-120 alone and Ig-120 + rHuPH20 is shown in Table 22, and individual animal data are shown in Figure 24 with the mean ± SEM.

[0364] [Table 23]

[0365] Assessment of post-injection bleb volume, area, and height (caliper measurements): Swelling at the local injection site was marked and measured using a digital caliper. The bleb volume, dispersion area, and swelling height for each bleb were determined as described above and are summarized in Table 23 for Ig-120 and Ig-120 + rHuPH20. Individual post-injection bleb volume, area, and height values ​​are shown in Figures 25-27.

[0366] [Table 24]

[0367] Assessment of bleb 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 these two images through multipoint surface registration. The distance between any two points is represented using a colorimetric surface contour map. Areas with no difference between the two images are displayed in gray. If the post-injection image is higher than the pre-injection image, the area is displayed in a blue shade. If the post-injection image is lower than the pre-injection image, the distance is displayed in an orange shade. The color intensity is proportional to the amount of distance measured between the images and the ranges set for positive and negative measurements. Out-of-range measurements are shown in white. Bleb measurements of volume and height include out-of-range areas.

[0368] Each animal had a 3D image of the injection site taken before injection, followed by a second image immediately after injection, and these images were mapped to each other using multipoint registration. These registered pre- and post-injection images were then used to calculate the bleb volume, height, circumference, length, and width for each bleb using proprietary software. Colorimetric surface contour maps of each post-injection bleb for Ig-120 and Ig-120 + rHuPH20 are shown in Figures 28A and 28B, respectively.

[0369] The bleb volume, area, and height calculated from 3D images after injection of Ig-120 and Ig-120 + rHuPH20 are summarized in Table 24. The bleb volume, area, and height after each injection are shown graphically in Figures 29-31.

[0370] [Table 25]

[0371] Assessment of temperature changes after injection: The temperature at the injection site was measured immediately prior to needle insertion using an infrared thermometer. It was then remeasured at the end of injection to determine if any significant changes in temperature could occur as a result of the flow rate. The temperature changes are summarized in Figure 32. Although the variability in surface temperature was greater with Ig-120 alone, the mean change in surface temperature between the two test solutions was not significantly different.

[0372] Qualitative assessment of local injection sites After completion of the 10 mL injection, qualitative assessment of erythema, swelling size, and hardness by three different assessors was performed as described above.

[0373] Qualitative assessment of post-injection erythema: Erythema was mild for both test solutions. It was most frequently observed at T15 post-injection but rapidly resolved in all cases, being substantially reduced by T30 and nearly completely resolved by T2h. Scoring by three assessors of erythema (mean ± SEM) for each test solution is shown in Figure 33 and summarized in Table 25.

[0374] [Table 26]

[0375] Qualitative assessment of swelling size after injection: Scoring by three assessors of swelling size (mean ± SEM) for each test solution is shown in Figure 34 and summarized in Table 26.

[0376] [Table 27]

[0377] Qualitative assessment of post-injection hardness (hardness): Post-injection bleb hardness (hardness) was also assessed by an independent assessor. Scoring over time for hardness (mean ± SEM) for each test solution is shown in Figure 35 and summarized in Table 27.

[0378] [Table 28]

[0379] The injection sites were photographed before and after the 10 mL injection procedure. Photographs are shown in Figures 36A-42B. Note that at the 2-hour time point (T2h), photographs of the animals were taken while they were anesthetized and hand-held by an animal technician. Due to increased stress on the animals, this resulted in some flushing of the skin in some animals. Additionally, the injection site may have had some increased tension (skin stretching) at the time of photography. Therefore, qualitative scoring is considered a more accurate assessment of the injection site at the 2-hour time point.

[0380] Summary and Conclusion Reflux leakage was reduced by 66% by adding rHuPH20.

[0381] The applied force using a 23G needle was reduced by approximately 40% from previous studies using a 25G needle, and the addition of rHuPH20 reduced the applied force by approximately 7% compared to the control injection.

