SYRINGE

Abstract

There is provided a syringe comprising:a reservoir filled with 2 ml of a 150 mg / ml formulation of omalizumab, wherein 2 ml of the 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter > 10 µm and / or 600 or fewer particles having a diameter > 25 µm; and which syringe further comprises:a stopper, anda 27 gauge needle; andthe syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper. Figure 5 accompanies the abstract.

Description

Title of the invention: SYRINGE

[0001] This application claims the benefit of European patent applications 23188544.3 filed on July 28, 2023 and 24171754.5 filed on April 22, 2024.

[0002] The present disclosure relates to methods of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering a 150 mg / ml formulation of omalizumab to the patient, which omalizumab formulation is administered subcutaneously by means of a syringe. The present disclosure also relates to a 150 mg / ml formulation of omalizumab for use in accordance with the methods described herein. The present disclosure also relates to syringes comprising a reservoir filled with a 150 mg / ml formulation of omalizumab and configured to carry out the methods described herein.This disclosure also relates to the use of a 150 mg / ml formulation of omalizumab for the manufacture of a medicament for any of the methods of treatment disclosed herein. Background of the invention

[0003] Omalizumab is a recombinant DNA-derived humanized IgGlk monoclonal antibody that selectively binds to human immunoglobulin E (IgE) and is used to treat allergic asthma, chronic urticaria and nasal polyps, IgE-mediated food allergy, and chronic spontaneous urticaria.

[0004] When omalizumab first came to market in 2003, it was available only as a dry lyophilized powder (XOLAIR® lyophilized powder). To administer XOLAIR® to the patient, it was necessary to reconstitute the powder with sterile water and then inject the resulting solution. The method for reconstituting XOLAIR® lyophilized powder involves adding 0.9 or 1.4 ml of water for injection to a vial of 75 or 150 mg of lyophilized powder, respectively, and swirling the vial for approximately 5 to 10 seconds every 5 minutes for approximately 15 to 20 minutes to allow the powder to dissolve completely. Because this process is time-consuming and complex, XOLAIR® lyophilized powder can only be administered by a healthcare professional, limiting ease of use and patient experience.As described in document US2002 / 0045571, this reconstituted formulation is approximately 80 times more viscous than water at 25°C.

[0005] Following its initial approval, omalizumab (XOLAIR®) became available as a 75 mg / 0.5 ml or 150 mg / 1 ml solution in a pre-filled single-dose syringe for subcutaneous delivery, the syringe having a 26 gauge needle. This eliminated the need for reconstitution immediately prior to administration, greatly improving ease of use, patient experience, and ultimately patient acceptance and outcomes. In addition, XOLAIR® was approved for self-injection, further improving ease of use.

[0006] Subcutaneous injection of a 150 mg / ml formulation of omalizumab offers advantages (Shi et al. Subcutaneous Injection Performance in Yucatan Miniature Pigs with and without Human Hyaluronidase and Auto-injector Tolerability in Humans. AAPS PharmSciTech. January 2021;22(1):39). First, it offers the possibility of self-administration, which limits the need for patients to visit healthcare providers to receive treatment. Second, subcutaneous injections are typically less painful than other injections such as intravenous and intramuscular injections. As a result, subcutaneous injection is often the preferred route of delivery for patients and also healthcare professionals.

[0007] However, there are still challenges associated with current omalizumab dosing regimens and administration methods. First, omalizumab is usually administered at a dose of 150 mg to 375 mg subcutaneously every 2 to 4 weeks, but only 15% to 20% of patients can receive their XOLAIR® treatment with a single injection using the currently available doses of 75 mg / 0.5 ml and 150 mg / 1 ml. Second, omalizumab formulations are very viscous and therefore subcutaneous injection using the currently available pre-filled syringes requires high injection force and long injection duration. As a result, patients and caregivers may not be able to perform omalizumab injections with confidence.Third, omalizumab injections can cause injection-site reactions—indeed, in asthmatic patients, injection-site reactions of all severities occur at a rate of 45%, and severe injection-site reactions occur at a rate of 12%. This problem is exacerbated by the need to administer each injection to a new injection site, and by the fact that 80% to 85% of patients must administer the contents of multiple syringes to reach their prescribed dose. Each of these difficulties negatively impacts the patient experience and convenience, and thus negatively impacts patient adherence to omalizumab therapy. In chronic conditions such as those treated with omalizumab, nonadherence is estimated to be approximately 50% (Baryakova et al. 'Overcoming barriers to patient adherence: the case for developing . innovative drug delivery systems'. Nature Reviews Drug Discovery. March 2023; volume 22, pages 387-409). Therefore, there is a need to address the above challenges to improve usability and patient experience, thereby improving patient adherence and outcomes. Summary of the invention

[0008] Omalizumab is currently proposed for use in the treatment of one or more of: allergic asthma; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids. The antibody is administered to the patient subcutaneously as a 150 mg / ml formulation of omalizumab, using a syringe having a reservoir filled with 0.5 ml or 1 ml of the 150 mg / ml formulation of omalizumab.

[0009] It is an object of the invention to provide new uses of omalizumab, new syringes, and new administration / dosing regimens for omalizumab that can overcome the above obstacles to improve ease of use, patient experience, patient compliance, and outcomes when using omalizumab. In particular, it is an object of the invention to provide new uses that reduce the required number of individual injections per treatment, reduce the injection time and forces required to deliver the omalizumab formulation subcutaneously, and reduce the risk of injection site reactions. It is also an object of the invention to achieve these improvements without loss of stability and purity of the antibody, and while achieving bioequivalence with known syringes.

[0010] There are, however, significant difficulties in providing a mode of administration of omalizumab that achieves these objects, because omalizumab is abnormally viscous in solution, particularly at the high concentration required for a 150 mg / ml dose. These difficulties are described in more detail below.

[0011] The formulation of XOLAIR® is 150 mg / ml antibody with 42.1 mg / ml L-arginine hydrochloride, 1.37 mg / ml L-histidine, 2.34 mg / ml L-histidine hydrochloride monohydrate, 0.4 mg / ml polysorbate 20 as an aqueous solution (in Sterile Water for Injection (USP)). Omalizumab Xolair® 75 mg / 0.5 ml, 150 mg / 1 ml and 300 mg / 2 ml all have the same formulation, with a high concentration of 150 mg / ml antibody. The viscosity of omalizumab XOLAIR® is 12-14 mPa.s at room temperature. In one experiment, the viscosity measured at a shear rate of 200 s 1 was: 24.7 ± 0.5 mPa.s at 5.0 ± 0.2°C, 15.3 ± 0.5 mPa.s at 15.0 ± 0.2°C, 11.4 ± 0.5 mPa.s at 25.0 ± 0.2°C and 7.2 ± 1.2 mPa.s at 40.0 ± 0.2°C.

[0012] The high viscosity of omalizumab formulations presents several difficulties in obtaining the subject matter of the invention.

[0013] In general, the higher the viscosity of a fluid, the more force and time it takes to inject it using a syringe. Patients may struggle to apply high injection forces to syringes and therefore may fail to push the stoppers to their terminal positions in the syringe to administer a full dose. In addition, high injection forces increase the risk of syringe breakage.

[0014] Long injection times greatly reduce patient experience and compliance. It is generally accepted that patients can comfortably hold a syringe in place for a maximum of 20 seconds. Therefore, when using syringes that inject medications for a duration approaching 20 seconds, there is an increased risk of incomplete administration because patients prematurely withdraw the syringe from the injection site due to discomfort.

[0015] These problems of high injection forces and long injection times are also exacerbated when administering larger volumes of omalizumab (> 1 ml) because the larger the volume of fluid that needs to be injected, the more force and time it takes to inject it. In addition, larger administration volumes also result in higher pressures at the injection site, leading to a higher likelihood of injection site reaction and associated injection errors.

[0016] Lubricants may be incorporated inside a syringe (e.g., by siliconization) to reduce injection force and duration, but they may cause protein aggregation, which reduces the purity and efficacy of the omalizumab solution. In addition, protein aggregation may cause blockages, thus requiring more force to inject the solution, reducing ease of use. Finally, it is necessary to keep in mind that regulatory and international standards must be met when making any improvements to currently available omalizumab pre-filled syringes.

[0017] Studies have been conducted to investigate the impact of viscosity, volume, and flow rate on the patient's experience of subcutaneous injection, see: 1) Rini et al. Enabling faster subcutaneous delivery of larger volume, high viscosity fluids. Expert Opinion on Drug Delivery. 2022, Vol. 19, No. 9, 1165-1176, 2) Roberts et al. Novel cannula design improves large volume auto-injection rates for high viscosity solutions. Drug Delivery, 29: 1 43-51 and 3) Berteau et al. Evaluation of the impact ofviscosity, injection volume, and injection flow rate on subcutaneous injection tolerance. Medical Devices: Evidence and Research 2015: 8473-484. However, some of these studies were conducted on non-biological solutions and therefore the applicability of the findings to the uses of romalizumab is limited. Berteau et al. (2015) and Rini et al. (2022) make it clear that it is difficult to accurately predict the behavior of any biologic agent when administered subcutaneously because the unique characteristics of each drug will impact its behavior. These unique characteristics include particle size, shape, sedimentation / resuspension characteristics and aggregation / agglomeration potential, as well as viscoelastic flow behavior. Berteau et al.(2015) conclude that each drug delivery device for high-speed, large-volume subcutaneous injection should be designed specifically for each drug to optimize ease of use, patient experience, patient compliance, and outcomes.

