Subcutaneous infusion kit

Abstract

A subcutaneous infusion kit includes a hyaluronidase formulation, a concentrated immunoglobulin G (IgG) formulation, and a needle set for subcutaneously infusing the hyaluronidase formulation and the IgG formulation at an infusion site of a subject. The concentrated IgG formulation has a relatively high viscosity compared to standard therapeutic protein formulations. The needle set includes a needle for administering a useful dosage of the concentrated IgG formulation within a reasonable time frame while minimizing leakage at the infusion site and discomfort to the subject.

Description

SUBCUTANEOUS INFUSION KITCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 669,106, filed on July 9, 2024, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION

[0002] The invention resides in the field of antibody therapeutics and in the subcutaneous delivery of viscous formulations of therapeutic antibodies.BACKGROUND OF THE INVENTION

[0003] Immunoglobulin G (IgG) is the most common ty pe of antibody found in blood and, fractionated from plasma and formulated as a medicament, is used to treat immune deficiency and other diseases. Though the initial IgG formulations were intended for intravenous administration, subcutaneous (SC) administration of IgG has become widely accepted with the development of formulations allowing the SC self-administration of an acceptable dosage of IgG by an IgG recipient. The convenience of self-administration makes SC IgG therapy the preferred option for many patients.

[0004] The first SC IgG product (VIVAGLOBIN®, 16%) was introduced to the US in 2006. Since then, the only major change has been in the concentration of IgG in the formulations. At least two 10% IgG products previously licensed for IV administration have received FDA approval for SC administration (GAMMAGARD LIQUID), (GAMUNEX-C) and another 10% IgG product (GAMMAKED) has been introduced for both IV and SC administration. 20% IgG products (CUVITRU), (HIZENTRA) solely for SC administration are also now available in the US.

[0005] The promise of concentrated IgG formulations (e.g, 20% IgG products) to achieve full-dose delivery with lowered administration volumes and shortened administration times, both of which are attractive to patients and enhance compliance with a prescribed dosing regimen has not been realized. Concentrated IgG solutions are highly viscous, a property which significantly complicates product handling (e.g.. loading a syringe) and infusion. For instance, due to their high viscosity, concentrated IgG formulations exhibit strong resistance to flow through a standard infusion needle, making them difficult to administer by subcutaneous infusion.

[0006] Patient compliance with a subcutaneous infusion regimen is critical to managing the disease being treated by infusion of the medicament. Subcutaneous infusion of medicaments is accompaniedby patient discomfort and inconvenience due to long infusion times, both of which can lead to skipped or truncated infusions. Further, significant mechanical issues with subcutaneous infusion can also arise. For example, incomplete insertion of the needle at the infusion site can lead to leakage of the medicament from the site, resulting in administration of an improper, incomplete dosage. Occlusion of the needle or other component of the infusion apparatus is a concern: any occlusion of the needle or other component of an infusion apparatus can result in the need to remove, clean or replace the needle and insert it anew at an infusion site. Small bore needles utilized with viscous medicaments produce increased delivery pressure, which can result in patient discomfort, pump alanning and arresting leading to terminated infusions, and other issues. An interrupted infusion is detrimental to adherence to a prescribed infusion regimen.

[0007] Though infusing a highly concentrated, viscous protein-based medicament is a desirable goal from a patient compliance standpoint. If a usefully high flow rate of the medicament can be established and maintained throughout the infusion, infusion of a highly concentrated formulation of the therapeutic protein should lead to a more rapid infusion of the prescribed amount of the therapeutic than an identical infusion of a medicament containing a lower concentration of the therapeutic.

[0008] The challenges accompanying the handing and SC infusion of a concentrated, viscous medicament, e.g., a 20% IgG formulation, are not trivial. The challenges are, to some degree, traceable to the absence from the market of a subcutaneous infusion kit or needle set providing satisfactorily rapid SC administration of a viscous, concentrated IgG formulation. Currently available commercial needle sets used to infuse IgG formulations are accompanied by the difficulties discussed above when combined with a viscous, concentrated IgG formulation. For example, infusion of a concentrated (e.g., approx. 20%) protein solution results in significant back pressure (“delivery pressure”) build up throughout the infusion device an in the patient tissue adjacent tire needle, triggering occlusion alarms on the infusion pumps before reaching target flow rates. As a result, using currently available commercial needle sets to administer concentrated IgG formulations does not shorten administration times, or more often requires infusion at more than one site to shorten infusion duration, and thus does not achieve a significant potential benefit on patient compliance of concentrated IgG formulations. High back pressure can also be associated with increased pain during infusion, also potentially reducing compliance with a prescribed dosage regimen.

[0009] As noted above, to shorten administration times, a current approach for SC administration of concentrated IgG fonnulations is to infuse a concentrated IgG formulation at multiple sites (e.g., abdomen, thighs, upper arms, or lower back) at a relatively low infusion rate and / or over a longer period of time. This introduces additional pain and inconvenience into the infusion process for thepatient. For instance, the product guide for the 20% IgG product (CUVITRU)1 2suggests administering the 20% IgG product at an infusion rate of from 10 to 20 mL / hr / site for the first two infusions, and also indicates the maximum infusion rate achievable using a 24-gauge needle is 60 mL / liour / site. The product guide states that delivery of a total of 240 mL / hr requires injecting the 20% IgG product simultaneously at four sites with each at a maximum infusion rate of 60 mL / hour / site. Clearly, if the goal is to maximize patient compliance by designing an infusion regimen as pain free and convenient as possible, the multiple infusion site fonnat is contrary to such a goal. Alternative approaches may be to use larger bore needles or increase administration frequencies (e.g., daily instead of weekly). These alternative approaches, however, do little to minimize patient discomfort and inconvenience.

[0010] Given the value to patients of complying with a prescribed SC IgG dosing regimen, a convenient and relatively pain free infusion protocol incorporating an infusion apparatus capable of ameliorating die issues noted above, and kits containing such an apparatus and one or more protein medicaments, e.g.. 20%. IgG solution, would represent a significant advance in the care of patients receiving SC IgG therapy. In answer to this need, the present invention provides an infusion apparatus designed to facilitate the SC infusion of a viscous, concentrated protein solution while minimizing patient discomfort and inconvenience.BRIEF SUMMARY OF THE INVENTION

[0011] As set forth herein, the inventors have devised a SC infusion apparatus, including a means for infusing a viscous medicament into the body of a subject being treated with the medicament. The invention was conceived applying design principles in a maimer contrary to the general understanding in the art of the parameters and properties of similar infusing apparatuses. In various embodiments, the present invention provides a novel infusing means, comprising a device having an inlet end for receiving the medicament, and an outlet end for infusing the medicament into the body of the subject. Exemplary infusing means include, without limitation, a needle, cannula and equivalent structures. In various embodiments the infusion means of the invention facilitates simpler, fewer and less painful subcutaneous infusions of useful dosages of a concentrated IgG fonnulation within more reasonable,convenient, time frames than presently achievable with current needle sets and kits used with concentrated IgG formulations.

[0012] In an exemplary embodiment, the infusing means is characterized by its ability to facilitate subcutaneous infusion of a fluid having a viscosity of from about 10 cP to about 40 cP into a subject at a first infusion site at an infusion rate of not less than about 240 mL / hr, e.g., not less than about 260 mL / lir, e.g., not less than about 280 mL / hr, e.g., not less than about 300 mL / hr, with a pressure drop not more than about 10 pounds per square inch (psi) across the infusing means at about 240 mL / hr. e.g., at about 260 mL / hr, e.g., at about 280 mL / hr, e.g.. at about 300 mL / hr.

[0013] In certain embodiments, it is an object of the invention to ramp up the infusion rate to as close as possible to not less than about 240 mL / hr, e.g., not less than about 260 mL / hr, e.g., not less than about 280 mL / hr, e.g., not less than about 300 mL / hr as quickly as possible with the goal of completing the infusion over as short a duration as possible.

[0014] In various embodiments, at least 90%, at least 80%, at least 70%. at least 60% or at least 50% of the infusion is conducted at an infusion rate of not less than about 240 mL / hr, e.g., not less than about 260 mL / hr, e.g., not less than about 280 mL / hr, e.g., not less than about 300 mL / hr.

[0015] In various embodiments, the infusing means is a needle set, which includes a novel needle specifically designed for administering a useful dosage of the viscous medicament, e.g., concentrated IgG formulation, within a reasonable time frame without requiring a significantly larger puncture than that required with current needle sets, giving rise to backpressure sufficient to trigger a pump alarm, or causing discomfort greater than that experienced with current needle sets. In various embodiments, the infusing means is specifically designed with an outer diameter approximately the same or the same as a typical subcutaneous (“a nominal 24-gauge needle”) needle so as not to require a larger puncture or to cause discomfort to the subject greater than that experienced with puncture by / infusion with a typical 24-gauge needle. An exemplary infusion means is structured with an enlarged inner diameter larger than that of a standard 24-gauge needle, and with a proper total length to facilitate flow of the viscous medicament, e.g., concentrated IgG formulation, within the infusion means. In some embodiments, the infusing means is designed with an insertion length adequate to minimize leakage of the viscous medicament at infusion sitc(s), e.g., around the outer circumference, during infusion.

[0016] In some embodiments, in which the infusing means is a subcutaneous needle with a nominal outside diameter (OD) of 24-gauge. the inner diameter of the needle is not less than about 0.36 mm, not less than about 0.37 mm, not less than about 0.38 mm, not less than about 0.39 mm, not less than about 0.40 mm, not less than about 0.41 mm, not less than about 0.42 mm, not less than about 0.43 mm, not less than about 0.44 mm, or not less than about 0.45 mm.

[0017] In some embodiments, in which die infusing means is a subcutaneous needle with a nominal outside diameter (OD) of 24-gauge. the inner diameter of the needle is substantially constant along a length direction of the needle and has a value within a range of from about 0.38 mm to about 0.43 mm, from about 0.39 mm to about 0.44 mm, or from about 0.40 to about 0.45 mm.

[0018] In some embodiments, in which the infusing means is a subcutaneous needle with a nominal outside diameter (OD) of 24-gauge. the inner diameter of the needle is about 0.413 + / - 0.019 mm.

[0019] In an exemplary embodiment, in which the infusing means is a subcutaneous needle with a nominal outside diameter (OD) of 24-gauge, the inner diameter of the needle is about 0.41 mm, about 0.42 mm, or about 0.43 mm.

[0020] In some embodiments, in which the infusing means is a subcutaneous needle with a nominal outside diameter of 24-gauge, the needle has an outer diameter (OD) of about 0.56 mm, about 0.57 mm, or about 0.58 mm.

[0021] In an exemplary embodiment, in which the infusing means is a subcutaneous needle with a nominal outside diameter (OD) of 24-gauge, the needle has an outer diameter of about 0.559 mm.

[0022] In some embodiments, the infusing means, e.g., the subcutaneous nominal 24-gauge needle, has a wall with a thickness less than about 200 pm, less than about 190 pm, less than about 180 pm, less than about 170 pm. less than about 160 pm, less than about 150 pm, less than about 140 pm. less than about 130 pm. less than about 120 pm, less than about 110 pm, less than about 100 pm, less than about 90 pm, or less than about 80 pm.

[0023] In an exemplary embodiment, the infusing means, e.g., the subcutaneous nominal 24-gauge needle, has a wall with a thickness within a range of from about 100 pm to about 200 pm, or about 118 pm to about 186 pm.

[0024] In some embodiments, the total length of the infusing means, e.g.. the subcutaneous nominal 24-gauge needle, is not more than about 34 mm, not more than about 33 mm, not more than about 32 mm, not more than about 31 mm, or not more than about 30 mm.

[0025] In some embodiments, the infusing means allows infusion of the viscous medicament through a single infusing means to the subject at the flow rate of not less than about 240 mL / hr, e.g., not less than about 260 mL / hr, e.g., not less than about 280 mL / hr, e.g., not less than about 300 mL / hr. In an exemplary' embodiment, the infusing means is the nominal 24-gauge OD needle of set out in this disclosure. In an exemplary' embodiment, the viscous medicament is a concentrated (e.g., approx. 20%) IgG formulation.

[0026] In an exemplary embodiment, the insertion length of the infusing means is not less than about 12 mm, not less than about 13 mm, not less than about 14 mm, not less than about 15 mm, or not less than about 16 mm. In an exemplary' embodiment, the insertion length is about 12 mm or about 14 mm.