[0382] Swelling and hardening were reduced more rapidly with injection of Ig-120 rHuPH20 compared to injection of Ig-120 alone.

[0383] Example 3: Evaluation of 10 mL Subcutaneous Vertical Injection Using a 25G Needle with 5000 U / mL rHuPH20 for the Development of an Autoinjector overview This study investigated the delivery of a 120 mg / mL formulated Ig solution using a handheld simulated autoinjector. Test solutions were delivered with and without rHuPH20 at a concentration of 5,000 U / mL. All injections were performed using a handheld device that held the needle in place so that it could be inserted vertically into the subcutaneous space at an injection depth of 7.5 mm. The test solution volume was 10 mL and was delivered in 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 load cell to the end of the syringe flange. Additionally, reflux leakage was collected after injection and quantified by weight. Post-injection swelling was measured using a vernier caliper and 3D imaging. After injection, three independent raters assessed the injection site over time (at times T=0, 15, 30 min, 2 h, and 24 h) for erythema, swelling size, and induration to assess the time to resolution of swelling after injection.

[0384] Introduction Current autoinjectors (AIs) are limited to extremely small volumes (typically ≤2.25 mL), limiting their usefulness for delivering larger volumes. For larger volumes, high flow rates are required to make AIs practical. Currently, the recommended amount of time the device can be held in place during self-administration to prevent injection fatigue and potential interruptions is 30 seconds.

[0385] rHuPH20 has been shown to facilitate SC administration of fluids and drugs by transiently and locally depolymerizing hyaluronan (HA) in the extracellular matrix (ECM). HA depolymerization subsequently reduces tissue backpressure in the SC space, allowing for rapid, large-volume administration of drugs. Previous studies have shown that rHuPH20 can facilitate the delivery of large volumes to the SC space at high flow rates using an infusion set.

[0386] The minipig model was chosen due to its high similarity to the human subcutaneous space. Previous studies using the minipig model demonstrated the applicability of the model for use in preclinical (Kang et al., 2013) and autoinjector testing (Shi et al., 2021).

[0387] In summary, the purpose of this study was to determine whether rHuPH20 could enhance the development of high-volume AIs capable of delivering clinically relevant volumes to the SC space at high flow rates, using minipigs as an animal model. In this study, the use of a higher concentration of rHuPH20 using a 25-gauge needle was investigated for all injections (5000 U / mL). This study also builds on data from a previous study in which Ig120 ± rHuPH20 was injected using vertical needle insertion with a 25-gauge needle, but a lower concentration of rHuPH20 (2,000 U / mL) was used. All injections in this study were performed through a vertically positioned 25-gauge needle using a handheld simulated autoinjector device at a depth of 7.5 mm.

[0388] Test Materials and Methods Test substance Human gamma globulin (Ig-120: 12% solution) Lot number: 1032-17 Description: Lyophilized powder to be reconstituted at 120mg / mL Manufacture date: September 21, 2020 Formula: 10mM histidine, 130mM sodium chloride, pH 6.5 Storage conditions: 2~8℃ Supplier: BioMed Supply Formulated by: Halozyme Product Development

[0389] Recombinant Human Hyaluronidase rHuPH20 (ENHANZE™ Pharmaceuticals) Lot number: 462-022 Description: Colorless and transparent solution Concentration: 10mg / mL Manufacture date: December 30, 2014 Re-examination date: February 2023 Enzyme activity: 1,229,456U / mL Storage:≦70℃ Formula: 10mM histidine, 130mM sodium chloride, pH 6.5 Handling conditions: Standard laboratory precautions Supplier: Halozyme Therapeutics, Inc.

[0390] formulation Preparation of test solutions The two test solutions administered in this study were Ig-120 alone and Ig-120 + rHuPH20. These were prepared by adding rHuPH20 from a concentrated stock to a previously prepared Ig solution at 120 mg / mL. The final concentration of rHuPH20 in the test solutions was 5,000 U / mL.