[0018] The inventors have overcome the difficulties set forth above to provide novel uses of romalizumab and methods of treatment that address the various problems involved. According to one aspect of the invention, there is provided a method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps;moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient X ml of a 150 mg / ml formulation of omalizumab, wherein X is 2, and wherein X ml of 150 mg / ml formulation of omalizumab are administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, wherein X ml of 150 mg / ml formulation of omalizumab have 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a stopper, and a 27 gauge needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper. ;

[0019] Providing a syringe containing 2 ml of a 150 mg / ml formulation of omalizumab reduces the required number of individual injections per treatment for patients prescribed a dose greater than 150 mg of omalizumab. Reduced dosing frequency improves patient adherence and experience. (Baryakova et al. 2023). In addition, a small number of injections leads to a reduced risk of injection site reaction, which further improves patient adherence and experience. In this way, the present invention improves ease of use, patient experience, patient adherence, and outcomes when using omalizumab.

[0020] As will be demonstrated below, providing a syringe containing a 27 gauge needle reduces the time required to deliver romalizumab, as compared to currently available syringes. In this way, the present invention reduces the injection time required to administer the dose. In addition, because the needle gauge is larger than that of the prior art, the needle of the present invention has a smaller outer diameter, which reduces pain during needle insertion. Thus, the present invention improves ease of use, patient experience, patient compliance, and outcomes when using omalizumab.

[0021] In some embodiments, the needle has one of: (a) a minimum internal diameter of 0.277 mm; (b) a minimum internal diameter of 0.191 mm; (c) a minimum internal diameter of 0.184 mm; and (d) a minimum internal diameter of 0.241 mm.

[0022] Larger minimum internal diameters further reduce the injection time required to administer romalizumab.

[0023] According to a second aspect of the invention, there is provided a method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient X ml of a 150 mg / ml formulation of omalizumab, wherein X is 2, 1 or 0.5, and wherein X ml of 150 mg / ml formulation of omalizumab is administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, which X ml of 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a stopper, and a 25 gauge to 29 gauge needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, and wherein one of the following is satisfied when a constant force of 10 N is applied to the stopper, a) when X is 2, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 16 seconds; b) when X is 1, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 5 seconds; and c) when X is 0.5, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 4 seconds.

[0024] Systems for measuring syringe injection time and methods of configuring such systems are well known in the art.

[0025] The invention reduces the required injection forces, improving ease of use and making it more likely that a full dose will be administered. Thus, the present invention improves ease of use, patient experience, patient compliance and outcomes when using omalizumab.

[0026] In certain embodiments of the invention wherein X is 2, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in one or more of: (a) less than 8.5 seconds when a constant force of 17 N is applied to the stopper; and b) less than 5 seconds when a constant force of 30 N is applied to the stopper.

[0027] In some embodiments in which X is 2, the syringe is configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle in one or more of: a) about 16 seconds to about 14 seconds when a constant force of 10 N is applied to the stopper; (b) about 8.5 seconds to about 6 seconds when a constant force of 17 N is applied to the plug; and c) about 5 seconds to about 4 seconds when a constant force of 30 N is applied to the stopper.

[0028] In some embodiments wherein X is 1, the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 5 seconds, less than 4.75 seconds, less than 4.5 seconds, less than 4.25 seconds, or about 4 seconds when a constant force of 10 N is applied to the stopper; (b) less than 3 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds when a constant force of 30 N is applied to the stopper.

[0029] In some embodiments in which X is 1, the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 5 seconds to about 4 seconds, less than 4.75 seconds to about 4 seconds, less than 4.5 seconds to about 4 seconds, less than 4.25 seconds to about 4 seconds, or about 4 seconds when a constant force of 10 N is applied to the stopper; (b) less than 3.5 seconds to about 2 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30 N is applied to the stopper.

[0030] In some embodiments wherein X is 0.5, the syringe is for expelling X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 2 seconds when a constant force of 17 N is applied to the stopper; and b) less than 1 second when a constant force of 30 N is applied to the stopper.

[0031] In certain embodiments in which X is 0.5, the syringe is intended to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 4 seconds to about 2 seconds when a constant force of 10 N is applied to the stopper; (b) less than 2 seconds to about 1 second when a constant force of 17 N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30 N is applied to the plug.

[0032] In certain embodiments of the invention, the syringe contains: (a) at least 76% of the major charge variant of romalizumab, measured by ion exchange chromatography after it has been filled with a 150 mg / ml solution of omalizumab stored at 5°C ± 3°C; and / or (b) at least 77% of the major charge variant of romalizumab, measured by ion exchange chromatography after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 3°C for 2.5 months.

[0033] In some embodiments, the percentage of major charge variant of omalizumab in the syringe, measured using exchange chromatography ions, is reduced by 2% or less after the syringe has been stored at 5°C ± 3°C for 2.5 months (e.g. measured from filling).

[0034] In certain embodiments of the invention, the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is at least: a) 62% after filling with a 150 mg / ml solution of omalizumab stored at 5°C ± 3°C; and / or b) 62% after it was filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 3°C for 2.5 months.

[0035] In some embodiments of the invention, the proportion of the first peak of the syringe, measured using hydrophobic chromatography, is reduced by 0.4% or less after the syringe has been stored at 5°C ± 3°C for 2.5 months.

[0036] In some embodiments of the invention, the syringe contains at least 0.4 mg / ml of polysorbate 20 after filling with a 150 mg / ml solution of omalizumab stored at 5°C ± 3°C.

[0037] In some embodiments of the invention, the syringe contains at least 69% of the major charge variant of romalizumab, as measured by ion exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 3°C for 1.5 months.

[0038] In some embodiments of the invention, the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is at least: a) 56% for the syringe after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 3°C for 1.5 months; and / or b) 51% for the syringe after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 3°C for 2.5 months.

[0039] In some embodiments, the syringe contains: a) at least 0.4 mg / ml polysorbate 20 after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 3°C for 1.5 months; and / or b) at least 0.3 mg ml polysorbate 20 after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 3°C for 6 months.

[0040] The percentages of major charge variant of romalizumab, the peak by hydrophobic chromatography, and the polysorbate 20 content are measures of the purity and stability of romalizumab. As will be demonstrated below, the present invention preserves the purity and stability of omalizumab in a manner similar to that of current uses.

[0041] In some embodiments of the invention, the needle has a gauge of one of: 23 gauge, 24 gauge, 25 gauge, 26 gauge, 27 gauge, 28 gauge, 29 gauge, 30 gauge, 31 gauge, and 32 gauge.

[0042] In some embodiments of the invention, the needle has one of a gauge: a) 23 gauge defining a minimum internal diameter of 0.370 mm, b) 23 gauge defining a minimum internal diameter of 0.317 mm, c) 24 gauge defining a minimum internal diameter of 0.343 mm, d) 24 gauge defining a minimum internal diameter of 0.280 mm, e) 25 gauge defining a minimum internal diameter of 0.292 mm, f) 25 gauge defining a minimum internal diameter of 0.232 mm, g) 26 gauge defining a minimum internal diameter of 0.292 mm, h) 26 gauge defining a minimum internal diameter of 0.232 mm, i) 27 gauge defining a minimum internal diameter of 0.277 mm, j) 27 gauge defining a minimum internal diameter of 0.191 mm, k) 27 gauge defining a minimum internal diameter of 0.184 mm, 1) 27 gauge defining a minimum internal diameter of 0.241 mm, m) 28 gauge defining a minimum internal diameter of 0.133 mm, n) 28 gauge defining a minimum internal diameter of 0.190 mm, o) 29 gauge defining a minimum internal diameter of 0.265 mm,p) 29 gauge defining a minimum internal diameter of 0.240 mm, q) 29 gauge defining a minimum internal diameter of 0.190 mm, r) 29 gauge defining a minimum internal diameter of 0.133 mm, s) 30 gauge defining a minimum internal diameter of 0.240 mm, t) 30 gauge defining a minimum internal diameter of 0.190 mm, u) 30 gauge defining a minimum internal diameter of 0.165 mm, v) 30 gauge defining a minimum internal diameter of 0.133 mm, w) 31 gauge defining a minimum internal diameter of 0.176 mm, x) 31 gauge defining a minimum internal diameter of 0.146 mm, y) 31 gauge defining a minimum internal diameter of 0.125 mm, z) 31 gauge defining a minimum internal diameter of 0.114 mm, aa) 32 gauge defining a minimum internal diameter of 0.146 mm, bb) 32 gauge defining a minimum internal diameter of 0.125 mm, ce) 32 gauge defining a minimum internal diameter of 0.105 mm, and dd) 32 gauge defining a minimum internal diameter of 0.089 mm. ,

[0043] In some embodiments of the invention, the needle is 25 gauge to 29 gauge, preferably 26 gauge to 28 gauge, most preferably 27 gauge.