[0027] In some embodiments, the infusing means is a component of a kit, further including a fluid deliver means configured having a first end for receiving a fluid and a second end configured to fluidically connect to the infusing means. An exemplary fluid is selected from the recombinant human hyaluronidase formulation, the IgG formulation, and a combination thereof.

[0028] In some embodiments, the fluid delivery means has an inner diameter of not less than about 1.2 mm.

[0029] An exemplary fluid delivery means is a flexible polymer tube or an equivalent. The fluid delivery means is optionally equipped with one or more connecting means, e.g.. luer fittings or an equivalent.

[0030] In some embodiments, the infusing means includes a first segment, a second segment and an intermediate segment. The first segment is at least partially inserted into the second end of the fluid delivery' means. The second segment of the infusing means is configured to be inserted subcutaneously to the desired depth into the subject at the first infusion site and defines the insertion length of the infusing means. The intermediate segment is between the first and second segments and connects the first segment with the second segment. In some embodiments, each of the first and second segments is substantially straight, and the intermediate segment is arched and has a radius of not less than about 2.24 mm and a predetermined central angle.

[0031] In some embodiments, the first segment has a length of not more than about 15 mm.

[0032] In some embodiments, the second segment has a length of not more than about 19 mm, e.g., not more than about 14 mm, e.g., not more than about 12 mm.

[0033] In some embodiments, the intermediate segment has the predetermined central angle of from about 45° to about 90°.

[0034] In some embodiments, the radius of the intermediate segment is not less than 2.2 mm.

[0035] In some embodiments, the infusing means, e.g., the needle set, further includes a hub to accommodate the second end of the fluid delivery' means and the first segment of the infusing means. The hub includes a port adjacent to the second end of the fluid delivery means, and the second end of the fluid delivery' means and the first segment of the infusing means arc secured to the hub by an adhesive injected through the port.

[0036] In some embodiments, the hub supports, at least partially, the intermediate segment of the subcutaneous infusing means.

[0037] In an exemplary embodiment, the viscosity of the viscous medicament is from about 14 cP to about 22 cP. The inner diameter of the infusing means is from about 0.40 mm to about 0.43 mm. The total length of the infusing means is from about 28 mm to about 35 mm. An exemplary insertion length of the infusing means is from about 6 mm to about 16 mm.

[0038] In various embodiments, the infusing means of the present invention is a needle set capable of subcutaneously infusing a viscous fluid into a subject at a first infusion site, where the fluid has a viscosity of from about 10 cP to about 40 cP. The needle set includes a subcutaneous 24-gauge needle having: (i) an inner diameter of from about 0.35 millimeter (mm) to about 0.5 mm and a total length of from about 25 to about 35 mm to allow infusion at the first infusion site of the fluid at a flow rate of not less than about 240 mL / hr. e.g., not less than about 260 mL / hr. e.g., not less than about 280 mL / hr, e.g., not less 300 milliliter / hour (mL / hr) with a pressure drop across the infusing means of not more than about 12 pounds per square inch (psi) at about 240 mL / hr, e.g., at about 260 mL / hr, e.g., at about 280 mL / hr. e.g., at about 300 milliliter / hour (mL / hr), and (ii) an insertion length of from about 6 mm to about 16 mm, thereby minimizing leakage at the first infusion site. In an exemplary embodiment, the insertion length is about 12 mm, about 13 mm, or about 14 mm.

[0039] In some embodiments, the fluid includes a medicament.

[0040] In an exemplary embodiment, the medicament includes a recombinant human hyaluronidase formulation, an IgG formulation having a concentration of IgG from about 1 % w / v to about 22% w / v. or a combination thereof.

[0041] In various embodiments, the infusing means of the present invention is a needle set for subcutaneously infusing a fluid into a subject at a first infusion site. The needle set includes a hub, a tube and a subcutaneous needle. The hub includes a tunnel and a port. The tunnel includes a first opening at a first end of the tunnel and a second opening at a second end of the tunnel, and the port is formed on a side wall of the tunnel. The tube includes a first end and a second end, with the first end disposed outside of the hub for receiving the fluid and the second end inserted into the tunnel through the first opening of the tunnel. The subcutaneous needle includes a first segment, a second segment and an intermediate segment. The first segment is at least partially inserted into die tunnel through the second opening of die tunnel and at least partially inserted into the second end of the tube. The second segment is to be inserted at least partially into the subject at the first infusion site. The intermediate segment is formed between the first and second segments and connects the first segment with the second segment. In addition, the intermediate segment is arched and has a radius of not less than about 0.5 mm and a central angle of from about 45°to about 90°. The second end of the tube andthe first segment of the subcutaneous needle are seemed to the hub by an adhesive injected into the tunnel through the port.

[0042] In some embodiments, the second segment of the subcutaneous needle has a length to facilitate an insertion length of about 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, or 16 mm to reduce leakage at an infusion site.

[0043] In an exemplary embodiment, the subcutaneous needle is a subcutaneous 24-gauge needle having an outer diameter of about 0.56 mm, an inner diameter of not less than 0.35 mm and a total length of at most 35 mm.

[0044] In some embodiments, the fluid is an IgG formulation having a concentration of from about 18% w / v to about 22% w / v a viscosity of not less than about 10 cP. The subcutaneous needle is capable of infusing the fluid at a flow rate of not less than about 200 mL / lir , not less than about 220 mL / hr, not less than about 240 mL / lir. e.g., not less than about 260 mL / lir. e.g., not less than about 280 mL / hr, e.g., not less than about 300 milliliter / hour (mL / hr) with a pressure drop no more than about 12 psi at the relevant infusion rate.

[0045] In an exemplary embodiment, the viscosity of the fluid is from about 16 cP to about 22 cP. The inner diameter of the infusing means, e.g., a subcutaneous 24-gauge needle is from about 0.40 mm to about 0.43 mm. The total length of the infusing means, e.g., the 24 gauge needle described herein, is from about 28 mm to about 32 mm. An exemplary insertion length is from about 12 mm to about 15 mm, e.g., 12 mm, 13 mm, 14 mm, or 15 mm.

[0046] In various embodiments, the present invention provides a subcutaneous infusion kit including one or more needle sets disclosed herein.

[0047] Though the infusing means, e.g., the needle set of the invention, is an exemplary embodiment useful on its own with any viscous medicament, in various embodiments, the invention provides a kit for administration of a 20% IgG formulation or the facilitated administration of such a formulation. An exemplary kit of the present invention generally includes a concentrated IgG formulation (e.g., approx. 20%) and a needle set configured for subcutaneously infusing the concentrated IgG formulation to a subject (e.g.. a patient in need of IgG therapy). In various embodiments, the concentrated IgG formulation is formatted for subcutaneous administration with a viscosity lower than about 50 centipoise (cP), the amount authorized by the U.S. FDA for subcutaneous injections of volumes over approximately 1.5 milliliter (inL). In some embodiments, the viscosity of the concentrated IgG formulation is from about 10 centipoise (cP) to about 40 cP. In an exemplar}' embodiment, the viscosity of the concentrated IgG formulation is about 16.5 cp.

[0048] In various embodiments, the present invention provides a subcutaneous infusion kit including an immunoglobulin G (IgG) formulation having a concentration of IgG from about 18% weight per volume (w / v) to about 22% w / v and a viscosity of from about 10 cP to about 40 cP. The subcutaneous infusion kit also includes a means, e.g., a needle set, for subcutaneously infusing the concentrated IgG formulation to a subject at a first infusion site. The needle set includes a subcutaneous nominal 24- gauge needle having: (i) an inner diameter of from about 0.35 millimeter (mm) to about 0.5 mm and a total length of from about 25 mm to about 35 mm to allow infusion at the first infusion site of the IgG formulation at a flow rate of not less than about 240 mL / hr, e.g., not less than about 260 mL / hr, e.g., not less than about 280 mL / hr, e.g.. not less than about 300 mL / hr, with a pressure drop not more than about 12 pounds per square inch (psi), e.g., not more than about 10 pounds per square inch, and (ii) an insertion length of from about 6 mm to about 15 mm, thereby minimizing leakage at the first infusion site.

[0049] In some embodiments, the viscosity of the IgG formulation is not less than about 22 cP.

[0050] In an exemplary embodiment, in which facilitated infusion of concentrated IgG is the goal, the kit further comprises a recombinant human hyaluronidase formulation.

[0051] The needle sets and kits of the present disclosure have other features and advantages that will be apparent from, or are set forth in more detail in. the accompanying drawings, which are incorporated herein, and the following Detailed Description, which together serve to explain certain principles of exemplary embodiments of the present disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0052] The implementations disclosed herein are illustrated by way of example, and not by way of limitation, in the figures of the accompanying drawings. Like reference numerals refer to corresponding parts throughout the drawings.

[0053] FIG. 1 is a block diagram schematically illustrating an exemplar) subcutaneous infusion kit in accordance with some embodiments of the invention.

[0054] FIG. 2 is a perspective view schematically illustrating an exemplary needle set in accordance with some embodiments of the invention.

[0055] FIG. 3 is an exploded side view schematically illustrating some components of the exemplary needle set of FIG. 2.

[0056] FIG. 4 is a cross-section view schematically illustrating some components of the exemplary needle set of FIG. 2.

[0057] FIG. 5 is a perspective view schematically illustrating an exemplary hub in accordance with some embodiments of the invention.

[0058] FIG. 6 is a perspective view schematically illustrating an exemplary needle in accordance with some embodiments of the invention.

[0059] FIG. 7 is a side view schematically illustrating the exemplary' needle of FIG. 6.

[0060] FIG. 8 is a schematic representation of the connections for the administration of rHuPH20 / IG in pig models.

[0061] FIG. 9 demonstrates in-line pressure values of TS1 (BD Saf-T-Intima 24-gauge Needle, Pump #1) for the administration of rHuPH20 and IGSC, 20%. The color intense lines represent the mean of the animals and the softer colors are the SEM. N=2 animals.

[0062] FIG. 10 demonstrates in-line pressure values of TS2 (top; 24-gauge Needle. Pump #1) vs TS3 (bottom; 24-gauge Needle. Pump #2) for the administration of rHuPH20 + IGSC, 20% with 24G 0.05” Needle. The color intense lines represent the mean of the animals and the softer color are the SEM. N=3 animals.

[0063] FIG. 11 demonstrates maximize in-line pressure values observed with TS2 and TS3.

[0064] FIG. 12 is a schematic representation of the setup for administering rHuPH20 / IG in pig models.

[0065] FIG. 13 summarizes the pre-clamping flow rate results for Leg A of the bifurcated needle set.

[0066] FIG. 14 presents a process capability analysis of the pre-clamping flow rate for Leg A of the bifurcated needle set.

[0067] FIG. 15 summarizes the pre-clamping flow rate results for Leg B of the bifurcated needle set.

[0068] FIG. 16 presents a process capability analysis of the pre-clamping flow rate for Leg B of the bifurcated needle set.

[0069] FIG. 17 summarizes the flow rate results for the bifurcated needle set after 8 horns of clamping.

[0070] FIG. 18 presents a process capability analysis of the flow rate for the bifurcated needle set after 8 hours of clamping.

[0071] FIG. 19 summarizes flow rate comparison between Legs A and B.

[0072] FIG. 20 presents a process capability analysis of the flow rate for Legs A and B.

[0073] FIG. 21 provides a tolerance interval plot showing the 95% confidence range for flow rate measurements in a single leg needle set.

[0074] FIG. 22 presents a tolerance interval plot showing the 95% confidence range for flow rate measurements in the first leg of the bifurcated needle set.

[0075] FIG. 23 presents a tolerance interval plot showing the 95% confidence range for flow rate measurements in die second leg of the bifurcated needle set.

[0076] FIG. 24 presents a tolerance interval plot showing the 95% confidence upper bound for the percentage difference in flow rates between the two legs of the bifurcated needle set.DETAILED DESCRIPTION OF THE INVENTIONI. Introduction

[0077] The present invention addresses the shortcomings of current infusing devices used with SC administration of viscous medicaments, e.g.. concentrated IgG formulations (e.g., approx. 20% IgG), arising due to the high viscosity of such formulations.