[0391] Ig-120 was allowed to thaw overnight at 2-8°C. The next day, test solutions were prepared by adding rHuPH20 to the Ig-120 solution at room temperature. A concentrated stock of rHuPH20 was used for test article 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 immediately for syringe filling the day before testing.

[0392] The Ig-120 + rHuPH20 solutions were tested for rHuPH20 activity prior to the start of testing using a low turbidity assay. The activity of the Ig-120 + rHuPH20 test solutions was within 10% of the target concentration and was considered within the acceptable range for use in the test. The test solutions were stored at 2-8°C until the start of testing. The rHuPH20 activity values ​​are summarized in Table 28.

[0393] [Table 29]

[0394] At the end of the study, dose retention samples obtained during the study procedure were tested for rHuPH20 activity. After administration of the test solution, the remaining solution in the syringe was stored at 2-5°C (on ice) until transported back for activity testing at a later date. The activity of the Ig-120 + rHuPH20 test solutions is summarized in Table 29.

[0395] [Table 30]

[0396] Animal Description Species: Pig (Sus scrofa domestica) Lineage: Yucatan miniature Gender: Female Age: >3 months Weight: 12-16kg upon receipt Amount: 6 Supplier: Premier BioSource (Ramona, CA)

[0397] breeding The animals were received by the facility on September 9, 2022, and allowed to acclimate before the start of the study. They were group-housed in steel enclosures with water automatically provided ad libitum. They were fed twice daily (AM and PM), except on test days (PM only). The indoor environment was set to maintain a temperature of approximately 17-27°C, a relative humidity of 40-70%, and a 12-hour light / 12-hour dark time cycle. The animals were allowed to acclimate to the facility for 4 days before the start of the study.

[0398] Test materials

[0399] [Table 31]

[0400] Experimental design In this study, two 10 mL injections were administered into the abdomen of Yucatan minipigs. One side of the abdomen received a test solution of Ig-120 alone. The other opposite side of the animal received a second test solution of Ig-120 plus rHuPH20 (5000 U / mL). The location of the injection site was randomized by injecting each test solution three times into the left and right sides of the animals. A needle was attached to a handheld mock autoinjector device, and the needle was inserted perpendicularly into the SC space. The treatments and treatment descriptions for each animal are summarized in Table 31.

[0401] [Table 32]

[0402] Quantitative endpoints included in this study were measurements of the force applied to the syringe barrel during injection, the volume, area, and height of the swelling (bleb) after injection, and changes in skin temperature before and after injection were collected via an infrared thermometer. Additionally, post-injection reflux leakage of the test substance was collected from the injection site over a 30-second period after removal of the needle using an eye spear to absorb any leakage and quantified by weight. The volume of the bleb at the injection site was determined by digital caliper measurements (length, width, and height) and 3D camera imaging. Bleb dimensions were measured again using digital calipers at 15 minutes (T15) and 30 minutes (T30) after injection. Further post-injection qualitative injection site evaluations for erythema, swelling, and induration were performed immediately after injection (T0), as well as at T15, T30, 2 hours (T2h), and approximately 24 hours (T24h) after injection.

[0403] Qualitative evaluation of the injection site was performed with the animals under anesthesia at time points TO, T15, T30, and T24 h, while the T2 evaluation was performed while the animals were conscious and held by hand by an animal technician. Standard photographs were taken both pre-injection and post-injection at time points TO, T15, T30, T2, and T24 h. After euthanasia, 12 mm punch biopsies were obtained from the injection site and fixed in 10% formalin. In summary, the study endpoints were as follows: Applied force during injection Measurement of reflux leakage after injection Measurement of bleb size (length / width / height) over time after injection (T0, T15, T30) Measurement of bleb size (volume, height, area) using 3D imaging (T0 only) Assessment of blebs for erythema, swelling size, and induration at times T0, T15, T30, T2h, and T24h Measurement of temperature at the injection site both before and after injection

[0404] Test Procedure Prior to the start of testing, animals were evaluated for general health and body weights were collected. The day before testing, test material (approximately 17 mL) was drawn into a 20 mL syringe, capped, and stored at 2-8°C. On the day of testing, two syringes containing test solution for each animal were removed from 2-8°C, allowed to come to room temperature for at least 45 minutes, and administered within 1.5 hours. Dose retentates collected during the testing procedure were stored on ice until returned to product development for enzyme testing later in the testing procedure.