[0044] In some embodiments, when the needle is 25 gauge, the needle has one of: (a) a minimum internal diameter of 0.292 mm, and (b) a minimum internal diameter of 0.232 mm.

[0045] In some embodiments, when the needle is 26 gauge, the needle has one of: a) a minimum internal diameter of 0.292 mm, and b) a minimum internal diameter of 0.232 mm.

[0046] In some embodiments, when the needle is 27 gauge, the needle has one of: (a) a minimum internal diameter of 0.277 mm; (b) a minimum internal diameter of 0.191 mm; (c) a minimum internal diameter of 0.184 mm; and (d) a minimum internal diameter of 0.241 mm.

[0047] In some embodiments, when the needle is 28 gauge, the needle has one of: a) a minimum internal diameter of 0.133 mm; and b) a minimum internal diameter of 0.190 mm.

[0048] In some embodiments, when the needle is 29 gauge, the needle has one of: (a) a minimum internal diameter of 0.265 mm; (b) a minimum internal diameter of 0.240 mm; (c) a minimum internal diameter of 0.190 mm; and (d) a minimum internal diameter of 0.133 mm; preferably the needle has a minimum internal diameter of 0.240 mm or 0.265 mm.

[0049] In another preferred embodiment of the invention, the needle is 29 gauge. In another preferred embodiment of the invention, the needle is 29 gauge and has a minimum inner diameter of 0.240 mm. In another preferred embodiment of the invention, the needle is 29 gauge and has a minimum inner diameter of 0.265 mm.

[0050] In some embodiments of the invention, the stopper has a fluororesin on the product-contacting side or an ethylene tetrafluoroethylene (ETFE) barrier film lamination. The lamination of the stopper reduces friction, reducing injection forces, reducing injection time, and making it more likely that a full dose will be delivered. In this way, the present invention improves ease of use, patient experience, patient compliance, and outcomes when using omalizumab.Additionally, lamination helps prevent contamination between the stopper material and romalizumab, preserving the stability and purity of romalizumab.

[0051] In some embodiments of the invention, the stopper has a UV-cured B2-40 lubricating coating or is lubricated with a 1000 cSt silicone oil. The stopper coating reduces friction, reducing injection forces and reducing injection time and making it more likely that a full dose will be delivered. In this way, the present invention improves ease of use, patient experience, patient compliance, and outcomes during the use of omalizumab. In addition, the cap coating helps prevent contamination between the cap material and romalizumab, preserving the stability and purity of romalizumab.

[0052] In some embodiments of the invention, the syringe has an inner coating of between 0.3 and 1.0 mg (e.g., 0.4 ± 0.2 mg or 0.7 ± 0.2 mg) of polydimethylsiloxane. The inner coating of the syringe reduces friction, reducing injection forces, reducing injection time, and making it more likely that a full dose will be administered. In this way, the present invention improves ease of use, patient experience, patient compliance, and outcomes when using omalizumab. In addition, the inner coating of the syringe helps preserve the stability and purity of romalizumab.

[0053] In some embodiments of the invention, the needle has 3 bevels on its distal surface or 5 bevels on its distal surface. The beveled distal surface reduces pain during needle insertion, improving patient experience and thus patient compliance and outcomes.

[0054] In certain embodiments of the invention, the apparent viscosity of the 150 mg / ml formulation of omalizumab at a shear rate of 200 s 1 is: 24.7 ± 0.5 mPa.s at 5.0 ± 0.2°C, 15.3 ± 0.5 mPa.s at 15.0 ± 0.2°C, 11.4 ± 0.5 mPa.s at 25.0 ± 0.2°C or 7.2 ± 1.2 mPa.s at 40.0 ± 0.2°C.

[0055] In some embodiments of the invention, the syringe has a latex-free needle shield. The latex-free needle shield reduces the risk of injection site reaction, improving the patient experience and therefore patient compliance and outcomes.

[0056] In some embodiments of the invention the syringe has a round flange at a proximal end of the reservoir. In some embodiments of the invention the round flange has a maximum diameter of 11 ± 0.25 mm or 14.7 ± 0.25 mm. The round flange helps the syringe better withstand large injection forces, reducing the risk of syringe breakage and improving the patient experience. This is particularly advantageous when the syringe of the present invention is used in combination with an auto-injector that holds the syringe by the flange.

[0057] In some embodiments of the invention, when X is 1 or 0.5, the syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 6.35 mm ± 0.05 mm.

[0058] In some embodiments of the invention, when X is 1 or 0.5, when the cap is not inserted into the reservoir, it has one of: (a) a maximum external diameter of 6.67 mm to 7.10 mm and / or a length of 7.85 ± 0.4 mm; and (b) a maximum external diameter of 6.70 ± 0.15 mm and / or a length of 7.85 ± 0.4 mm.

[0059] In some embodiments of the invention, when X is 1 or 0.5, the stopper has at least one circumferential rib having an outer diameter of 6.60 ±0.15 mm. The circumferential ribs help reduce contact between the stopper and the syringe, minimizing friction and thus reducing injection force and duration. In this way, the present invention improves patient experience, adherence, and results.

[0060] In some embodiments of the invention, when X is 2, the syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 8.65 mm ± 0.05 mm.

[0061] In some embodiments of the invention, when X is 2, the plug has a maximum external diameter of 9.05 ± 0.15 mm and / or a length of 7.70 ± 0.4 mm when not inserted into the reservoir.

[0062] In some embodiments of the invention, when X is 2, the stopper has at least one circumferential rib having an outer diameter of 9.00 ±0.15 mm. The ribs help reduce contact between the stopper and the syringe, minimizing friction and thus reducing injection force and duration. In this way, the present invention improves patient experience, compliance, and results. In some embodiments of the invention, the peel force for moving the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) about 2 N to about 4 N after storage at 5°C ± 3°C for 2.5 months after filling; b) about 2 N to about 4 N after storage at 5°C ± 3°C for 6 months after filling.

[0063] In some embodiments of the invention, the peeling force for moving the plug of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) about 2 N to about 3.5 N at 25°C ± 3°C after filling; b) about 2 N to about 4.5 N after storage at 25°C ± 3°C for 1.5 months after filling; (c) about 2.5 N to about 5 N after storage at 25°C ± 3°C for 2.5 months after filling; and / or d) about 2.5 N to about 5.5 N after storage at 25°C ± 3°C for 6 months after filling.

[0064] In some embodiments of the invention, the peeling force for moving the plug of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: (a) about 3 N to about 4.5 N after storage at 40°C ± 3°C for 1.5 months after filling; and b) about 3 N to about 5 N after storage at 40°C ± 3°C for 2.5 months after filling.

[0065] The syringes of the present invention require a lower debonding force than prior art syringes, reducing injection force and duration. In addition, the debonding forces of the syringes of the present invention are less variable than for prior art syringes. Syringe reliability has been shown to be an important factor in reducing injection errors (Menzella et al. Self-administration of omalizumab: why not? A literature review and expert opinion. Expert Opinion on Biological Therapy; Vol. 21, 2021 - 4th issue, pages 499-507). In this way, the present invention reduces the risk of injection errors, improving patient experience, patient compliance and outcomes.

[0066] Needle phobia reduces patient adherence (Baryakova et al.). The needle protector device of the present invention covers the needle to improve the experience of patients with needle phobia, improving patient adherence and outcomes.

[0067] In some embodiments of the invention, the syringe is provided in a needle shield device comprising a needle sleeve and a plunger; and wherein manual force can be applied to the plunger to expel the 150 mg / ml formulation of omalizumab and unlock the needle sleeve so that the needle sleeve can cover the needle after injection.

[0068] In certain embodiments of the invention, the syringe is manufactured by a method comprising: aseptic filling of the reservoir with the 150 mg / ml formulation of omalizumab; and clogging the tank with the cap.

[0069] In certain embodiments of the invention, the aseptic filling is carried out by means of a peristaltic pump or a stainless steel piston pump.

[0070] In some embodiments of the invention, prior to aseptic filling, the reservoir and needle are sterilized by ethylene oxide gas treatment, electron beam (e-beam) and / or autoclave steam sterilization.

[0071] Although the present claims relate to a method of treatment in which the 150 mg / ml formulation of omalizumab is administered subcutaneously by means of a syringe, it will be understood that the syringes of the present invention may be provided alone, or in combination with an auto-injector, and that the present invention also encompasses novel dosage regimens of omalizumab utilizing the syringe of the present invention. Accordingly, additional clauses covering the syringe of the present invention are set forth below.

[0072] The invention has been described in relation to the treatment of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids. More particularly, it may be used for one or more of: moderate to severe persistent asthma in adults and pediatric patients aged 6 years and older with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled with inhaled corticosteroids; chronic rhinosinusitis with nasal polyps (CRSwNP) in adult patients aged 18 years and older with an inadequate response to nasal corticosteroids, as adjunctive maintenance therapy; IgE-mediated food allergy in adults and pediatric patients aged 1 year and older for the reduction of allergic (Type I) reactions, including anaphylaxis, that may occur upon accidental exposure to one or more foods (and for use in conjunction with food allergen avoidance); and / or chronic spontaneous urticaria (CSU) in adults and adolescents aged 12 years and older who remain symptomatic despite H1 antihistamine treatment. Brief description of the drawings

[0073] [Fig.l] [Fig.l] is a schematic diagram of a syringe for subcutaneous delivery in accordance with the prior art.