[0078] As set forth herein, the inventors have devised a SC infusion apparatus, including a means for infusing a viscous medicament into the body of a subject being treated with the medicament. In various embodiments, the present invention provides a novel infusing means, comprising a device having an inlet end for receiving the medicament, and an outlet end for infusing the medicament into the body of the subject. Exemplar}' means for infusing include, without limitation, a needle, cannula and equivalent structures. In various embodiments the infusion means of the invention facilitates simpler, fewer and less painful subcutaneous infusions of useful dosages of a concentrated IgG formulation within more reasonable, convenient, time frames than presently achievable with current needle sets and kits used with concentrated IgG formulations.

[0079] In an exemplary embodiment, the infusing means is characterized by its ability to facilitate subcutaneous infusion of a fluid having a viscosity of from about 10 cP to about 40 cP into a subject at a first infusion site at an infusion rate of not less than about 240 mL / hr, e.g., not less than about 260 mL / hr, e.g., not less than about 280 mL / hr, e.g., not less than about 300 mL / hr, with a pressure drop not more than about 10 pounds per square inch (psi) across the infusing means at about 240 mL / hr. e.g., at about 260 mL / hr, e.g., at about 280 mL / hr, e.g.. at about 300 mL / hr. Any infusing means capable of carrying out an infusion according to these parameters is an “infusing means” as this term is used herein.

[0080] In various embodiments, the present invention provides a subcutaneous infusion kit including a concentrated IgG fonnulation specifically formatted for subcutaneous administration with aviscosity, which is quite high but lower than the 50 centipoise (cP) permitted by the U.S. FDA for subcutaneous injections of volumes over approximately 1.5 milliliter (mL). An exemplary IgG formulation is of a viscosity of from about 10 cP to about 40 cP. An exemplary subcutaneous infusion kit also includes an infusing means specifically configured for subcutaneously infusing a useful dosage of a viscous medicament (e.g. , the specifically formatted concentrated IgG formulation) within a reasonable time frame without causing more pain to a subject being infused that what would be experienced with a standard 24-gauge infusion needle. The infusing means is specifically designed to allow rapid infusion of a viscous protein fonnulation. In some embodiments, the infusion means is configured with an outer diameter substantially the same as a typical subcutaneous infusion needle (e.g., a subcutaneous 24-gauge needle). The infusion means, however, is designed to have a wider bore than a standard 24-gauge infusion needle without, however, a substantial increase in the outer diameter of the infusion means relative to a standard 24-gauge needle. The design of the infusion means avoids or minimizes additional insertion discomfort to the patient while providing an apparatus supporting rapid infusion of the concentrated protein formulation. The enlarged inner diameter and selection of an appropriate total infusion means length ensures relatively higher flow rates of the viscous formulation, and a needle insertion depth sufficient to minimize leakage at an infusion site.

[0081] Reference will now be made in detail to implementation of exemplary embodiments of the present disclosure as illustrated in the accompanying drawings. The same reference indicators will be used throughout the drawings and the following detailed description to refer to the same or like parts. Those of ordinary skill in the art will understand that the following detailed description is illustrative only and is not intended to be in any way limiting. Other embodiments of the present disclosure will readily suggest themselves to such skilled persons having benefit of this disclosure.

[0082] In the interest of clarity, not all the routine features of the implementations described herein are shown and described. It will be appreciated that, in the development of any such actual implementation, numerous implementation-specific decisions are made in order to achieve the developer’s specific goals, such as compliance with application- and business-related constraints, and that these specific goals will vary from one implementation to another and from one developer to another. Moreover, it will be appreciated that such a development effort might be complex and timeconsuming, but would nevertheless be within the abilities of those of ordinary skill in the art having the benefit of this disclosure.

[0083] Many modifications and variations of the exemplaiy embodiments set forth in this disclosure can be made without departing from tire spirit and scope of the exemplary embodiments, as will be apparent to those skilled in the art. The specific exemplary embodiments described herein are offered by way of example only, and the disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled.II. Definitions

[0084] Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry', pharmaceutical formulation, medical devices, and medical imaging are those well-known and commonly employed in the art.

[0085] The articles “a” and "an " are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element” means one element or more than one element.

[0086] A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.

[0087] As used herein, the term “proximal” refers to the portion or end of an injection device or component in the injection device furthest from an injection site of the user when the device is held against the person for an injection.

[0088] As used herein, the term “distal” refers to the portion or end of an injection device or a component of the injection device closest to an injection site of the user during an injection.

[0089] As used herein, the term “administration” typically refers to the administration of a composition to a subject or system to achieve delivery of an agent that is. or is included in, the composition. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g.. a plurality of doses separated in time) and / or periodic (e g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e g., perfusion) for at least a selected period of time.

[0090] As used herein, the term “injection force” refers to the force required to push a given liquid formulation through a given infusion means with a given needle gauge at a given injection speed. The injection force is typically reported in Newtons. For example, the injection force may be measured as the force required to push a liquid formulation through a 1 mb plastic syringe with a 0.25 inch inside diameter that is equipped with a 0.50 inch, 27 gauge needle at a 250 mm / min injection speed. Testing equipment can be used to measure the injection force. When measured under die same conditions, a formulation with lower viscosity will generally require an overall lower injection force. “Injection force” is related to the concept of “delivery pressure”.

[0091] As used herein, the terms “improve”, “enhance”, “increase”, “inhibit”, “decrease”, “reduce”, or grammatical equivalents thereof, indicate values that are relative to a baseline or other reference measurement. In some embodiments, an appropriate reference measurement may be or include a measurement in a particular system (e.g., in a single individual) under otherwise comparable conditions using a protein formulation of lower concentration, less viscosity, etc. In some embodiments, an appropriate reference measurement may be or include a measurement in comparable system known or expected to respond in a particular way, in presence of the relevant agent or treatment. In exemplary embodiments, the term "enhance" or "increase" refers to an increase in the specified parameter of at least about 1.25-fold, 1.5-fold, -fold, 3-fold. 4-fold, 5-fold. 6-fold, 8-fold. 10-fold, twelve-fold, or even fifteen-fold and / or can be expressed in the enhancement and / or increase of a specified level and / or activity of at least about 1%, 5%, 10%, 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%. 95% or more.

[0092] As used herein, the term “inner diameter” of a needle refers to a nominal diameter of the needle’s lumen (z.e., the hollow bore that runs the length of the needle).

[0093] As used herein, the term “nominal” indicates acceptable conditions within manufacturing tolerances and / or measurement precision. For instance, a nominal radius / diameter / length of 1 mm with manufacturing tolerances and / or measurement precision of ± 0.1 mm represents acceptable real radius / diameter / length with a value in a range of from 0.9 mm to 1.1 mm. A nominal angle of 90° with manufacturing tolerances and / or measurement precision of ± 5° represents acceptable real angle with a value in a range of from 85° to 95°. A nominal pressure difference (e.g., a pressure drop) of 10 pounds per square inch (psi) with measurement precision of ± 0.2 represents acceptable real pressure difference with a value in a range of from 9.8 psi to 10.2 psi.

[0094] As used herein, the term “outer diameter” of an infusion means refers to a nominal diameter of the infusion means, generally denominated as a needle gauge. The larger the gauge, the smaller the outer diameter of the infusion means. The smaller the gauge, the larger the outer diameter of the infusion means. For example, a 10 gauge needle has an outer diameter of 3.4 mm, whereas a 34 gauge needle has an outer diameter of 0.16 mm.

[0095] As used herein, the term “nominal outside diameter of 24-gauge” refers to an outside diameter of from about 0.53 mm to about 0.58 mm, e.g., about 0.53, 0.54, 0.55, 0.56, 0.57, 0.58 mm. An exemplary “ nominal outside diameter of 24-gauge” is 0.559 mm.

[0096] As used herein, tire term “length” of an element is a nominal length measured from one end of the element to another end of the element. For instance, the total length of a needle is a nominal length measured from one end of the needle to another end of the needle. Similarly, a length of asegment of a needle is a nominal length measured from one end of the segment of the needle to another end of the segment of the needle.

[0097] As used herein, the term “radius” of an arc or segment is a nominal radius of the circle of which it is a part.

[0098] As used herein, the term “angle” of an arc or segment is a nominal angle subtended by the arc or segment at the center of the circle of which it is a part.

[0099] As used herein, tire term “insertion length” refers to a nominal length of a segment of a needle that can be inserted into a subject.

[0100] As used herein, the term “pressure drop” refers to a nominal pressure difference in total pressure between two points of a fluid carrying network. A pressure drop occurs when frictional forces, caused by the resistance to flow, act on a fluid as it flows through a conduit (such as a needle, channel, pipe, or tube). The pressure drop caused by the resistance as a fluid flows through an infusion means is the nominal pressure difference in total pressure between the two end points of the infusion means.III. Subcutaneous Infusion Kits

[0101] FIG. 1 illustrates an exemplary SC infusion kit, generally designated 100. in accordance with some embodiments of the present invention. The kit includes a first formulation, generally designated 110. First formulation 110 includes IgG (and thus also termed herein as the IgG formulation) and is formatted for SC administration to a subject (e.g.. a patient) to treat a disease. In some embodiments, first formulation 110 includes other ingredients in addition to IgG.

[0102] In various embodiments, first formulation 110 is a concentrated IgG fonnulation, e.g., having a concentration of IgG higher than about 15% weight per volume (w / v). In some embodiments, first formulation 110 is formulated such that it has a concentration of IgG from about 18% w / v to about 22% w / v and a viscosity of from about 10 centipoise (cP) to about 40 cP. In some embodiments, first formulation 110 is formulated such that the viscosity of the solution is not less than about 12 cP, 14 cP, 16 cP. 1 cP. 20 cP, 22 cp, 24 cP, 26 cp, 28 cP, or 30 cP. In some embodiments, first formulation 110 is formulated such that the viscosity of the solution is not greater than 30 cP, 25 cP, 20 cP, or 15 cP. In an exemplary embodiment, first formulation 110 is formulated such that the viscosity of the solution is about 16 ap, about 16.5 cp, or about 17 cp. In some embodiments, first formulation 110 is formulated the same as or similar to those disclosed in the International Patent Application No. PCT / IB22 / 58670, filed September 14, 2022, the entire content of which is hereby incorporated herein by reference in their entirety.

[0103] In an exemplary embodiment, first formulation 110 contains IgG for treating a disease, e.g., a unit dosage of IgG. In some embodiments, first formulation 110 contains more than one dose of IgG for treating a disease. For instance, in some embodiments, first formulation 110 contains 2, 3, 4, 5, 6. 7, 8, 9, 10 or more than 10 doses of IgG.

[0104] It is understood that the precise dosage and duration of treatment is a function of the disease being treated, and the subject to whom it is administered. The precise dosage and duration of treatment can be determined empirically using known testing protocols or by extrapolation from in vivo or m vitro test data. It is to be noted that dosage amount and treatment duration can also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens can be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the IgG formulations. Dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed formulations.

[0105] The kit includes an infusing means, e.g., a needle set. generally designated 200, configured for subcutaneously injecting a fluid (e.g., the first IgG formulation) to a subject in need thereof. As will be described in more detail hereinbelow, the infusing means is configured for effective and / or relatively less painful infusion of a useful dosage of a viscous fluid such as a concentrated IgG formulation within time frame reasonable to and convenient for the subject undergoing the infusion. Generally, a subject is more compliant with an infusion regimen that is as unintrusive, convenient and of as short of a duration as possible.

[0106] In some embodiments, the infusing means is configured to allow infusion of first formulation 110 to a subject at an infusion site at a flow rate of not less than about 200 milliliter / hour (mL / lir). In some embodiments, the infusing means is configured to allow infusion of first formulation 110 to a subject at an infusion site, e.g., a single infusion site, at a flow rate of not less than about 240 mL / hr, e.g., not less than about 260 mL / lir, e.g., not less than about 280 mL / hr, e.g., not less than about 300 mL / hr, not less than about 350 mL / hr, not less than about 400 mL / hr, not less than about 450 mL / hr, not less than about 500 mL / hr, not less than about 550 mL / hr, or not less than about 600 mL / hr. In an exemplary embodiment, tire infusing means is configured to allow infusion of first formulation 110 to a subject at an infusion site, e.g., a single infusion site, at a flow rate of not less than about 240 mL / hr, e.g.. not less than about 260 mL / hr, e.g., not less than about 280 mL / hr, e.g., not less than about 300 mL / hr, with a pressure drop not more than about 12 psi. e.g., not more than 10 psi at the relevant infusion rate. Providing such high infusion rates, the infusing means of the present invention reduces the infusion time and, in some embodiments, eliminates the need for simultaneously infusing first formulation 110 at multiple infusion sites. This significantly simplifies and speeds the infusion process. An exemplary infusion process of a concentrated IgG formulationusing an infusing means of the invention is no more, painful than an identical infusion with a standard 24-gauge infusion needle, and can enhance compliance with a prescribed infusion regimen.