[0405] Animals were anesthetized with isoflurane gas, placed supine on a foam wedge placed on a heated operating table, and maintained under isoflurane gas for the entire procedure. The abdominal area was cleansed with Nolvasan, followed by wiping the injection site with gauze containing 70% isopropanol and wiping it dry with sterile gauze.

[0406] Injection sites were located in the left and right abdominal regions of the animals, approximately 6 cm cranial to the midline from the inguinal fold and approximately 3 cm toward the midline. Each injection site was marked with a permanent marker and then photographed with a standard camera and a 3D camera before needle insertion. Skin temperature at the injection site was recorded before the start of the injection using an infrared thermometer. The first injection for each animal was a control solution (Ig-120 alone). The second...

Claims

1. 1. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject via subcutaneous administration about 3 mL to about 50 mL of a formulation comprising a therapeutically effective amount of an active ingredient selected from a small molecule, a peptide fragment, a biologic, a nanoparticle, an antibody, an antibody fragment, and a small molecule antiviral, wherein the subcutaneous administration occurs via a high volume autoinjector at a starting delivery force of about 3 lbf to about 50 lbf, a finishing delivery force of about 5 lbf to about 20 lbf, a starting pressure of about 50 psi to about 200 psi, and / or a finishing pressure of about 20 psi to about 75 psi.

2. 10. The method of claim 1, wherein the formulation further comprises a hyaluronidase enzyme.

3. 3. The method of claim 2, wherein the hyaluronidase enzyme is a recombinant human hyaluronidase enzyme.

4. 4. The method of claim 2 or 3, wherein the hyaluronidase enzyme is a recombinant human hyaluronidase PH20 enzyme.

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

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

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

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

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

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

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

12. 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 L, 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, 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 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, approximately 10.4 mL, approximately 10.5 mL, approximately 10.6 mL, approximately 10.7 mL 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 L, 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, approximately 13.6 mL, approximately 13.7 mL, approximately 13.8 mL, approximately 13.9 mL 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 L, 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 16.7 mL, approximately 16.8 mL, approximately 16.9 mL, approximately 17 mL, approximately 17.1 mLApproximately 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, about 18.3 mL, about 18.4 mL, about 18.5 mL, about 18.6 mL, about 18.7 mL, about 18.8 mL, about 18.9 mL, about 19 mL, about 19.1 mL, about 19.2 mL , about 19.3 mL, about 19.4 mL, about 19.5 mL, about 19.6 mL, about 19.7 mL, about 19.8 mL, about 19.9 mL, about 20 mL, about 20.1 mL, about 20.2 mL, about 20 .3 mL, about 20.4 mL, about 20.5 mL, about 20.6 mL, about 20.7 mL, about 20.8 mL, about 20.9 mL, about 21 mL, about 21.1 mL, about 21.2 mL, about 21.3 mL , about 21.4 mL, about 21.5 mL, about 21.6 mL, about 21.7 mL, about 21.8 mL, about 21.9 mL, about 22 mL, about 22.1 mL, about 22.2 mL, about 22.3 mL, about 2 2.4 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 m 12. The method of any one of claims 1 to 11, comprising administering to the subject about 23.5 mL, about 23.6 mL, about 23.7 mL, about 23.8 mL, about 23.9 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.

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

14. 14. The method of any one of claims 1 to 13, comprising administering the formulation using a high volume autoinjector at a starting delivery force of about 3 lbf to about 50 lbf.

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

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

17. 17. The method of any one of claims 1 to 16, comprising administering the formulation using a high volume autoinjector at an end pressure of about 20 psi to about 75 psi.