[0074] [Fig.2] [Fig.2] shows the dosage regimens currently used to administer a 150 mg / ml formulation of omalizumab.

[0075] [Fig.3] [Fig.3] is a schematic diagram of a syringe for subcutaneous delivery in accordance with one embodiment of the invention.

[0076] [Fig.4] [Fig.4] is a schematic diagram of a syringe for subcutaneous delivery in accordance with one embodiment of the invention.

[0077] [Fig.5] [Fig.5] is a schematic diagram of a syringe for subcutaneous delivery in accordance with one embodiment of the invention.

[0078] [Fig.6] [Fig.6] is a schematic diagram of a syringe for subcutaneous delivery in accordance with one embodiment of the invention.

[0079] [Fig.7] [Fig.7] shows the experimental results of injection time as a function of constant force for the prior art syringe and the syringes of the present invention.

[0080] [Fig.8] [Fig.8] shows the experimental results of peel force as a function of storage time and temperature for the prior art syringe and the syringes of the present invention.

[0081] [Fig.9] [Fig.9] shows the percentage of major charge variant of romalizumab, measured using ion exchange chromatography, for the prior art syringe and the syringes of the present invention.

[0082] [Fig. 10] [Fig. 10] shows the proportion of the first HIC peak (obtained by hydrophobic chromatography) for the prior art syringe and the syringes of the present invention.

[0083] [Fig. 11] [Fig. 11] shows the proportion of the second HIC peak for the prior art syringe and the syringes of the present invention.

[0084] [Fig. 12] [Fig. 12] shows the proportion of the third HIC peak for the prior art syringe and the syringes of the present invention.

[0085] [Fig. 13] [Fig. 13] shows the polysorbate 20 (PS20) content of the prior art syringe and the syringes of the present invention.

[0086] [Fig.l4A] Figures 14A and 14B show schematic diagrams of a pre-filled syringe with a needle guard device.

[0087] [Fig.14B] Figures 14A and 14B show schematic diagrams of a pre-filled syringe with a needle guard device.

[0088] [Fig. 15] [Fig. 15] is a schematic diagram of a pre-filled syringe inside an auto-injector.

[0089] [Fig. 16] [Fig. 16] shows the measured time to expel the 150 mg / ml formulation of omalizumab from the reservoir and through the needle using an auto-injector when combined with syringes of the invention.

[0090] [Fig. 17] [Fig. 17] shows novel 150 mg / ml formulation dosage regimens of omalizumab in accordance with the present invention. Detailed description

[0091] The present invention provides novel uses of romalizumab, novel syringes, and novel administration regimens that improve ease of use, patient experience, patient compliance, and outcomes when using omalizumab. In particular, the present invention provides novel uses of romalizumab, novel syringes, and novel administration regimens that reduce the required number of individual injections per treatment, reduce the injection duration and forces required to deliver the omalizumab formulation subcutaneously, and reduce the risk of injection site reactions.

[0092] Presented below is a detailed description of the present invention and its advantages and improvements over current uses of omalizumab, current syringes, and current administration regimens. The detailed description of the present invention is structured as follows. First, the syringe currently used for administering omalizumab subcutaneously is described with reference to [Fig. 1]. The method of manufacturing the syringe of [Fig. 1] is also described. Second, seven embodiments of the syringes of the present invention, together with methods of manufacturing, are described with reference to Figures 3 to 6. Third, experimental results of tests performed on the prior art syringes and five embodiments of syringes of the present invention are described with reference to Figures 7 to 13.

[0093] As will be explained in detail below, the experimental results of tests carried out on the prior art syringe and five embodiments of syringes of the invention highlight the following points. i) The syringes of the present invention expel omalizumab in less time than prior art syringes when forces are applied to the stopper (see [Fig.7] and associated description). ii) Multiple features of the syringes of the present invention contribute to the reduced injection time referenced in (i), including, but not limited to: needle gauge, minimum inner diameter of the needle, cap lamination, cap coating, number of bevels on the distal surface of the needle, syringe flange, maximum inner diameter of the cap, and diameter of the outer rib on the cap (see [Fig. 7] and the associated description). iii) The syringes of the present invention require a lower peel force than the prior art syringe (see [Fig.8] and the associated description). iv) The syringes of the present invention preserve the purity and stability of omalizumab and therefore improve the bioavailability of omalizumab (see Figures 9 to 13 and the associated description).

[0094] As a result, the experimental results demonstrate that the inventors have provided syringes that reduce the injection time and forces required to deliver the omalizumab formulation subcutaneously and reduce the risk of injection site reactions.

[0095] In particular, in accordance with one aspect of the present invention, there is provided a method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient X ml of a 150 mg / ml formulation of omalizumab, wherein X is 2, 1 or 0.5 and wherein X ml of 150 mg / ml formulation of omalizumab is administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, which X ml of 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a stopper, and a needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, wherein one of the following is satisfied when a constant force of 10 N is applied to the stopper, a) when X is 2, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 16 seconds; b) when X is 1, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 5 seconds; and c) when X is 0.5, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 4 seconds.

[0096] As noted in (ii) above, multiple features of the syringes of the present invention contribute to the reduced injection time achieved in one aspect of the invention. However, as demonstrated in Figures 7 and 8 and the associated description, a 27 gauge needle is particularly advantageous in achieving the reduced injection time.Therefore, in accordance with one aspect of the invention, the present invention provides a method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 2 ml of a 150 mg / ml formulation of omalizumab, in . wherein the omalizumab formulation is administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, which X ml of 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a stopper, and a 27 gauge needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when force is applied to the stopper.

[0097] As will be demonstrated with reference to Figures 7 and 8, for syringes that administer 0.5 ml or 1 ml of omalizumab, the syringe of the present invention that administers romalizumab most rapidly is the syringe described with reference to [Fig. 5]. Therefore, a preferred embodiment of the invention is a syringe according to the first or second aspect above, wherein one or more of the following are satisfied. a) The syringe is configured to expel 1 mL of 150 mg / mL omalizumab formulation in one or more of: 4.64 ± 0.22 seconds when a constant force of 10 N is applied to the stopper, 2.54 ± 0.11 seconds when a constant force of 17 N is applied to the stopper, and 1.39 ± 0.04 seconds when a constant force of 30 N is applied to the stopper. b) The syringe has an internal coating of 0.4 ± 0.2 mg of polydimethylsiloxane (PDMS). c) The syringe has a 27 gauge needle defining a minimum internal diameter 1D N of 0.277 mm. d) The stopper, when not inserted into the syringe reservoir, has a maximum external diameter D s of 6.70 ± 0.15 mm and a length L s of 7.85 ± 0.4 mm. e) The plug has a conically shaped distal surface and at least one circumferential rib having an outer diameter R s of 6.60 ±0.15 mm. f) The stopper is formed from a bromobutyl elastomer and has an ethylene tetrafluoroethylene (ETFE) barrier film lamination. g) The cap has a UV-cured B2-40 lubricating coating.

[0098] Finally, because the syringes of the present invention achieve reduced injection time, reduced peel force compared to prior art syringes, while maintaining comparable purity, stability and bioavailability of romalizumab, the syringes of the invention can be used to administer larger volumes of omalizumab than those of prior art syringes. of the prior art, i.e. greater than 0.5 ml or 1 ml of omalizumab at 150 mg / ml.

[0099] TERMINOLOGY USED IN THE DETAILED DESCRIPTION

[0100] The term "distal" refers to a location that is relatively closer to an injection site, and the term "proximal" refers to a location that is relatively further from the injection site. The term "about," in relation to a numerical value x, is optional and means x ± 5%.

[0101] Filling volume

[0102] It is necessary to refill the syringes in order to take into account the residue remaining in the syringe and ensure that the recommended dose is expelled from the syringe. Therefore, in this application, when referring to syringes filled with 0.5 ml of 150 mg / ml omalizumab formulation, this should be understood as 0.520 ml ± 5%. When referring to syringes filled with 1 ml of 150 mg / ml omalizumab formulation, this should be understood as 1.020 ml ± 2.5%. When referring to syringes filled with 2 ml of 150 mg / ml omalizumab formulation, this should be understood as 2.040 ml ± 2.75%.

[0103] Extractable volume

[0104] When a 150 mg / ml formulation of omalizumab is expelled from a syringe, some residue will remain. In this application, when referring to syringes expelling 0.5 ml, this should be understood as 0.5 ml ± 5%. When referring to syringes expelling 1 ml, this should be understood as 1 ml ± 5%. When referring to syringes expelling 2 ml, this should be understood as 2 ml ± 5%.

[0105] Formulation of omalizumab

[0106] Containers having a nominal strength of less than 100 ml of 150 mg / ml omalizumab formulation (150 mg / ml antibody with 42.1 mg / ml L-arginine hydrochloride, 1.37 mg / ml L-histidine, 2.34 mg / ml L-histidine hydrochloride monohydrate, 0.4 mg / ml polysorbate 20 as an aqueous solution (in Sterile Water for Injection (USP)) have 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm. The number of particles having a diameter >10 pm and / or 25 pm can be measured by a light-shielding particle count test or a microscopic particle count test as set forth in the Pharmacopeia of the United States of America, Chapter 788.