[0107] In an exemplary embodiment, tire kit consists of a single infusing means. In some embodiments, the kit includes two, three, four, or more than four infusing means, which allow for administering first formulation 110 at two or more sites when needed or preferred.

[0108] In some embodiments, the kit includes a second formulation, 120. The second formulation includes hyaluronidase. As used herein, the term “hyaluronidase" refers to an enzyme catalyzing hydrolysis of glycosaminoglycans including hyaluronans in all forms. Hyaluronidase can be used to improve the subcutaneous delivery of the concentrated IgG fonnulation by degrading hyaluronic acid in the extracellular matrix of the subcutaneous tissue, thereby decreasing interstitial pressure during a subcutaneous infusion. Hyaluronidase can be co-administered or co-formulated with the concentrated IgG formulation disclosed herein.

[0109] In some embodiments, the hyaluronidase is formulated the same as or similar to those formulations disclosed in International Patent Application No. PCT / 1B22 / 58670, fded September 14. 2022. the entire content of which is incorporated herein by reference its entirety for all purposes. In some embodiments, the hyaluronidase of second formulation 120 is a recombinant human hyaluronidase.

[0110] The volume of second formulation 120 provided in a kit of the invention can vary, for instance, ranging from less than about 0.1 mL to greater than about 100 mL. In some embodiments, the volume of second formulation 120 is in the range of about 0.5 mL to 20 mL, about 1 mL to about 10 mL, or about 2 to about 5 mL. The volume of second formulation 120 can also be specifically optimized within such ranges for a particular application as desired, e.g., by comparing standard pharmacokinetic and / or pharmacodynamic profiles over a range of test volumes.

[0111] In some embodiments, the kit includes one or more optional or additional components. Examples of optional or additional components include but are not limited to: a warming device 130, a structural element 140, one or more preparation pads 150, one or more bandaids 160, one or more instruction document 170. a pump 180, a container 190, or any combination thereof.

[0112] The warming device is for bringing a pharmaceutical formulation (e.g., the IgG formulation) to a desired infusion temperature, e.g., from about 30 °C to about 40 °C. In some embodiments, the wanning device is selected from a syringe warmer and an inline w armer. The structural element is a tubing device for diverting the flow of the pharmaceutical formulation to two or more sites. The one or more preparation pads are for cleaning and preparing an infusion site priorY1to injecting the recombinant human hyaluronidase formulation or the IgG formulation. In some embodiments, the preparation pads are alcohol disinfectant pads. The one or more band-aids are for protecting the infusion site after injecting the IgG formulation. The one or more instruction document includes instructions for infusing the recombinant human hyaluronidase formulation and / or the IgG formulation by a clinician or by the subject. The pump is configured to facilitate infusing the recombinant human hyaluronidase formulation and / or the IgG formulation under pressure from the needle set into an infusion site of a subject. The container (e.g., a box, a bag, a casing, or the like) is for accommodating the first formulation, the second formulation, the needle set. and / or other optional or additional components.

[0113] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art (see, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,352). Examples of pharmaceutical packaging materials include, but are not limited to. blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.

[0114] The kit can be used in the subject’s home, a clinic, or other facility. It allows a user to self-administer a concentrated IgG formulation at his / her location (e.g., home) to treat a disease improved by administration of the concentrated IgG formulation, e.g., immune deficiency and / or other diseases. It is to be understood that the kit can also be used by a healthcare professional (e.g.. a nurse) or other person to administer the concentrated IgG formulation to a subject.IV. Infusing Means

[0115] FIGS. 2-7 schematically illustrate an exemplary infusing means by reference to needle set 200 in accordance with some embodiments of the present invention. Structural elements exemplified by the needle set are of use in other infusing means. The needle set is specifically designed for subcutaneously infusing viscous fluids, e.g.. to a region of tissue below the dermis and epidermis of a subject. The design principles underlying the needle set are equally applicable to equivalent infusing means.

[0116] Examples of viscous fluids include but are not limited to concentrated IgG formulations, other medicaments, and nutritional products. In some embodiments, the needle set not only allows for subcutaneous infusions of a useful dosage of a viscous fluid within a time frame reasonable to and convenient for the subject, but also eliminates or minimizes potential issues with the infusion of a viscous medicament, e.g., build-up of excessive delivery' pressure during the infusion, clogging of the needle or occlusion of areas adjacent to the point of insertion during infusion, andleakage from the infusion site. In some embodiments, die needle set also allows for relatively facile and pain free subcutaneous infusions of a viscous medicament.

[0117] Referring in particular to FIGS. 6 and 7, needle set 200 includes a needle, generally designated 210. The needle is specifically configured for administering a viscous fluid, such as a concentrated IgG formulation, at a relatively high flow rate. In an exemplary embodiment, achievable infusion rates are higher than those achievable w ith a needle typically used to infuse a 10% IgG formulation. An exemplary' needle is tubular with an axis 218, an timer diameter “dl" and an outer diameter (12 In various embodiments, the needle is comprised of multiple segments, such as first segment 211, second segment 212 and intermediate segment 213. In some embodiments, the needle is made of a stainless steel.

[0118] First segment 211 is a proximal segment of the needle, e.g. first segment 211 is the portion of the needle away from an injection site of the user when the needle is inserted into the subject for infusion, and is not configured for inserting into the subject. First segment 211 has first end 214. second end 215. and a length “LI” measured from first end 214 to second end 215 along axis 218 of the first segment of the needle (e.g., along the x-direction in FIG. 7). The first segment is substantially straight. In some embodiments, at least a portion of the exterior circumferential surface of the first segment is treated, for instance by grit blasting, to clean or modify its surface properties.

[0119] Second segment 212 is a distal segment of the needle, e.g., second segment 212 is the portion of the needle close to an injection site of the subject during an injection and is configured for inserting into the user. Second segment 212 has first end 216, second end 217, and a length “L2” measured from first end 216 to second end 217 along axis 218 of the second segment of the needle (e.g., along the y-direction in FIG. 7). The second segment is substantially straight. To facilitate insertion of the second segment of the needle into a subject, a portion adjacent to second end 217 of the second segment is beveled.

[0120] Intermediate segment 213 is disposed between the first and second segments and connects the first segment with the second segment. More specifically, the intermediate segment is disposed between second end 215 of the first segment and first end 216 of the second segment and connects the second end of the first segment with the first end of the second segment. Unlike the first and second segments, in an exemplary embodiment, the intermediate segment is smoothly curved and has a length “L3”. In some embodiments, the intermediate segment is in the form of an arc at a predetermined radius “R” and a predetermined angle “0”. In such embodiments, the length of the intermediate segment (e.g.. the arc length) can be calculated by L3 = nR0 / 1 G, where 0 is in degrees.

[0121] The total length of the needle is the sum of the lengths of all segments. For instance, in embodiments illustrated in FIGS. 6 and 7 where there are three segments, the total length of the needle is the sum of the length of the first segment (LI), the length of the second segment (L2) and the length of the intermediate segment (L3).

[0122] Exemplary' equivalent infusing means of the invention are configured substantially similarly.

[0123] Configuration of the needle has a significant impact on the flow within the needle, which is generally true for infusing means of the invention. For instance, according to Poiscuillc's law, the resistance Rs to laminar flow of an incompressible fluid having viscosity i] through a horizontal channel of uniform radius r and length Ax is given by Eq. (1):

[0124] For a fluid flowing in the channel at a volumetric flow rate Q, the pressure drop Ap due to the resistance is given by Eq. (2):(2) ^ = ^ <2

[0125] Assuming the pressure at first end 214 of the first segment of the needle provided by a pressurizing means such as a pump is Pl, and the pressure at second end 217 of the second segment of the needle (i.e., at an infusion site) is P2, the volumetric flow rate Q of the fluid in the needle may be estimated by Eq. (3):(3) Q = -n(rfl / 2)4( -P1-P2)

[0126] As can be seen, the volumetric flow rate Q is proportional to the fourth power of the inner diameter dl of tire needle and inversely' proportional to the total length of the needle. As such, it is contemplated that increasing the diameter of the needle slightly can have a significant positive impact on the flow of viscous fluids within the needle (e.g., increasing flow rates and / or reducing pressure drops); however, increasing the diameter of the needle also increases the pain experienced by the subject upon insertion of the needle and, thus, is an undesirable option.

[0127] Though it is contemplated by the equations above that reducing the total length of the needle or other infusing means will have a positive impact on the flow of viscous fluids within the infusing means, a shorter infusing means risks complications with successfully inserting it to a useful depth for the infusion, may result in leakage of the medicament from the infusion site, and may fall out and require reinsertion. Any of these undesirable events can lead to the subject receiving an insufficient dose of the medicament, becoming frustrated with the infusion process and terminating itor avoiding it altogether, resulting in delayed or skipped infusions due to inconvenience, discomfort, etc.

[0128] In some embodiments, the present invention provides an infusing means in which the imrer diameter, outer diameter, radius and angle of the intermediate segment, lengths of multiple segments (e.g., dl, d2, R, 0, LI, L2, L3) and / or other parameters of the means are configured such that die infusing means can deliver to a subject a useful dosage of a viscous medicament within a time frame reasonable and convenient for the subject. The infusing means disclosed herein provides other benefits, including but not limited to (i) minimizing build-up of excessive delivery' pressure during the SC infusion of a viscous medicament, (ii) minimizing occlusion of the infusing means or tissue adjacent to the point of insertion during infusion, (iii) minimizing leakage at an infusion site, (iv) allowing for relatively easy, convenient and pain free subcutaneous infusions, or any combination thereof.

[0129] In some embodiments, needle 210 or other infusing means is configured to have substantially the same outer diameter as a standard subcutaneous 24-gauge needle. As such, needle 210 is referred to herein as a "subcutaneous nominal 24-gauge needle” even though one or more parameters of needle 210 are variable from equivalent parameters of a standard subcutaneous 24- gauge needle. In an exemplary embodiment, the inner diameter of the needle is greater than the inner diameter of a standard 24-gauge needle.

[0130] In some embodiments, the outer diameter d2 of infusing means (needle) 210 has a value within a range of from about 0.54 millimeter (mm) to about 0.58 mm. In some embodiments, the outer diameter d2 of needle 210 is about 0.56 mm, about 0.57 mm, or about 0.58 mm. In an exemplary embodiment, the outer diameter d2 of needle 210 is about 0.559 mm. As it has substantially the same outer diameter as a standard subcutaneous 24-gauge needle, use of needle 210 in an infusion does not cause any more discomfort than currently used infusion needles.

[0131] In some embodiments, an infusing means, e.g., needle 210, is configured to have a member selected from: (i) an inner diameter dl of from about 0.35 mm to about 0.5 mm (larger than the inner diameter of a standard 24-gauge needle, which is about 0.311 mm); (ii) a total length of from about 25 mm to about 35 mm; (iii) an insertion length (e.g., the length L2 of the second segment) of from about 12 mm to about 16 mm (e.g., 12, 13, 14, 15 or 16 mm), and any combination thereof. Such a configuration is advantageous compared to existing needles, allowing for infusion of a viscous medicament at a higher flow rate than a standard 24-gauge needle, and also for deeper insertion into the subcutaneous compartment of the subject, thereby minimizing leakage at an infusion site. The configuration of the needle disclosed herein is counterintuitive and unconventional: a longer needle produces greater resistance to fluid flow than a shorter needle; because an increased resistance to fluidflow leads to increased deliver}' pressure of a viscous medicament, designing a longer needle for infusion of such a medicament is an unlikely design a needle to increase the insertion length. However, the present disclosure is not limited thereto. For instance, in some embodiments, needle 210 is configured to have an insertion length of from about 6 mm to about 15 mm. In an exemplary embodiment, needle 210 is configured to have an insertion length of about 12 mm. In an exemplary embodiment, needle 210 is configured to have an insertion length of about 14 mm.