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

19. Preface Prescription, 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 L, 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, 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, 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, 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 16.7 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, 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 22.5 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 23.9 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, and approximately 25 mL. The method described in request item 18.

20. 20. The method of claim 18 or 19, wherein the pre-filled syringe is equipped with a needle having a gauge of about 20 to about 33.

21. 21. The method of any one of claims 18-20, 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. 22. The method of any one of claims 1 to 21, comprising administering the formulation at a rate of about 0.08 to about 1.00 mL / second.

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

24. 23. The method of any one of claims 1 to 22, comprising administering the formulation at a rate of at least about 0.08 to about 1.00 mL / second or faster.

25. 25. The method of any one of claims 1 to 24, wherein the administering takes a time period of about 10 seconds to about 40 seconds.

26. 25. The method of any one of claims 1 to 24, wherein the administering takes a time period of at least about 10 seconds to about 40 seconds.

27. 25. The method of any one of claims 1 to 24, wherein the administering takes a time period of at least about 10 seconds to about 40 seconds or less.

28. 25. The method of any one of claims 1 to 24, wherein the administering takes a time period of about 15 seconds to about 30 seconds.

29. 25. The method of any one of claims 1 to 24, wherein the administering takes a time period of at least about 15 seconds to about 30 seconds.

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

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

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

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

34. 33. The method of any one of claims 1 to 32, wherein administration of the formulation requires less application force compared to a similar formulation that does not contain a hyaluronidase enzyme.

35. 35. The method of any one of claims 1-34, comprising administering about 5 mL of the formulation at a rate of about 0.14 mL / sec to about 0.21 mL / sec with an applied force of about 10 N to about 45 N.

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

37. 35. The method of any one of claims 1-34, comprising administering about 10 mL of the formulation to the subject at a rate of about 0.32 mL / sec to about 0.42 mL / sec with an applied force of about 25 N to about 50 N.

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

39. 39. The method of any one of claims 2 to 38, wherein administration of the formulation is faster compared to a similar formulation that does not contain the hyaluronidase enzyme.

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

41. 41. The method of any one of claims 2-40, wherein administration of the formulation causes less pain and discomfort in the subject compared to a similar formulation that does not include the hyaluronidase enzyme.

42. 42. The method of any one of claims 2-41, wherein administration of the formulation results in less reflux leakage at the injection site compared to a similar formulation that does not contain the hyaluronidase enzyme.

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

44. 44. The method of any one of claims 2-43, wherein administration of the formulation results in less swelling volume and / or swelling height at the injection site compared to a similar formulation that does not include a hyaluronidase enzyme.

45. 45. The method of claim 44, wherein the formulation results in about 35% to about 5% less swelling and / or swelling height at the injection site compared to a similar formulation that does not include the hyaluronidase enzyme.

46. 46. ​​The method of any one of claims 2-45, wherein administration of the formulation results in smaller bleb swelling size, less bleb hardening, and / or more rapid bleb resolution compared to a similar formulation that does not include a hyaluronidase enzyme.

47. 47. The method of any one of claims 1-46, wherein administration of the formulation results in a more consistent delivery time compared to a similar formulation that does not contain the hyaluronidase enzyme.

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

49. 49. The method of any one of claims 1 to 48, wherein said administering comprises said subject self-administering said formulation.

50. 50. The method of any one of claims 1 to 49, wherein said administering comprises a healthcare provider or caregiver administering the formulation to the subject.

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

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

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

54. 1. A pharmaceutical kit comprising: a high volume autoinjector; and about 3 mL to about 50 mL of a formulation comprising a therapeutically effective amount of an active ingredient selected from a small molecule, a peptide fragment, a biologic, a nanoparticle, an antibody, an antibody fragment, and a small molecule antiviral.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

72. 72. The pharmaceutical kit of any one of claims 54 to 71, wherein 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.

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

74. 74. The pharmaceutical kit of 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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