[0107] Formulations of omalizumab used in accordance with the invention may contain a histidine buffer, arginine hydrochloride, and a polysorbate (such as polysorbate 20). They may have a pH in the range of 5.5 at 6.5. A useful formulation for omalizumab 150 mg / ml has 42.1 mg / ml arginine hydrochloride, 1.37 mg / ml histidine, 2.34 mg / ml histidine hydrochloride monohydrate, and 0.4 mg / ml polysorbate 20.

[0108] CURRENT USES OF OMALIZUMAB

[0109] Current syringe (also called prior art syringe)

[0110] [Fig.l] shows a schematic diagram of a syringe 1 currently used to deliver a 150 mg / ml solution of omalizumab (XOLAIR®). The syringe has a reservoir 2 having a length 1R of 54 ± 0.5 mm and an internal diameter d R of 6.35 ± 0.1 mm, filled with 0.5 ml or 1 ml of 150 mg / ml solution of omalizumab (XOLAIR®). The length 1R of the syringe is the maximum internal length of the syringe reservoir. The syringe is formed from borosilicate glass and the inner surface of the syringe has an internal coating of < 1.0 mg of polydimethylsiloxane (PDMS) having a kinematic viscosity of about 1000 cSt. Needle 3 has a 1N length of 12.7 ± 0.2 mm extending outside the syringe, a GN gauge of 26 defining a minimum internal diameter ID N of 0.232 mm (inset 3' shows a close-up view of the internal diameter ID N) and 3 bevels on its distal surface.The needle 3 has an internal coating of polydimethylsiloxane (PDMS) having a kinematic viscosity of about 12,500 cSt. The needle 3 is captive, meaning that it is inserted into the syringe and secured in place with an adhesive; the length of the fluid path IP between the distal end of the reservoir and the proximal end of the portion of the needle 3 extending from the syringe is about 8 mm. A flange 4 having the shape of a cut-out collar is located at the proximal end of the reservoir.

[0111] The syringe also includes a stopper 5 which, when not inserted into the syringe reservoir 2, has a maximum outer diameter D s of 6.67 mm to 7.10 mm and a length L s of 7.85 ± 0.4 mm. The stopper has a conically shaped distal surface 5a and at least three circumferential ribs 5b having an outer diameter R s of 6.60 ± 0.1 mm. The inset labeled 5' shows a close-up view of the stopper. The stopper is formed of a bromobutyl elastomer and has a fluororesin on the product-contacting side. The stopper is lubricated with DC360 Medical Fluid 1000 cSt silicone oil.

[0112] Prior to use, the needle is enclosed by a rubber needle shield (not shown) to maintain the sterility of the needle. The rubber needle shield is formed from styrene-butadiene rubber which is made from epoxypyrene, derived from natural rubber latex. The rubber needle shield is enclosed by an outer rigid polypropylene cap.

[0113] Syringe 1 is a BD Hypak™ 1 ml glass pre-fillable syringe with a captive needle fitted with a stopper 5 which is a BD (West) 4023 / 50 FluroTec® stopper. The BD Hypak™ 1 ml glass pre-fillable syringe with a captive needle is manufactured by Becton Dickinson. The elastomer formulation of the bromobutyl elastomer is 4023 / 50 and the fluorinated resin is a FluroTec® coating. Stopper 5 is manufactured by West Pharmaceutical Services and supplied by Becton Dickinson. The rubber needle shield is an FM27 / 0 rubber component and is enclosed by a rigid polypropylene cap; the rubber needle shield is manufactured by AptarGroup.

[0114] Method of manufacturing the syringe of the prior art

[0115] The method of manufacturing the syringe of the prior art presented and described with reference to [Fig.l] is stated below.

[0116] The first step is thawing and homogenizing a frozen preformulated 15% omalizumab drug substance. Thawing may be accomplished by circulating a heat transfer fluid in a jacketed container containing the 15% omalizumab drug substance. Homogenization may be accomplished by recirculating the thawed 15% omalizumab drug substance in a recirculation loop of the jacketed container.

[0117] The second step is filtration and mixing of the 15% omalizumab drug substance. Filtration may be accomplished by passing the 15% omalizumab drug substance through a nominal 0.2 µm membrane filter made of polyvinylidene fluoride. Mixing may be accomplished with a magnetically coupled stirrer within a jacketed storage container containing the 15% omalizumab drug substance. The 15% omalizumab drug substance may optionally be pooled and refrozen during this second step.

[0118] The third step is a sterile in-line filtration of the 15% omalizumab drug substance. The in-line filtration may be accomplished by passing the 15% omalizumab drug substance through a nominal 0.2 µm membrane filter made of poly(vinylidene fluoride).

[0119] The fourth step is an aseptic filling of the reservoir 2 with the captive needle 3 as shown and described with reference to [Fig.l]. The reservoir 2 is filled with 1 ml or 0.5 ml of omalizumab formulation by means of a stainless steel piston pump. The accuracy of the dosage can be monitored offline by determining the extractable volume. Before the aseptic filling, the following treatments are carried out: a) the reservoir 2 and the captive needle 3 are washed with water for injection (WFI) and the inner coating of < 1.0 mg of polydimethylsiloxane (PDMS) having a kinematic viscosity of about 1000 cSt is sprayed onto the reservoir body by means of a submerged nozzle; (b) the rubber needle shield and the outer rigid polypropylene cap are assembled with the reservoir 2 and the captive needle 3 so that they enclose the captive needle 3; and c) the reservoir 2, the captive needle 3, the rubber needle protector and the outer rigid polypropylene cap, assembled, undergo steam sterilization in an autoclave.

[0120] The fifth step is a capping of the syringe, i.e., the placement of the stopper 5 in the reservoir 2. The stopper can be placed in the appropriate position in the reservoir 2 by a tube stopper placement technology. Before capping the syringe, the stopper 5 is steam sterilized in an autoclave.

[0121] Current dosage regimens of romalizumab

[0122] [Fig. 2] shows currently used dosage regimens for the administration of a 150 mg / ml formulation of omalizumab. The 150 mg / ml formulation of omalizumab is administered at doses of 75 mg to 600 mg by subcutaneous injection every 2 or 4 weeks. The 150 mg / ml formulation of omalizumab is currently offered in syringes containing 0.5 ml or 1 ml of the 150 mg / ml formulation of omalizumab. Therefore, as shown in [Fig. 2], if a patient requires a dose of 225 mg of omalizumab, the dose should be administered using a syringe containing 1 ml of the 150 mg / ml formulation of omalizumab and a syringe containing 0.5 ml of the 150 mg / ml formulation of omalizumab. If a patient requires a 300 mg dose of omalizumab, the dose should be administered using two syringes, each containing 1 mL of the 150 mg / mL formulation of omalizumab.If a patient requires a 375 mg dose of omalizumab, the dose should be administered using three syringes - two syringes each containing 1 ml of the 150 mg / ml formulation of omalizumab and one syringe containing 0.5 ml of the 150 mg / ml formulation of omalizumab. If a patient requires a 450 mg dose of omalizumab, the dose should be administered using three syringes each containing 1 ml of the 150 mg / ml formulation of omalizumab. If a patient requires a 525 mg dose of omalizumab, the dose should be administered using four syringes - three syringes each containing 1 ml of the 150 mg / ml formulation of omalizumab and one syringe containing 0.5 ml of the 150 mg / ml formulation of omalizumab. If a patient requires a 600 mg dose of omalizumab, the dose should be administered using four syringes, each containing 1 ml of the 150 mg / ml formulation of omalizumab.

[0123] Difficulties related to current uses of romalizumab

[0124] The difficulties associated with current uses of omalizumab have been set out in detail above. In summary, the syringe 1 currently used to deliver a 150 mg / ml formulation of omalizumab is unsuitable for use with volumes greater than 1 ml. Due to the high viscosity of the 150 mg / ml omalizumab solution, significant injection forces are required to inject more than 1 ml of the 150 mg / ml omalizumab formulation in an injection time acceptable to patients. As a result, patients may struggle to apply the necessary injection forces and thus may fail to push the stopper 5 to its terminal position within the syringe 1 to administer a full dose.Furthermore, even when syringe 1 is used to deliver 0.5 ml or 1 ml of 150 mg / ml omalizumab formulation, it would be advantageous to reduce the required injection forces and duration, and any risk of injection site reaction.

[0125] NEW USES OF OMALIZUMAB

[0126] Figures 3 to 6 show syringes which are part of the invention.