[0132] In various embodiments, this unconventional configuration of needle 210 or other infusing means allows for infusion of a viscous fluid (e.g., the IgG formulation) at an infusion site at a flow rate of not less than about not less than about 240 mL / lir. e g., not less than about 260 mL / lir. e.g., not less than about 280 mL / hr, e.g.. not less than about 300 mL / hr .with a pressure drop not more than about 12 pounds per square inch (psi) at the relevant infusion rate while minimizing leakage at a single infusion site. In some embodiments, this unconventional configuration of needle 210 allows infusion of the viscous fluid (e.g., the IgG formulation) through the needle into a single infusion site at a flow rate of not less than about 250 mL / hr, not less than about 300 mL / hr. not less than about 350 mL / hr. not less than about 400 mL / hr, not less than about 450 mL / hr, not less than about 500 mL / hr, not less than about 550 mL / hr, or not less than about 600 mL / hr, with a pressure drop across the infusing means of not more than about 12 pounds per square inch (psi), e.g.. not more than about 10 pounds per square inch (psi). In an exemplary embodiment, this unconventional configuration of needle 210 allows infusion of the viscous fluid (e.g., the IgG formulation) through the needle into a single infusion site at a flow rate set forth above with a pressure drop across the infusing means of not more than about 12 psi. In certain embodiments, it is an object of the invention to ramp up the infusion rate to not less than about 240 mL / hr, e.g., not less than about 260 mL / hr, e.g., not less than about 280 mL / hr, e.g., not less than about 300 mL / hr as quickly as possible with the goal of completing the infusion over as short a duration as possible.

[0133] In some embodiments, the inner diameter dl of the needle or other infusing means is not less than about 0.36 mm, not less than about 0.37 mm, not less than about 0.38 mm, not less than about 0.39 mm, not less than about 0.40 mm, not less than about 0.41 mm, not less than about 0.42 mm, not less than about 0.43 mm, not less than about 0.44 mm, or not less than about 0.45 mm. In some embodiments, the inner diameter dl of the needle is substantially constant along die length direction of the needle (e.g., along axis 218 of the needle illustrated in FIG. 7) and has a value within a range of from about 0.38 mm to about 0.43 mm, from about 0.39 mm to about 0.44 mm, or from about 0.40 to about 0.45 mm. In some embodiments, the inner diameter dl of the needle is about 0.41 mm, about 0.42 mm. or about 0.43 mm. In an exemplary embodiment, the inner diameter dl of the needle is about 0.413 + / - 0.019 mm.

[0134] Because the outer diameter of the infusing means, e.g., needle 210, is substantially the same as drat of the standard subcutaneous nominal 24-gauge needle while the inner diameter of needle 210 is larger than that of the standard subcutaneous 24-gauge needle, the wall of needle 210 is thinner than the standard subcutaneous 24-gauge needle. In some embodiments, the wall of needle 210 has a thickness less than about 200 pm, less than about 190 |im, less than about 180 gm, less than about 170 gm, less than about 160 gm, less than about 150 gm, less than about 140 gm. less than about 130 gm. less than about 120 gm, less than about 110 gm, less than about 100 gm, less than about 90 gm, or less than about 80 gm. In an exemplary embodiment, the wall of needle 210 has a thickness within a range of from about 100 gm to about 200 gm. or about 118 gm to about 186 gm.

[0135] In some embodiments, the first segment has a length LI of not more than about 14 mm, not more than about 13 mm. not more than about 12 mm, not more than about 11 mm, not more than about 10 mm, not more than about 9 mm, or not more than about 8 mm. In an exemplary embodiment, the first segment has a length LI of about 11.5 mm. about 11 mm, or about 10.5 mm.

[0136] In some embodiments, the second segment has a length L2 (e.g., the insertion length) that is longer than the insertion length of a standard subcutaneous 24-gauge needle, which in many cases is up to 12 mm and in some cases is up to 14 mm. In some embodiments, the second segment of needle 210 has a length L2 of not less than about 14 mm or not less than about 15 mm. In an exemplary embodiment, the second segment of needle 210 has a length L2 of about 11 mm, 11.5 mm. 12 mm,12.5 mm, 13 mm, 13.5 mm, 14.5 mm. about 15 mm, about 15.5 mm or about 16 mm. In some embodiments, the second segment of needle 210 has a length L2 of not more than about 18 mm or not more than about 19 mm.

[0137] In some embodiments, the intermediate segment is an arc with a predetermined radius R and a predetermined central angle 0. In some embodiments, the radius R of the intermediate segment is not less than about 0.5 mm, not less than 1 mm, not less than 1.5 mm, not less than 2 mm, not less than 2.1 mm, not less than 2.2 mm, not less than 2.3 mm, not less than 2.4 mm, or not less than 2.5 mm. In some embodiments, the radius R of the intermediate segment has a value within a range of from about 0.5 mm to about 1.5 mm, from about 1 mm to about 2 mm, from about 1.5 mm to about2.5 mm. or from about 2 to 3 mm. In an exemplary embodiment, the radius R of the intermediate segment has a value of about 2 mm, about 2.1 mm, about 2.2 mm, about 2.3 mm, about 2.4 mm or about 2.5 mm. In some embodiments, the predetermined central angle 0 has a value of from about 45° to about 90°. In an exemplary embodiment, the predetermined central angle 0 has a value of about 90° (i.e., the first and second segments of the needle are substantially perpendicular to each other).

[0138] In some embodiments, the total length of the infusing means, e.g., the needle, (i.e., the sum of the lengths of the first, second and intermediate segments) is not more than about 34 mm, not morethan about 33 mm, not more than about 32 mm, not more than about 31 mm, or not more than about 30 mm. In some embodiments, the total length of the needle has a value of from about 28 mm to about 30 mm, from about 29 mm to about 31 mm, or from about 30 mm to about 32 mm. In an exemplary embodiment, the total length of the needle is about 29.5 mm, about 30 mm, about 30.5, about 31 mm or about 31.5 mm.

[0139] Referring in particular to FIGS. 2-4, in some embodiments, an infusion means, e.g., needle 210, is in fluidic communication with a fluid delivery means (e.g., a tube), generally designated 220. The fluid delivery means is configured for receiving a fluid such as first formulation 110 (the IgG formulation) and / or second formulation 120 (the hyaluronidase formulation). For instance, as a nonlimiting example, FIG. 4 illustrates that first end 214 of the first segment of the infusion means is disposed within the fluid delivery means at a location adjacent to an end 221 of the fluid delivery means, fluidically connecting the infusing means with the fluid deliver,' means, and thus allows a fluid to flow from the fluid delivery means to the infusing means (e.g., from the left side of the figure to the right side in FIG. 4). However, the present invention is not limited thereto. Fluidic communication between the infusing means and the fluid delivery can be achieved by other ways, w hich are apparent to one of skill in the art.

[0140] Typically, fluid delivery means 220 is flexible and elongated. In some embodiments, the fluid delivery means has an inner diameter “d3” of not less than about 1 mm, not less than about 1.1 mm. not less than about 1.2 mm, not less than about 1 .3 mm, not less than about 1 .4 mm. or not less than about 1.5 mm. In an exemplary embodiment, the inner diameter d3 of the tube is about 1.2 mm. about 1.25 mm, about 1.3 mm or about 1.35 mm. In some embodiments, the tube has a length of from about 10 inches to about 30 inches, from about 20 inches to about 40 inches, or from about 30 inches to about 50 inches.

[0141] In some embodiments, the fluid delivery' means is attached to a connector 230 configured for connecting the fluid delivery' means to other devices or components. The comrector 230 can be of any suitable type. As a non-limiting example, FIG. 2 illustrates a female luer connector, and implies its equivalents. In some embodiments, flow of the fluid in the fluid delivery' means is regulated by a regulator 240 configured for adjusting the flow' rate of the fluid in the fluid delivery means. The regulator 240 can be of any suitable ty pe. As a nonlimiting example, FIG. 2 illustrates the regulator in a form of a clamp disposed at the fluid delivery means.

[0142] Referring in particular to FIGS. 2-5, in some embodiments, infusing means 200 includes a hub, generally designated 250. The hub is configured to support and secure at least a portion of the infusing means and a portion of tire fluid delivery means, and / or to facilitate proper insertion of the infusing means at an infusion site. In some embodiments, the hub includes a middle section.generally designated 251, for accommodating and / or securing at least a portion of the infusing means and a portion of the fluid delivery means. In some embodiments, the hub also includes a first wing, designated 252, at a first side (e.g., left side in FIG. 5) and a second wing, designated 253, at a second side (e.g., right side in FIG. 5) of the middle section. The first and second wings are foldable, e.g.. the first and second wings can be folded back away from the fluid delivery means and pinched together for instance between two fingers of a user. In some embodiments, the first and second wings are formed with rib(s) 254. snapping feature(s) 255, hinge(s) 256, and / or optional / additional / altemative features to enhance the strength, facilitate gripping, provide stability, reduce shears or stress, and / or achieve other desired functions.

[0143] In some embodiments, middle section 251 of the hub includes a tunnel, designated 261, across at least a portion of the middle section. The tunnel includes a first opening 262 at a first end of the tunnel, and a second opening 263 at a second end of the tunnel. The first opening is in general relatively larger than the second opening. A position of the tube adjacent to end 221 of the fluid delivery means is inserted into the tunnel through the first opening, and at least a portion of the first segment of the infusing means is inserted into the tunnel through the second opening. In some embodiments, the tunnel is formed with a stopper 264 (e.g.. a step, a raiser) so that the fluid delivery means is prevented from inserting further into the tunnel beyond the stopper (e.g., the fluid delivery means is prevented from inserting further to the left side of the stopper in FIG. 4).

[0144] In some embodiments, middle section 251 of the hub includes a shoulder, designated 265, adjacent to the second opening and configured for supporting the intermediate segment of the infusing means. In some embodiments, the shoulder is shaped and sized in accordance with the intermediate segment of the infusing means such drat when the first segment of the infusing means is inserted into the tunnel through the first opening of the tunnel, the shoulder abuts and supports the intermediate segment of the infusing means.

[0145] In some embodiments, the middle section of the hub is configured such that second end 215 of the first segment of the infusing means is aligned substantially with the second opening and first end 216 of the second segment of the infusing means is aligned substantially with a bottom surface of the shoulder. Such a configuration not only provides support for the intermediate segment of the infusing means and thus reduces the risk of infusing means breakage, but also allows the use of the entire second segment of the infusing means for insertion if necessary to prevent leakage at infusion sites.

[0146] In some embodiments, the hub is made of a thermoplastic material such as Polyvinyl Chloride (PVC) by molding, and the infusing means and the fluid delivery means are assembled to the hub using an adhesive. For instance, in some embodiments, middle section 251 of the hub includes aport, designated 266. The port is in fluid communication with the tunnel. Through the port, an adhesive is applied to the tunnel to bond at least a portion of tire fluid delivery means and at least a portion of the infusing means with the middle section, and / or to bond at least a portion of the fluid delivery means with at least a portion of the infusing means. In some embodiments, the port is formed on a side wall of the middle section (e.g., on a top side of the middle section in FIG. 5) at a locating adjacent to end 221 of the fluid delivery' means. In some embodiments, the adhesive is a UV glue (e.g, a glue activated or cured by ultraviolet light). However, the present invention is not limited to such an adhesive. Other adhesives can be used. In some embodiments, an adhesive is additionally or optionally applied through the second opening of the tunnel to bond at least a portion of the first segment of the infusing means with a portion of the middle section adjacent to the second opening. Applying adhesives through the port and through the second opening can be conducted concurrently or sequentially.

[0147] In some embodiments, the tunnel is formed with an adhesive constriction, designated 267. The adhesive constriction is configured to prevent the adhesive from flowing further toward the first opening of the tunnel (e.g., preventing the adhesive from flowing further to the right side of the adhesive constriction in FIG. 4). In some embodiments, the adhesive constriction is a protrusion (e.g., rib. ridge, bump) protruded radially inwardly from the surface of the tunnel.

[0148] Referring in particular to FIGS. 3 and 4. in some embodiments, infusing means 200 includes a protector, designated 270. The protector is configured to be slidably fitted into at least a portion of the second segment of the infusing means to safeguard the infusing means and / or users when the infusing means is not in use.