[0127] First and second embodiments of the invention

[0128] [Fig. 3] shows a syringe 11 according to the invention. The syringe has a reservoir 12 having a length 1R of 54.0 ± 0.5 mm and an internal diameter d R of 6.35 mm ± 0.05 mm and is filled with 0.5 ml (in a first embodiment) or 1 ml (in a second embodiment) of 150 mg / ml solution of omalizumab (XOLAIR®). The syringe 11 is formed of borosilicate glass and the inner surface of the syringe has an internal coating of 0.4 ± 0.2 mg of polydimethylsiloxane (PDMS). The syringe has a round flange 14 having a maximum diameter of 11 ± 0.25 mm. The syringe includes a captive needle 13 having a length 1N of 12.7 mm extending outside the syringe, and is 27 gauge defining a minimum internal diameter 1D N of 0.277 mm (inset 13' shows a close-up view of the internal diameter 1D N).The needle 13 is captive, meaning that it is inserted into the syringe and secured in place with an adhesive; the length of the fluid path 1P between the distal end of the reservoir and the proximal end of the portion of the needle 13 extending from the syringe is approximately 8 mm. The needle has 5 bevels on its distal surface. Before use, the needle 13 is enclosed by an elastomeric needle shield (not shown) to maintain the sterility of the needle. The elastomeric needle shield may include an outer rigid polypropylene cap. The needle shield is latex-free.

[0129] The syringe also includes a stopper 15 which, when not inserted into the syringe reservoir 12, has a maximum outer diameter D s of 6.67 mm to 7.10 mm and a length L s of 7.85 ± 0.4 mm. The stopper has a conically shaped distal surface 15a and at least three circumferential ribs 15b having an outer diameter of 6.60 ±0.1 mm. The inset labeled 15' shows a close-up view of the stopper. The stopper is formed of a bromobutyl elastomer and has a fluororesin on the product contacting side. The stopper is lubricated with DC360 Medical Fluid 1000 cSt silicone oil.

[0130] Syringe 11 is a BD Neopak™ 1 ml long glass pre-fillable syringe with a captive needle fitted with a stopper 15 which is a BD (West) 4023 / 50 FluroTec® stopper. The BD Neopak™ 1 ml long glass pre-fillable syringe with a captive needle is manufactured by Becton Dickinson. The elastomer formulation of the bromobutyl elastomer is 4023 / 50 and the fluororesin is a FluroTec® coating. Stopper 15 is manufactured by West Pharmaceutical Services and supplied by Becton Dickinson.

[0131] Third and fourth embodiments of the invention

[0132] [Fig.4] shows a syringe 21 according to the invention. The syringe 21 has a reservoir 22 having a length 1R of 54 ± 0.5 mm and an internal diameter d R of 6.35 mm ± 0.05 mm and is filled with 0.5 ml (in a third embodiment) or 1 ml (in a fourth embodiment) of 150 mg / ml solution of omalizumab (XOLAIR®). The syringe is formed of borosilicate glass and the inner surface of the syringe has an internal coating of silicone oil. The syringe has a round collar 24 having a maximum diameter of 11 ± 0.25 mm.The syringe includes a needle having a length 1N of 12.7 mm extending outside the syringe, and is 27 gauge defining a minimum inner diameter 1D N of 0.191 mm (inset 23' shows a close-up view of the inner diameter 1D N). The needle 23 is captive, meaning that it is inserted into the syringe and secured in place with an adhesive; the length of the fluid path 1P between the distal end of the reservoir and the proximal end of the portion of the needle 23 extending from the syringe is approximately 8 mm. Before use, the needle 23 is enclosed by an elastomeric needle shield (not shown) serving to maintain the sterility of the needle. The elastomeric needle shield may include an outer rigid polypropylene cap. The needle shield is latex-free.

[0133] The syringe also includes a stopper 25 which, when not inserted into the syringe reservoir 22, has a maximum outer diameter D s of 6.70 ± 0.15 mm and a length L s of 7.85 ± 0.4 mm. The stopper has a conically shaped distal surface 25a and at least one circumferential rib 25b having an outer diameter R $ of 6.60 ± 0.15 mm. The inset labeled 25' shows a close-up view of the stopper. The stopper is formed of a bromobutyl elastomer and has an ethylene-tetrafluoroethylene (ETFE) barrier film lamination. The stopper has a lubricating coating made of B2-40 UV cured; this is a coating in which PDMS is sprayed onto the cap, heated and UV cured on the cap surface.

[0134] Syringe 21 is a Nexa® 1 ml long glass pre-fillable syringe with a captive needle fitted with a stopper 25 which is a West NovaPure® 1 ml long glass pre-fillable syringe with a captive needle. The Nexa® 1 ml glass pre-fillable syringe with a captive needle is manufactured by Ompi, a Stevanato Group brand. The elastomer formulation of the bromobutyl elastomer is 4023 / 50 and the ethylene-tetrafluoroethylene (ETFE) barrier film lamination is a FluroTec® coating. Stopper 25 is manufactured and supplied by West Pharmaceutical Services.

[0135] Fifth and sixth embodiments of the invention

[0136] [Fig. 5] shows a syringe 31 according to the invention. The syringe has a reservoir 32 having a length 1R of 54.0 ± 0.5 mm and an internal diameter d R of 6.35 mm ± 0.05 mm and is filled with 0.5 ml (in a fifth embodiment) or 1 ml (in a sixth embodiment) of 150 mg / ml solution of omalizumab (XOLAIR®). The syringe 31 is formed of borosilicate glass and the inner surface of the syringe has an internal coating of 0.4 ± 0.2 mg of polydimethylsiloxane (PDMS). The syringe has a round flange 34 having a maximum diameter of 11 ± 0.25 mm.The syringe includes a needle 33 having a length 1N of 12.7 mm extending outside the syringe, and is 27 gauge defining a minimum inner diameter 1D N of 0.277 mm (inset 33' shows a close-up view of the inner diameter 1D N). The needle 33 is captive, meaning that it is inserted into the syringe and secured in place with an adhesive; the length of the fluid path 1P between the distal end of the reservoir and the proximal end of the portion of the needle 33 extending from the syringe is approximately 8 mm. The needle has 5 bevels on its distal surface. Before use, the needle 33 is enclosed by an elastomeric needle shield (not shown) serving to maintain the sterility of the needle. The elastomeric needle shield may include an outer rigid polypropylene cap. The shield needle is latex free.

[0137] The syringe also includes a stopper 35 which, when not inserted into the syringe reservoir 32, has a maximum outer diameter D s of 6.70 ± 0.15 mm and a length L s of 7.85 ± 0.4 mm. The stopper has a conically shaped distal surface 35a and at least one circumferential rib 35b having an outer diameter R $ of 6.60 ± 0.15 mm. The inset labeled 35' shows a close-up view of the stopper. The stopper is formed of a bromobutyl elastomer and has an ethylene tetrafluoroethylene (ETFE) barrier film lamination. The stopper has a UV-cured B2-40 lubrication coating; this is a coating in which PDMS is sprayed onto the stopper, heated, and UV-cured onto the surface of the stopper.

[0138] Syringe 31 is a BD Neopak™ 1 ml long glass pre-fillable syringe with a captive needle fitted with a stopper 35 which is a West NovaPure® 1 ml long glass pre-fillable syringe with a captive needle. The BD Neopak™ 1 ml long glass pre-fillable syringe with a captive needle is manufactured by Becton Dickinson. The elastomer formulation of the bromobutyl elastomer is 4023 / 50 and the ethylene tetrafluoroethylene (ETFE) barrier film lamination is a FluroTec® coating. Stopper 35 is manufactured and supplied by West Pharmaceutical Services.

[0139] Seventh embodiment of the invention

[0140] [Fig. 6] shows a syringe 41 according to a seventh embodiment of the present invention. The syringe has a reservoir 42 having a length 1R of 54.5 ± 0.4 mm and an internal diameter d R of 8.65 mm ± 0.1 mm and is filled with 2 ml of 150 mg / ml solution of omalizumab (XOLAIR®). The syringe is formed of borosilicate glass and the inner surface of the syringe has an internal coating of 0.7 ± 0.2 mg of polydimethylsiloxane (PDMS). The syringe has a round flange 44 having a maximum diameter of 14.7 ± 0.25 mm.The syringe includes a needle having a length 1N of 12.7 mm extending outside the syringe, and is 27 gauge defining a minimum inner diameter 1D N of 0.277 mm (inset 43' shows a close-up view of the inner diameter 1D N). The needle 43 is captive, meaning that it is inserted into the syringe and secured in place with an adhesive; the length of the fluid path 1P between the distal end of the reservoir and the proximal end of the portion of the needle 43 extending from the syringe is approximately 8 mm. The needle has 5 bevels on its distal surface. Before use, the needle 43 is enclosed by a thermoplastic elastomer needle shield to maintain the sterility of the needle. The needle shield may include an outer rigid polypropylene cap. The needle shield is latex-free.

[0141] The syringe also includes a stopper 45 which, when not inserted into the syringe, has a maximum outer diameter D s of 9.05 ± 0.15 mm and a length L s of 7.70 ± 0.4 mm. The stopper has a conically shaped distal surface 45a and includes at least one circumferential rib 45b having an outer diameter R $ of 9.00 ± 0.15 mm. The inset labeled 45' shows a close-up view of the stopper. The stopper is formed of a bromobutyl elastomer and has an ethylene tetrafluoroethylene (ETFE) barrier film lamination. The stopper has a UV-cured B2-40 lubrication coating; this is a coating in which PDMS is sprayed onto the stopper, heated, and UV-cured onto the surface of the stopper.