[0149] In an exemplary embodiment, in operation, the present infusing means and kits can be used in the infusion of various viscous medicaments. For instance, the user places the infusing means in fluidic communication with the hyaluronidase formulation and / or IgG formulation using the connector of the infusing means. The user identifies and cleans an infusion site. To facilitate an infusion at a cleaned, desired infusion site, the user folds die wings of the hub back away from the infusing means, pinches the wings together betw een tw o fingers, and removes the protector from the infusing means. Then, the user inserts the infusing means into the skin at the desired infusion site. The user confirms that the infusing means is properly placed and secures the infusing means in place. Afterward, the user starts the infusion as instructed in the instruction document, or as directed by a healthcare professional.

[0150] In an exemplary embodiment, there is provided a method of infusing a viscous fluid into a first infusion site of a subject, the method comprising: (a) inserting into die first infusion site a first infusing means described herein; and (b) commencing infusion though the first infusing means,ramping to an infusion rate of not less than about 240 mL / hr, e.g., not less than about 260 mL / hr, e.g., not less than about 280 mL / hr. e.g., not less than about 300 mL / hr with a pressure drop across the first infusion means of not more than about 12 pounds per square inch (psi), e.g., not more than about 10 pounds per square inch (psi).

[0151] In certain embodiments, it is an object of the invention to ramp up the infusion rate to as close as possible to not less than about 240 mL / hr, e.g., not less than about 260 mL / hr, e.g., not less than about 280 mL / hr, e.g., not less than about 300 mL / hr as quickly as possible with the goal of completing the infusion over as short a duration as possible.

[0152] In various embodiments, at least 90%, at least 80%, at least 70%, at least 60% or at least 50% of the infusion is conducted at an infusion rate of not less than about 240 mL / hr, e.g., not less than about 260 mL / hr, e.g., not less than about 280 mL / hr, e.g., not less than about 300 mL / hr.

[0153] In various embodiments, the viscous fluid comprises a medicament. Exemplary medicaments include protein medicaments, e.g., an antibody. An exemplary antibody is IgG.

[0154] In an exemplary embodiment, the viscous solution is a 20% (w / v) pharmaceutical formulation of a protein formulated for subcutaneous administration, for example, 20% (w / v) IgG formulated for subcutaneous administration.

[0155] In an exemplary embodiment, the viscosity of the viscous fluid is not less than about 12 cP. 14 cP, 16 cP, 18 cP, 20 cP, 22 cp, 24 cP, 26 cp, 28 cP, or 30 cP.

[0156] In some embodiments, the method further comprises: (c) infusing a pharmaceutical formulation of recombinant human hyaluronidase into the first infusion site through the first infusing means.

[0157] Though it is an object of the invention to provide rapid, convenient and comfortable infusions of viscous solutions at a single infusion site, the method also contemplates the infusion of the solution at more than one. more than two, more than three, or more than four infusion sites using multiple infusion means. Accordingly, there is a provided a method further comprising: (al) inserting into a second infusion site a second infusion means as described herein; and (bl) commencing infusion though the second infusion means, ramping to a floyv rate of pounds per square inch (psi) yvith a pressure drop across the second infusion means of not more than about 12 pounds per square inch (psi), e.g., not more than about 10 pounds per square inch (psi) at an infusion rate of not less than about 240 mL / hr, e.g., not less than about 260 mL / hr, e.g., not less than about 280 mL / hr, e.g., not less than about 300 mL / hr.

[0158] The method of the invention further contemplates facilitating delivery of the yiscous formulation by co-infusing recombinant human hyaluronidase to the infusion site. Thus, there is 1provided a method further comprising: (cl) infusing a pharmaceutical formulation of recombinant human hyaluronidase into the second infusion site through the second infusing means.

[0159] In various embodiments, tire method is performed in accordance with user administration / dosing instructions accompanying a subcutaneous infusion kit comprising: (a) an infusing means for infusing a viscous liquid having a viscosity’ of from about 10 centipoise (cP) to about 40 cP into a single subcutaneous infusion site in a subject at an infusion rate of not less than about 240 mL / hr, c.g., not less than about 260 mL / hr, c.g., not less than about 280 mL / hr, c.g., not less than about 300 mL / hr, with a pressure drop not more than about 12 pounds per square inch (psi), e.g., not more than about 10 pounds per square inch (psi); (b) an immunoglobulin G (IgG) formulation having a concentration of IgG from about 18% (w / v) to about 22% (w / v) and a viscosity of from about 10 centipoise (cP) to about 40 cP: and (c) optionally, a pharmaceutical formulation of recombinant human hyaluronidase.

[0160] When the method of invention is a facilitated delivery method, the IgG and hy aluronidase can be delivered to the infusion site in any useful order. Thus, the pharmaceutical formulation of IgG and the pharmaceutical formulation of recombinant human hyalouronidase are administered simultaneously to the first infusion site, the pharmaceutical formulation of recombinant human hyalouronidase is administered to the first infusion site first, followed by the pharmaceutical formulation of IgG, or the pharmaceutical formulation of IgG is administered first, followed by the pharmaceutical formulation of recombinant human hyalouronidase.

[0161] The invention also provides user administration / dosing instructions for infusing a pharmaceutical formulation of 20% (w / v) IgG to a first infusion site utilizing a first infusion means configured to infuse the pharmaceutical formulation at a maximum infusion rate of not less than about 240 mL / hr, e.g., not less than about 260 mL / hr, e.g., not less than about 280 mL / hr, e.g., not less than about 300 mL / hr, with a pressure drop of not more than about 12 pounds per square inch (psi), e.g., not more than about 10 pounds per square inch (psi) across the infusion means, wherein the pharmaceutical formulation has a viscosity of from about 10 centipoise (cP) to about 40 cP.

[0162] In an exemplary embodiment, the instructions further comprising administration / dosing instructions for infusing at the first infusion site a pharmaceutical formulation of recombinant human hyaluronidase.

[0163] Exemplary' instructions are provided to the user in electronic form (e.g., a website) or as a tangible package insert accompanying a subcutaneous infusion kit for a pharmaceutical formulation of 20% IgG.EXAMPLESExample 1- Assessment of rHuPH20 / IG in pig models for subcutaneous administration

[0164] This in vivo study consisted of the evaluation in pig models of the enzyme Recombinant Human Hyaluronidase PH20 (rHuPH20) for die administration of high and concentrated volumes of Immunoglobulins (IGs) using the subcutaneous route.

[0165] The classical method for the administration of Igs is intravenous infusion because it allows, in short periods of time and using only one injection site, the infusion of large volumes. However, the subcutaneous (SC) route offers important advantages such as the possibility of selfadministration at home by patients, improving their quality of life and reducing health system costs, and the avoidance of the systemic effects’ consequence of high peak concentrations. The inconvenience of SC infusion is the limited volumes allowed per injection site (—20 mL) and the local adverse effects, pain and skin reactions, that appear when these restricted amounts are exceeded.

[0166] Pig models to evaluate the tolerability of the SC route for the continued administration of large volumes of IG, have been developed. In these models, the treatment of the SC space with rHuPH20 transiently and locally depolymerizes the hyaluronan, reducing the viscosity of the extracellular matrix and increasing the dispersion and absorption of the infused IG solutions. The main read-outs of these experiments were the exerted pressure on the injection site as well as the local inflammatory responses.

[0167] In the present study, the administration of rHuPH20 + IGSC 20% with high volumes of the immunoglobulin suspension and at increasing rates for 1 hour comparing a 24-gauge needle used with two different Infusion Pumps #1 and #2.Table 1. Summary of the experimental conditions tested for each group of animals. Ratio rHuPH20 per IG solution: 80 U / g.Table 2. Characteristics of the administered product. The ratio of rHuPH20 was the same as for the licensed product HyQvia, which is approximately 80 U rHuPH20 per gram IgG.• rHuPH20: Vials of 10 and 15 mL (160 U / mL);• IG 20%: Containers of 40 mL; concentration 200 mg / mL. Incorporated into infusion bags;• Storage conditions: rHuPH20 2 °C to 8 °C; IG 20% 2 °C to 8 °C.

[0168] Aim of the study: the specific objectives of the study are summarized in the following points:Assessment of in-line pressures during administration, and local reaction and histological response after 24h. for the 24-gauge needle.Comparison of pressures during administration, and local reaction and histological response after 24h, for two different infusion Pumps #1 and #2 used in connection with the 24-gauge, 0.05” needle.

[0169] The comrections were done following the procedure described in the study plan and represented in Figure 8. IG solutions were administered using peristaltic infusion pumps with specific infusion set and extension tubes. The IgG tube ended in a 3-way stopcock that presented in other side a tube connected to a syringe that was placed in a syringe pump and containing the enzyme (rHuPH20) . The last side of the 3 -way stopcock was connected to the pressure transducer and right after this to the needle system used for the administration.

[0170] The rHuPH20 enzyme was administered first. It was used to fill the entire system, passing through the open 3 -way stopcock and reaching the needle inserted subcutaneously into the animal. After the enzyme injection was completed, the IgG solution was administered. The system was then purged up to the 3 -way stopcock, which was opened to allow flow to the needle.

[0171] In-line pressure transducers were connected to PowerLab and from it to a computer where the PowerLab LabChart software was installed. A template was available ith calibrated pressure transducers and acquisition parameters at 100 mV amplification and registration frequency of 10 / s. After injection all the system was prepared and zeroing was applied to the channels involved.

[0172] The curves for in-line pressure revealed from power lab chart software were digitally saved as a raw data of the study. Individual representations were plotted using GraphPad Prism Version 9.2.0 for each animal for the pressure data. For each of the three sets of animals, mean and maximum values were calculated for only the IG infusion time and these values were compared between treatments using the unpaired T-test statistical analysis with the software GraphPad Prism version 9.2.0. All these results are discussed in the following sections.In-line pressure with 24-gauge needle for the administration of rHuPH20 + IGSC 20%.

[0173] Three animals received SC infusions of 16 ml of rHuPH20 and 160 ml of IGSC. 20%, using the same infusion Pump #1, with a BD Saf-T-Intima 24-gauge needle in the abdominal region (TS1). The products were injected in both sites sequentially: first the rHuPH20 enzyme was delivered at 2 mL / min, and later the IG w as delivered at increasing speeds and volumes (see Figure 9). A summary of the global data and the descriptive statistics and analysis for the 24G Needle Pump #1 are presented in Table 3.Table 3. Descriptive statistics for in-line pressure in the TS1 administered at increasing rates.Comparison of two infusion pumps with 24-gauge needle

[0174] Three animals received two simultaneous SC infusions of 16 mL of rHuPH20 and 160 ml of IGSC, 20%, using the same needle 24G 0.05 ’’(Takeda), but two different infusion pumps settings in the contralateral sites of the abdominal region: TS2, Pump #1, and TS3, Pump #2. The products were injected in both sites sequentially, first the enzyme delivered at 2 mL / min, and later the IgG formulation at increasing speeds and volumes (see details in Table 4). In Figure 10, the results for the in-line pressures during the infusion are shown. A summary of the data and the descriptive statistics and analysis are presented in Table 4 and Table 5.Table 4. Descriptive statistics for in-line pressure: descriptive statistics for in-line pressure in the comparison TS2 vs TS3 administered at increasing rates with the needle system of the present disclosure. N=3 animals.Table 5. Comparison of mean in-line pressure: Comparison of mean in-line pressure for the administration of TS2 vs TS3 (Unpaired t test; GraphPad Prism Version 9.2.0).

[0175] For both settings compared — TS2 and TS3, the in-line pressure values showed a general trend of increasing with infusion rate. Another clear observation was that the continuous oscillations in pressure caused by the peristaltic action of the pumps were more pronounced with the Pump #1 infusion system than with Pump #2. Two animals (#5 and #6) under the TS2 / Pump #1 condition exhibited higher global maximum pressure values compared to Pump #2. However, the mean pressure values were comparable between the tw o pumps, though greater variability was noted with Pump #1, attributable to its wider peristaltic pressure oscillations. For animal #4, such differences in maximum pressure were not observed, and mean pressure values were generally similar, except at the highest infusion rate, where greater variability was again evident with Pump #1.

[0176] When considering all three animals, the results indicate a trend toward higher maximum pressure values in the Pump #1 setting (TS2) compared to Pump #2 (TS3), whereas mean pressure values were slightly higher in the Pump #2 setting, likely due to its narrower oscillatory pressure profile (see Table 5). Statistical analysis (Unpaired t test, GraphPad Prism Version 9.2.0) showed that the observed differences between TS2 and TS3 were not statistically significant for either the mean maximum in-line pressure or the mean in-line pressure at each infusion rate (see Table 5).Follow-up: Welfare, bleb size and local reaction

[0177] The following assessments were done previously to the infusion, directly at the end of the infusion and at approximately 2 hours. 4 hours and 24 hours after completion of the infusion

[0178] Bleb size assessment: The quantitative evaluation of the injection sites was carried out using a calliper and measuring the maximum length, width and height of the bleb formed. The length and width were defined as the edge-to-edge measurements of the bleb along their longest axes. These values were recorded and the volume and the area were calculated considering the formula for a half of an ellipsoid.

[0179] The measured bleb sizes for TS1 (BD Saf-T-Intima 24G Needle, Pump #1) are summarized in Table 6 below.Table 6. Bleb size measurements and calculations of TS1

[0180] The results for TS2 and TS3 (24G Needle, Pumps #1 and #2) is summarized in Table7 below.Table 7. Size measurements and calculations of TS2 vs TS3 (N=3).

[0181] Local reaction assessment: The qualitative evaluation was done considering the appearance and severity of erythema, swelling, and firmness (induration) using 4-point scoring system based on the 1992 OECD guidelines for grading skin reactions, a modified Draize Test. The sum of the scores for the 3 parameters was determined and used for evaluation.Table 8. Grading scale for erythema, swelling and firmness parameters

[0182] No significant differences in surface, volume and local scores were observed betweenTS1, or between TS2 and TS3(see Table 9 below).Table 9. Comparison of surface, volume and local scores between TS2 and TS3 (Paired t test; GraphPad Prism Version 9.2.0).

[0183] For all set-ups, in-line pressure increased with increasing flow rates.

[0184] For all infusions, bleb was regularly shaped indicating increased dispersion, no differences were revealed regarding tolerability scores.

[0185] Three different clinical settings: TS1, and TS2 vs TS3; were explored for the administration of rHuPH20 + IGSC, 20%, using increasing rates of infusion and high volume, 160 mL, of 20% concentrated IG solution.

[0186] Pump #1 (TS2) vs Pump #2 (TS3), when used with 24-gauge needle, the mean of maximum in-line pressure parameter presented highest values for the Pump #1 infusion pump. On thecontrary, for the other parameter, the mean in-line pressure, the Pump #2 showed highest values consequence of their lower dispersion in the oscillating peristaltic infusion. These differences were not statistically significant.

[0187] The blebs initially formed at time 0 (T=0) decreased in size over time and also die local reaction. No statistically significant differences were observed between the settings compared.Example 2- Assessment of subcutaneous IG and rHuPH20 administration in pig models

[0188] To evaluate the feasibility and tolerability of subcutaneous immunoglobulin (SCIG) administration under varying infusion conditions, a series of in vivo studies were conducted using a pig model. In each study cycle, three pigs were used in a side-by-side comparison format, with intraanimal control achieved through infusion into lateral sides of each animal.Study Design

[0189] Setup of the design is provided in Figure 12. Each pig received 50 mL of a 20% SCIG formulation using a 24-gauge. 14 mm needle connected to a syringe driver pump. The needle used in this study had a nominal 24-gauge outside diameter (i.e., approximately 0.56 mm) and a length of approximately 14 mm.

[0190] The following parameters were assessed:• Infusion feasibility7• In-line pressure and infusion force• Bleb size• Local reaction and clinical scoring at baseline (T=0), 2 hours, 4 horns, and 24 hours postinfusion• Gross necropsy and histopathology at 24 hours.Cycle 1 — 2.5 mL / min SCIG 20%

[0191] Fifty7milliliters of 20% SCIG were infused at a rate of 2.5 mL / min. All three pigs were successfully infused without pump blockage. The mean in-line pressure was 362.7 mmHg (maximum: 514 mmHg). No signs of discomfort, pain, or behavioral changes were observed. Local firmness, ery thema, and edema progressively subsided and were fully resolved within 24 hours.Cycle 2 - 1.0 mL / min SCIG 20%

[0192] Infusion at a slower rate of 1.0 mL / min yielded a lower mean in-line pressure of 78.8 mmHg (maximum: 245.3 mmHg). All animals tolerated the procedure well, and no adverse clinical signs were observed. All local reactions resolved completely by 24 hours.Cycle 3 — 2.5 mL / min facilitated SCIG 20%

[0193] 50 mL of 20% SCIG were infused subcutaneously at a rate of 2.5 mL / min with facilitation using recombinant human hyaluronidase (rHuPH20). The mean in-line pressure during infusion was 243.8 mmHg, with a recorded maximum of 328.3 mmHg. All infusions were completed successfully with no pump blockage or observable clinical concerns.

[0194] The concentration of rHuPH20 used in this cycle was 160 U / mL. To achieve a dose of 80 U rHuPH20 per gram of IgG, a total of 5 mL of rHuPH20 solution was co-administered. Local tissue effects, including erythema, edema, and firmness at the infusion site, resolved completely within 24 hours.Cycle 4 — 3.5 mL / min facilitated SCIG 20%

[0195] SCIG was infused at 3.5 mL / min via facilitation with recombinant human hyaluronidase (rHuPH20). At the highest tested infusion rate (3.5 mL / min), facilitated SCIG produced a mean in-line pressure of 269.1 mmHg (maximum: 292.8 mmHg). Infusions were well tolerated across all animals, and local tissue reactions resolved by 24 hours post-infusion.

[0196] The concentration of rHuPH20 used in this cycle was 160 U / mL. To achieve a dose of 80 U rHuPH20 per gram of IgG, a total of 5 mL of rHuPH20 solution was co-administered. Local tissue effects showing a lack of tolerability, including erythema, edema, and firmness at the infusion site, resolved completely within 24 hours.Table 10 summarizes the finding above for the SCIG 20% administration.Summary of Findings

[0197] Across all infusion cycles:• All pigs tolerated the procedure without clinical or behavioral abnormalities.• No pump blockages were observed.• Local tissue effects (bleb formation, erythema, firmness) were transient and fully resolved within 24 hours.• Facilitated SC1G enabled higher infusion rates while maintaining lower in-line pressure and force values compared to non-facilitated controls.Example 3 - Flow rate assay for bifurcated subcutaneous needle sets

[0198] Flow rate testing w as conducted to evaluate the performance of the 24-Gauge Bifurcated 15 mm subcutaneous (SC) Needle Sets under simulated clinical use conditions. The needle used in this study had a nominal 24-gauge outside diameter (i.e., approximately 0.56 mm). Each needle leg of die bifurcated needle set measured approximately 15 mm in length and was connected to a flexible PVC tube. The objective was to assess flow' consistency, performance stability’ post-clamping, and flow symmetry betw een legs of the bifurcated configuration.

[0199] The acceptance criteria for the bifurcated needle set were as follows:• Achieve a minimum flow rate of 300 mL / lir per leg at an applied pressure of 12 psi.• Demonstrate a <10% difference in flow rate between the two legs of the bifurcated configuration.• Maintain >80% of the original pre-clamping flow rate after 8 hours of clamping.

[0200] To satisfy the above criteria, all 27 tested samples were required to demonstrate compliance with the flow rate and leg-to-leg symmetry' specifications, maintain at least 80% of the original flow rate following 8 hours of clamping, and achieve 95% confidence at 95% reliability — collectively confinning robust process capability.Test Setup

[0201] Each needle set was connected to a fluid line with a 3.3 cP simulant. Pressure was applied at 12 psi using a regulated gauge, and simulant was collected in separate beakers for each leg (Leg A and Leg B). Flow rate was calculated by weighing the collected fluid. Testing was perfonnedboth pre-clamping and post 8-hour clamping, and included flow symmetry' analysis between the two legs.Results

[0202] All samples (n=27) meet aforesaid specifications, as detailed below:Pre- Clamping

[0203] Based on the flow rate measurements taken from both the A and B legs of the bifurcated tube set, it was confirmed that all l ' l samples passed the acceptance criteria of a minimum flow rate of 300 mL / hour per leg with an infusion differential of 12 psi per 1 minute. Per Minitab Statistics, Leg A had a maximum value of 1557.8 mL / hr., a minimum value of 1502.8 mL / hour, a mean value of 1526.6 mL / hr. and a process capability curve (Cpk) value of 36.31.

[0204] Leg B had a maximum value of 1563.3 mL / hr., a minimum value of 1480.7 mL / hr., a mean value of 1522.7 mL / hr. and a Cpk value of 23.86. The Cpk values for both being above 1 indicates that the process is capable of meeting the specification. See Figures 13 and 14 for Minitab Statistic Summary for leg A and Figures 15 and 16 for Leg B.Post-Clamping - flow rate After 8 hours clamping 80%

[0205] Based on the flow rate measurements taken from the A and B legs of the bifurcated tube set post-clamping, it was confirmed that all 27 samples passed their acceptance criteria by maintaining a flow rate of at least 80% (0.80) of their original flow rate after being clamped for 8 hours. 80% (0.80) was calculated by dividing the pre-clamping total weight and the post-clamping total weight.

[0206] Per Minitab Statistics, the data had a maximum value of 1.0218, and minimum value of 0.9858. and a Cpk value of 13.50, indicating that the process is capable of meeting the specification. See Figures 17 and 18 for Minitab Statistics Summary.Flow rate comparation between Legs (A & B) 10%

[0207] Based on the flow rate measurements taken from the A and B legs of the bifurcated tube set pre-clamping, it was confirmed that all samples passed their acceptance criteria by having a difference in flow rate less than or equal to 10% (0.10) between leg A and leg B when each leg experienced the same backpressure of 12 psi. The 10% was calculated by finding the absolute value of Leg A and Leg B weights and dividing by their total weight. Per Minitab Statistics, the data has a maximum value of 0.016, a minimum value of 0.00 mL / hr. a mean value of 0.005 mL / hr, and a Cpk value of 6.19, indicating that the process is capable of meeting the requirement. See Figures 19 and 20 for Minitab Statistics Summary.Example 4 - Flow rate testing of 24-gauge single and bifurcated needle sets

[0208] Single and bifurcated needle sets described herein were tested for occlusion risk, performance under pressurized conditions (air-over-water system), and flow' rate consistency between the tw o legs of the bifurcated needle configuration. The needle used in this study featured a nominal 24-gauge outer diameter (approximately 0.56 mm). Each needle leg — whether part of the single or bifurcated set — measured approximately 14 mm in length and was connected to a PVC tube with an inner diameter of 0.05 inches.

[0209] Alternatively, the length of the needle of the single or bifurcated needle set may be selected from 6 mm, 9 mm, or 12 mm.

[0210] It was hypothesized that the bifurcated (two-leg) needle set would exhibit minimal — preferably no more than a 10% — difference in flow rate betw een the two legs.Results

[0211] The flow' rates rate achieved were >300 mL / hr for both the single leg and bifurcated needle sets (see Figures 21-24 for detailed results) using a 16.7 cP solution / fluid at 10 psi pressure gradient.

[0212] The test results are summarized in Table 11 below. Single leg refers to 24 / 0.05 inch lx Needle 24-gauge 14 mm needle set, and Bifurcated Leg refers to 24 / 0.05 inch 2x Needle 24-gauge 14 mm needle set.Table 11. Flow Rate Comparison Between Single-leg and Bifurcated Needle Sets.

[0213] Based on the flow rate measurements taken from the A and B legs of the bifurcated tube set pre-clamping, it was confinned that the single leg and bifurcated needle sets passed their acceptance criteria by having a minimal difference in flow rate less than or equal to 10% (0.10) between leg A and leg B, when each legs experienced the same backpressure of 12 psi. The 10% w as calculated by finding the absolute value of Leg A and Leg B weights and dividing by their total weight.

[0214] The present invention has been illustrated by reference to various exemplary embodiments and examples. As will be apparent to those of skill in tire art other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are to be construed to include all such embodiments and equivalent variations.

[0215] The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety.