[0142] Syringe 41 is a BD Neopak™ 2.25 ml glass pre-fillable syringe with a captive needle fitted with a 45 stopper which is a West NovaPure® stopper for 1-3 ml. The 2.25 ml glass pre-fillable syringe BD Neopak™ with a captive needle is manufactured by Becton Dickinson. The elastomer formulation of the bromobutyl elastomer is 4023 / 50 and the ethylene tetrafluoroethylene (ETFE) barrier film lamination is a FluroTec® coating. The 45 stopper is manufactured and supplied by West Pharmaceutical Services.

[0143] In accordance with the invention, each of the syringes of Figures 3 to 6 may be used to subcutaneously administer a 150 mg / ml formulation of omalizumab.

[0144] Methods of manufacturing syringes according to the present invention

[0145] A method of manufacturing syringes according to the present invention is set forth below.

[0146] The first step is thawing and homogenizing a frozen preformulated 15% omalizumab drug substance. Thawing may be accomplished by circulating a heat transfer fluid in a jacketed container containing the 15% omalizumab drug substance. Homogenization may be accomplished by recirculating the thawed 15% omalizumab drug substance in a recirculation loop of the jacketed container.

[0147] The second step is filtration and mixing of the 15% omalizumab drug substance. Filtration may be accomplished by passing the 15% omalizumab drug substance through a nominal 0.2 µm membrane filter made of polyvinylidene fluoride. Mixing may be accomplished with a magnetically coupled stirrer within a jacketed storage container containing the 15% omalizumab drug substance. The 15% omalizumab drug substance may optionally be pooled and refrozen during this second step.

[0148] The third step is a sterile in-line filtration of the 15% omalizumab drug substance. The in-line filtration may be accomplished by passing the 15% omalizumab drug substance through a nominal 0.2 µm membrane filter made of poly(vinylidene fluoride).

[0149] The fourth step is an aseptic filling of a reservoir 12, 22, 32, 42 with a captive needle 13, 23, 33, 43 as shown and described with reference to any one of Figures 3 to 6. The reservoir 12, 22, 32, 42 is filled with 0.5 ml, 1 ml or 2 ml of omalizumab formulation by means of a peristaltic pump. The accuracy of the dosage can be monitored by automated weighing of the syringes before and after filling.

[0150] Aseptic filling using a peristaltic pump has advantages over aseptic filling using stainless steel piston pumps. Firstly, peristaltic pumps exert less stress on the proteins than stainless steel piston pumps. Second, unlike stainless steel piston pumps, peristaltic pumps do not require cleaning when used for single-use dispensing. In this way, the peristaltic pump reduces the likelihood of cross-contamination. Third, peristaltic pumps are faster to set up and calibrate than stainless steel piston pumps.

[0151] Before aseptic filling, the following treatments are carried out: a) the reservoir 12, 22, 32, 42 and the captive needle 13, 23, 33, 43 are washed with water for injection (WFI) and the internal coating of 0.4 ± 0.2 mg of polydimethylsiloxane (PDMS) having a kinematic viscosity of about 1000 cSt is sprayed onto the reservoir body by means of a submerged nozzle; (b) the elastomer needle shield and the outer rigid polypropylene cap are assembled with the reservoir 12, 22, 32, 42 and the captive needle 3 so that they enclose the captive needle 13, 23, 33, 43; and c) the reservoir 12, 22, 32, 42, the captive needle 13, 23, 33, 43, the elastomer needle protector and the outer rigid polypropylene cap, assembled, are sterilized by treatment with ethylene oxide gas.

[0152] The fifth step is a capping of the syringe, i.e., the placement of the stopper 15, 25, 35, 45 in the reservoir 12, 22, 32, 42. The stopper 15, 25, 35, 45 can be placed in the appropriate position in the reservoir 12, 22, 32, 42 by a tube stopper placement technology. Before capping the syringe, the stopper 15, 25, 35, 45 is sterilized. The sterilization can be carried out by steam sterilization in an autoclave, electron beam (e-beam) and / or ethylene oxide gas treatment.

[0153] Accordingly, the present invention provides a method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient X ml of a 150 mg / ml formulation of omalizumab, wherein X is 2, 1 or 0.5, and wherein X ml of 150 mg / ml formulation of omalizumab is administered subcutaneously by means of a syringe, wherein the syringe is manufactured by a method comprising: aseptic filling of the reservoir with the 150 mg / ml formulation of omalizumab; and clogging the tank with the cap.

[0154] In another embodiment, the present invention provides X ml of 150 mg / ml formulation of omalizumab, wherein aseptic filling is performed using a peristaltic pump or a stainless steel piston pump.

[0155] In another embodiment, the present invention provides X ml of 150 mg / ml formulation of omalizumab, wherein, prior to aseptic filling, the reservoir and needle are sterilized by treatment with ethylene oxide gas, electron beam (e-beam) and / or steam sterilization in an autoclave.

[0156] New dosage regimens of romalizumab

[0157] [Fig. 17] shows novel dosage regimens of the present invention. [Fig. 17] shows dosage regimens that include the use of an auto-injector having a syringe of the present invention filled with 0.5 ml, 1 ml or 2 ml of 150 mg / ml formulation of omalizumab. However, the use of an auto-injector is optional, and the dosage regimens shown may also be implemented using syringes of the invention when not inserted into a device and / or when inserted into a needle shield device.

[0158] Advantageously, syringes of the present invention configured to deliver 2 ml of 150 mg / ml omalizumab reduce the required number of injections compared to current administration regimens shown in [Fig. 2]. For example, as shown in [Fig. 17], if a patient requires a 300 mg dose of omalizumab, the dose may be delivered using a single syringe of the invention containing 2 ml of 150 mg / ml omalizumab formulation. If a patient requires a 375 mg dose of omalizumab, the dose may be delivered using two syringes - one syringe of the invention filled with 2 ml of 150 mg / ml omalizumab formulation and one syringe filled with 0.5 ml of 150 mg / ml omalizumab formulation.If a patient requires a 450 mg dose, the dose can be administered using two syringes - one syringe of the invention filled with 2 ml of 150 mg / ml omalizumab formulation and one syringe filled with 1 ml of 150 mg / ml omalizumab formulation. If a patient requires a 525 mg dose, the dose can be administered using three syringes - one syringe of the invention filled with 2 ml of 150 mg / ml omalizumab formulation, one syringe filled with 0.5 ml of 150 mg / ml omalizumab formulation and one syringe filled with 1 mg of 150 mg / ml omalizumab formulation. If a patient requires a 600 mg dose, the dose can be administered using two syringes of the invention filled with 2 ml of 150 mg / ml omalizumab formulation. The syringes filled with 0.5 ml of 150 mg / ml omalizumab formulation and 1 ml of 150 mg / ml omalizumab formulation may be syringes of the present invention or the current syringes.

[0159] The syringes may be provided alone, in an auto-injector such as the auto-injector described with reference to [Fig. 15], and / or in a needle protection device such as the needle protection device described with reference to Figures 14A and 14B. In this way, the present invention improves patient convenience and the risk of injection site reaction and thus improves patient acceptance.

[0160] It is further stated that larger volumes of highly viscous drugs are more likely to be deposited deeper in the subcutaneous layer than smaller volumes, and thus are less likely to leak into the intradermal layer, resulting in site leakage and injection site reaction. Therefore, providing a method of treatment comprising administering 2 ml of 150 mg / ml omalizumab formulation according to the invention will result in less leakage and a reduced risk of injection site reaction compared to current methods of treatment comprising administering 0.5 ml and 1 ml of 150 mg / ml omalizumab.

[0161] Furthermore, as previously described, the syringes of the present invention filled with 0.5 ml of 150 mg / ml omalizumab and 1 ml of 150 mg / ml omalizumab formulation reduce the force and / or time required for injection compared to current syringes, improving ease of use and making it more likely that a full dose will be administered. Thus, the present invention improves ease of use, patient experience, patient compliance, and outcomes when using omalizumab.

[0162] Accordingly, novel dosage regimens are also provided which are similar to those illustrated in [Fig. 2] but which utilize the syringes of the present invention filled with 0.5 ml of 150 mg / ml omalizumab and / or 1 ml of 150 mg / ml omalizumab formulation. If a patient requires a 75 mg dose, the dose may be administered using a single syringe of the present invention filled with 1 ml of 150 mg / ml omalizumab formulation. If a patient requires a 150 mg dose, the dose may be administered using a single syringe of the present invention filled with 1 ml of 150 mg / ml omalizumab formulation. If a patient requires a 225 mg dose, the dose may be administered using a syringe filled with 0.5 ml of omalizumab 150 mg / ml and a syringe filled with 1 ml of omalizumab 150 mg / ml formulation; one or both of which syringes are syringes of the present invention.If a patient requires a 300 mg dose, the dose may be administered using two syringes filled with 1 ml of 150 mg / ml omalizumab formulation; one or both of which syringes are syringes of the present invention. If a patient requires a 375 mg dose, the dose may be administered using three syringes - one syringe filled with 0.5 ml of 150 mg / ml omalizumab and two syringes filled with . of 1 ml of 150 mg / ml formulation of omalizumab; of which at least one of the syringes is a syringe of the present invention. If a patient requires a dose of 450 mg, the dose may be administered using three syringes, all three syringes being filled with 1 ml of 150 mg / ml formulation of omalizumab; of which at least one of the syringes is a syringe of the present invention. If a patient requires a dose of 525 mg, the dose may be administered using four syringes - one syringe filled with 0.5 ml of 150 mg / ml omalizumab and three syringes filled with 1 ml of 150 mg / ml formulation of omalizumab; of which at least one of the syringes is a syringe of the present invention.If a patient requires a 600 mg dose, the dose may be administered using four syringes, each of which is filled with 1 ml of 150 mg / ml omalizumab formulation; of which at least one of the syringes is a syringe of the present invention.