Claims

WHAT IS CLAIMED IS:

1. An infusing means for infusing a viscous liquid having a viscosity of from about 10 centipoise (cP) to about 40 cP into a single subcutaneous infusion site in a subject at an infusion rate of not less than about 240 inL / hr, e.g., not less than about 260 inL / hr, e.g., not less than about 280 mL / hr, e.g., not less than about 300 mL / hr with a pressure drop across the infusing means of not more than about 12 pounds per square inch (psi), e.g., not more than about 10 pounds per square inch (psi) at about 240 mL / hr, e.g., at about 260 mL / hr, e.g., at about 280 mL / hr, e.g., at about 300 mL / hr.

2. The infusing means according to claim 1, wherein the infusing means is a needle having a nominal 24-gauge outside diameter.

3. The infusing means according to claim 1 or claim 2, wherein the infusing means is a needle having a nominal 24-gauge outside diameter, and an inner diameter of from about 0.35 millimeter (mm) to about 0.5 mm.

4. The infusing means according to any of claims 1-3, wherein the insertion depth of the infusing means is from about 6 mm to about 15 mm.

5. The infusing means of claim 3, wherein the inner diameter is not less than about 0.36 mm, not less than about 0.37 mm. not less than about 0.38 mm. not less than about 0.39 mm, not less than about 0.40 mm, not less than about 0.41 mm, not less than about 0.42 mm, not less than about 0.43 mm, not less than about 0.44 mm, or not less than about 0.45 mm.

6. The infusing means of claim 3. wherein the inner diameter is substantially constant along a length direction of the needle and has a value within a range of from about 0.38 mm to about 0.43 mm, from about 0.39 mm to about 0.44 mm, or from about 0.40 to about 0.45 mm.

7. The infusing means of claim 3, wherein the inner diameter is about 0.41 mm, about 0.42 mm, or about 0.43 mm.

8. The infusing means of any of claims 2-7, wherein the outer diameter is about 0.56 mm.

9. The infusing means according to any of claims 1-8, wherein the infusion means is a subcutaneous needle with a nominal 24-gauge outside diameter, the needle defined by a wall with a thickness within a range of from about 100 pm to about 200 pm. or about 118 pm to about 186 pm.

10. The infusing means of any of claims 1-9, wherein the total length of the infusion means is not more than about 34 mm, not more than about 33 mm, not more than about 32 mm, not more than about 31 mm, or not more than about 30 mm.

11. The infusing means of any claims 1-10, wherein the infusion means allows infusion of die viscous fluid through the infusion means to the subject at the flow rate of not less than about 240 mL / lir, e.g., not less than about 260 mL / lir, e.g., not less than about 280 inL / hr. e.g., not less than about 300 mL / hr, e.g., not less than 350 mL / hr, e.g., not less than about 400 mL / hr, e.g., not less than about 450 mL / hr, e.g., not less than about 500 mL / hr, e.g., not less than about 550 mL / hr, or not less than about 600 mL / hr.

12. The infusing means of any of claims 1-11. wherein the insertion length of the infusion means is about 12 mm, about 13 mm, about 14 mm, about 15 mm or about 16 mm.

13. The infusing means of any of claims 1-12. wherein the infusion means further comprises: a fluid delivery means having a first end for receiving the viscous fluid and a second end for fluidly connecting with the infusion means.

14. The infusing means of any of claims 1-13. wherein the infusion means further comprises: a fluid delivery means having a first end for receiving the viscous fluid and a second end for fluidly connecting with the infusion means, wherein the fluid delivery means has an inner diameter of not less than about 1 mm, not less than about 1.1 mm, not less than about 1.2 mm. not less than about 1.3 mm, not less than about 1.4 mm, or not less than about 1.5 mm.

15. The infusing means of any of claims 1-14, wherein the infusion means comprises:(a) a first segment at configured to be at least partially inserted into the second end of the fluid deliver means;(b) a second segment configured to be at least partially inserted into the subject at the first infusion site, wherein the second segment defines the insertion length; and(c) an intermediate segment between the first and second segments and connecting the first segment with the second segment, wherein each of the first and second segments is substantially straight, and the intermediate segment is arched and has a radius of not less than about 0.5 mm and a predetermined central angle.

16. The infusing means of claim 15, wherein the first segment has a length of not more than about 14 mm, not more than about 13 mm, not more than about 12 mm, not more than about 11 mm, not more than about 10 mm, not more than about 9 mm, or not more than about 8 mm.

17. The infusing means of any of claims 15-16, wherein die second segment has a length of about 12 mm, about 13 mm, about 14 mm, about 15 mm, or about 16 mm.

18. The infusing means of any of claims 15-17, wherein die intermediate segment has the predetermined central angle of from about 45° to about 90°.

19. The infusing means of any of claims 15-18, wherein the radius of die intermediate segment is not less than 2.2 mm.

20. The infusing means of any of claims 13-19, wherein the infusing means further comprises: a hub to accommodate the second end of the fluid de lively means and the first segment of the infusing means, wherein(i) the hub comprises a port adjacent to the second end of the fluid delivery means, and (ii) the second end of the fluid deliver,' means and the first segment of the infusing means are secured to the hub by an adhesive injected through the port.

21. The infusing means of claim 20, wherein the hub supports at least partially the intermediate segment of the infusing means.

22. The infusing means of any of claims 1-20. wherein the viscous fluid is a pharmaceutical formulation of about 20% (w / w) IgG.

23. A subcutaneous infusion kit comprising:(a) an infusing means of any of claims 1-22: and(b) an immunoglobulin G (IgG) fonnulation having a concentration of IgG from about 18% (w / v) to about 22% (w / v) and a viscosity of from about 10 centipoise (cP) to about 40 cP.

24. The subcutaneous infusion kit according to claim 23, wherein the infusing means is a component of a needle set comprising: a hub comprising a tunnel and a port, wherein (i) the tunnel comprises a first opening at a first end of the tunnel and a second opening at a second end of the tunnel, and (ii) the port is formed on a side wall of the tunnel;a tube comprising a first end and a second end, wherein (i) the first end is disposed outside of the hub for receiving the fluid and (ii) the second end is inserted into the tunnel through the first opening of the tunnel; and a subcutaneous needle comprising a first segment, a second segment and an intermediate segment, wherein (i) the first segment is at least partially inserted into the tunnel through the second opening of the tunnel and at least partially inserted into the second end of the tube, (ii) the second segment is to be inserted at least partially into the subject at the first infusion site, (iii) the intermediate segment is formed between the first and second segments and connects the first segment with the second segment, and (iv) the intermediate segment is arched and has a radius of not less than about 0.5 mm and a central angle of from about 45° to about 90°, wherein the second end of the tube and the first segment of the subcutaneous needle are secured to the hub by an adhesive injected into the tunnel through the port.

25. The subcutaneous infusion kit according to any of claims 23-24, wherein the second segment of the subcutaneous needle has a length to facilitate an insertion length of not less than about 12 mm. not less than about 13 mm, not less than about 14 mm, not less than about not less than about 15 mm, or not less than about 16 mm to reduce leakage at an infusion site.

26. The subcutaneous infusion kit of any of claims 23-25, wherein the subcutaneous needle is a subcutaneous nominal 24-gauge needle having an outer diameter of about 0.56 mm, an inner diameter of not less than 0.35 mm and a total length of at most 35 mm.

27. The subcutaneous infusion kit of any of claims 23-26, further comprising a vessel containing recombinant human hyaluronidase.

28. The subcutaneous infusion kit of any of claims 23-27, further comprising instructions to the user detailing one or more of assembly of an infusion assembly comprising the infusing means, the fluid delivery means and the hub; charging the infusion assembly with the IgG formulation, the recombinant human hyaluronidase or a combination thereof; inserting the infusion assembly at an infusion site; and infusing the IgG formulation, the recombinant human hyaluronidase or a combination thereof.

29. A method of infusing a viscous fluid into a first infusion site of a subject, the method comprising:(a) inserting into the first infusion site a first infusion means according to any of claims 1-22; and(b) commencing infusion though the first infusion means, ramping to a flow rate of not less than about 240 mL / hr, e.g., not less than about 260 mL / lir, e.g., not less than about 280 mL / hr. e.g., not less than about 300 mL / hr with a pressure drop across the first infusion means of not more than about 12 pounds per square inch (psi) at about 240 mL / hr, e.g., at about 260 mL / hr, e.g., at about 280 mL / hr, e.g., at about 300 mL / hr.

30. The method according to claim 29, wherein the viscous fluid comprises a medicament.

31. The method according to any of claims 29-30, wherein the viscous fluid comprises a medicament, which is a protein medicament.

32. The method according to any of claims 29-31, wherein the viscous fluid comprises a protein medicament which is an antibody.

33. The method according to any of claims 29-32, wherein the protein medicament is an antibody at a concentration of about 20% (w / v).

34. The method according to any of claims 29-33, wherein the viscous fluid is a solution of IgG at about 20% (w / v).

35. The method according to any of claims 29-34, wherein the viscosity of the viscous fluid is not less than about 12 cP, 14 cP, 16 cP, 18 cP, 20 cP, 22 cp. 24 cP, 26 cp, 28 cP, or 30 cP.

36. The method according to any of claims 29-35, wherein the method further comprises:(c) infusing a pharmaceutical formulation of recombinant human hyaluronidase into the first infusion site through the first infusing means.

37. The method according to any of claims 29-36. further comprising:(al) inserting into a second infusion site a second infusion means according to any of claims 1-22; and(bl) commencing infusion though the second infusion means, ramping to a flow rate of not less than about 240 mL / hr. e.g.. not less than about 260 mL / hr. e.g., not less than about 280 mL / hr. e.g., not less than about 300 mL / hr. with a pressure drop across the second infusion means of not more than about 12 pounds per square inch (psi) at about 240 mL / hr, e.g., at about 260 mL / hr, e.g., at about 280 mL / hr. e.g., at about 300 mL / hr.

38. The method according to claim 37, wherein the method further comprises:(cl) infusing a pharmaceutical formulation of recombinant human hyaluronidase into the second infusion site through the second infusing means.

39. The method according to any of claims 29-38, wherein the method is performed in accordance with user administration / dosing instructions accompanying a subcutaneous infusion kit comprising:(a) an infusing means for infusing a viscous liquid having a viscosity of from about 10 centipoise (cP) to about 40 cP into a single subcutaneous infusion site in a subject at an infusion rate of not less than about 240 mL / hr, e.g., not less than about 260 mL / hr, e.g., not less than about 280 mL / hr, e.g., not less than about 300 mL / hr with a pressure drop across the infusing means of not more than about 12 pounds per square inch (psi) 240 mL / hr, e.g., at about 260 mL / hr, e.g., at about 280 mL / hr, e.g., at about 300 mL / hr;(b) an immunoglobulin G (IgG) fonnulation having a concentration of IgG from about 18% (w / v) to about 22% (w / v) and a viscosity of from about 10 centipoise (cP) to about 40 cP; and(c) optionally, a pharmaceutical formulation of recombinant human hyaluronidase.

40. The method according to any of claims 38-39. wherein the pharmaceutical formulation of IgG and the pharmaceutical formulation of recombinant human hyalouronidase are administered simultaneously to the first infusion site, the pharmaceutical formulation of recombinant human hyalouronidase is administered to the first infusion site first, followed by the pharmaceutical formulation of IgG. or the pharmaceutical formulation of IgG is administered first, followed by the pharmaceutical formulation of recombinant human hyalouronidase.

41. User administration / dosing instructions for infusing a pharmaceutical formulation of 20% (w / v) IgG to a first infusion site utilizing a first infusion means configured to infuse the pharmaceutical formulation at a maximum infusion rate of not less than about 240 mL / hr, e g., not less than about 260 mL / hr, e.g., not less than about 280 mL / hr, e.g., not less than about 300 mL / hr with a pressure drop of not more than about 12 pounds per square inch (psi), e.g., not more than about 10 pounds per square inch (psi) across the infusion means at about 240 mL / hr. e.g., at about 260 mL / hr, e.g., at about 280 mL / hr, e.g., at about 300 mL / hr, wherein the pharmacal formulation has a viscosity of from about 10 centipoise (cP) to about 40 cP.

42. The instructions according to claim 41, wherein the instructions are provided to the user in electronic form or as a tangible package insert accompanying a subcutaneous infusion kit for a pharmaceutical formulation of 20% IgG.

43. The instructions according to any of claims 41-42, further comprising administration / dosing instructions for infusing at the first infusion site a pharmaceutical formulation of recombinant human hyaluronidase.

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