[0163] In the novel dosage regimens of the present invention, the syringes may be provided alone, in an auto-injector such as the auto-injector described with reference to [Fig. 15], and / or in a needle shield device such as the needle shield device described with reference to Figures 14A and 14B.

[0164] Therefore, the invention provides the following novel treatment methods.

[0165] A method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 225 mg of a formulation of omalizumab; which method comprises one of: (a) implementing a method of the invention in which X is 0.5; and implementing a method of the invention in which X is 1; (b) carrying out a method of the invention in which X is 0.5; and administering 1 ml of 150 mg / ml formulation of omalizumab subcutaneously by means of a syringe; and (c) carrying out a method of the invention in which X is 1; and administering 0.5 ml of 150 mg / ml formulation of omalizumab subcutaneously by means of a syringe.

[0166] A method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; persistent asthma moderate to severe allergy in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 300 mg of an omalizumab formulation; which method comprises administering 1 ml of a 150 mg / ml omalizumab formulation subcutaneously by syringe and carrying out a method of the invention wherein X is 1.

[0167] A method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 375 mg of an omalizumab formulation; which method comprises administering 0.5 ml of a 150 mg / ml omalizumab formulation subcutaneously by means of a syringe; and one of: a) implementing a method of the invention comprising administering to the patient 2 ml of 150 mg / ml formulation of omalizumab; and b) implementing a method of the invention in which X is 1 and administering 1 ml of 150 mg / ml formulation of omalizumab subcutaneously using a syringe.

[0168] A method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 450 mg of an omalizumab formulation; which method comprises administering 1 ml of a 150 mg / ml omalizumab formulation subcutaneously by means of a syringe; and one of: a) implementing a method of the invention comprising administering to the patient 2 ml of 150 mg / ml formulation of omalizumab; and b) implementing a method of the invention in which X is 1 and administering 1 ml of 150 mg / ml formulation of omalizumab subcutaneously using a syringe.

[0169] A method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; persistent asthma moderate to severe allergy in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 525 mg of an omalizumab formulation; which method comprises administering 1 ml of a 150 mg / ml omalizumab formulation subcutaneously by means of a syringe; and administering 0.5 ml of a 150 mg / ml omalizumab formulation subcutaneously by means of a syringe; and one of: a) carrying out a method of the invention comprising administering to the patient 2 ml of a 150 mg / ml omalizumab formulation; and b) implementing a method of the invention in which X is 1 and administering 1 ml of 150 mg / ml formulation of omalizumab subcutaneously using a syringe.

[0170] A method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 600 mg of omalizumab formulation; which method comprises: a) carrying out a method of the invention comprising administering to the patient 2 ml of 150 mg / ml omalizumab formulation and carrying out a method of the invention comprising administering to the patient 2 ml of 150 mg / ml omalizumab formulation; or b) implementing a method of the invention in which X is 1, administering 1 ml of 150 mg / ml formulation of omalizumab subcutaneously using a syringe, and administering 1 ml of 150 mg / ml formulation of omalizumab subcutaneously using a syringe.

[0171] In any of these methods: (A) one of the steps requiring administration of 0.5 ml of 150 mg / ml formulation of omalizumab subcutaneously by means of a syringe may comprise carrying out a method of the invention in which X is 0.5; and (B) one of the steps requiring administration of 1 ml of 150 mg / ml formulation of omalizumab subcutaneously by means of a syringe may comprise carrying out a method of the invention in which X is 1.

[0172] Other embodiments of the invention

[0173] In certain embodiments of the present invention wherein X is 2, the syringe may be configured to expel the omalizumab formulation contained in the reservoir through the needle in one or more of: (a) less than 8.5 seconds when a constant force of 17 N is applied to the stopper; and b) less than 5 seconds when a constant force of 30 N is applied to the stopper.

[0174] Further, in some embodiments where X is 2, the syringe may be configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle in one or more of: a) about 16 seconds to about 14 seconds when a constant force of 10 N is applied to the stopper; (b) about 8.5 seconds to about 6 seconds when a constant force of 17 N is applied to the plug; and c) about 5 seconds to about 4 seconds when a constant force of 30 N is applied to the stopper.

[0175] In some embodiments wherein X is 1, the syringe may be configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 5 seconds, less than 4.75 seconds, less than 4.5 seconds, less than 4.25 seconds, or about 4 seconds when a constant force of 10 N is applied to the stopper; (b) less than 3 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds when a constant force of 30 N is applied to the stopper.

[0176] In certain embodiments in which X is 1, the syringe may be configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 5 seconds to about 4 seconds, less than 4.75 seconds to about 4 seconds, less than 4.5 seconds to about 4 seconds, less than 4.25 seconds to about 4 seconds, or about 4 seconds when a constant force of 10 N is applied to the stopper; (b) less than 3.5 seconds to about 2 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30 N is applied to the stopper.

[0177] In some embodiments wherein X is 0.5, the syringe may be configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 2 seconds when a constant force of 17 N is applied to the stopper; and b) less than 1 second when a constant force of 30 N is applied to the stopper.

[0178] In some embodiments wherein X is 0.5, the syringe may be configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 4 seconds to about 2 seconds when a constant force of 10 N is applied to the stopper; (b) less than 2 seconds to about 1 second when a constant force of 17 N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30 N is applied to the plug.

[0179] In some embodiments of the invention, the needle is 25 gauge to 29 gauge, preferably 26 gauge to 28 gauge, most preferably 27 gauge.

[0180] In some embodiments where the needle is 25 gauge, the needle has one of: (a) a minimum internal diameter of 0.292 mm, and (b) a minimum internal diameter of 0.232 mm.

[0181] In some embodiments where the needle is 26 gauge, the needle has one of: (a) a minimum internal diameter of 0.292 mm, and (b) a minimum internal diameter of 0.232 mm.

[0182] In some embodiments where the needle is 27 gauge, the needle has one of: (a) a minimum internal diameter of 0.277 mm; (b) a minimum internal diameter of 0.191 mm; (c) a minimum internal diameter of 0.184 mm; and (d) a minimum internal diameter of 0.241 mm.

[0183] In some embodiments where the needle is 28 gauge, the needle has one of: (a) a minimum internal diameter of 0.133 mm; and (b) a minimum internal diameter of 0.190 mm.

[0184] In some embodiments where the needle is 29 gauge, the needle has one of: (a) a minimum internal diameter of 0.265 mm; (b) a minimum internal diameter of 0.240 mm; (c) a minimum internal diameter of 0.190 mm; and (d) a minimum internal diameter of 0.133 mm; preferably the needle has a minimum internal diameter of 0.240 mm or 0.265 mm.

[0185] In some embodiments of the invention, the needle may include 3 bevels on its distal surface or 5 bevels on its distal surface.

[0186] In some embodiments, the cap may have a fluororesin on the product-contacting side or an ethylene-tetrafluoroethylene (ETFE) barrier film lamination.

[0187] In some embodiments, the plug may have a UV-cured B2-40 lubricating coating or is lubricated with a 1000 cSt silicone oil.

[0188] In some embodiments, the syringe may have an internal coating of 0.4 ± 0.2 mg or 0.7 ± 0.2 mg of polydimethylsiloxane.

[0189] In some embodiments, the syringe may have a latex-free needle shield.

[0190] In some embodiments, the syringe may have a round flange at a proximal end of the reservoir; in other embodiments, the round flange has a maximum diameter of 11 ± 0.25 mm or 14.7 ± 0.25 mm.

[0191] In embodiments where X is 1 or 0.5, the syringe may have a length of 54.0 ± 0.5 mm and an internal diameter of 6.35 mm ± 0.05 mm.

[0192] In embodiments where X is 1 or 0.5, when the cap is not inserted into the reservoir, it may have one of: (a) a maximum external diameter of 6.67 mm to 7.10 mm and / or a length of 7.85 ± 0.4 mm; and (b) a maximum external diameter of 6.70 ± 0.15 mm and / or a length of 7.85 ± 0.4 mm.

[0193] In some embodiments, when X is 1 or 0.5, the cap may have at least one circumferential rib having an outer diameter of 6.60 ±0.15 mm.

[0194] In some embodiments where X is 2, the syringe may have a length of 54.0 ± 0.5 mm and an internal diameter of 8.65 mm ± 0.05 mm.

[0195] In some embodiments where X is 2, when the plug is not inserted into the reservoir, the plug may have a maximum outer diameter of 9.05 ± 0.15 mm and / or a length of 7.70 ± 0.4 mm when not inserted into the reservoir.

[0196] In some embodiments where X is 2, the cap may have at least one circumferential rib having an outer diameter of 9.00 ±0.15 mm.

[0197] In some embodiments, the apparent viscosity of the 150 mg / ml formulation of omalizumab at a shear rate of 200 s 1 is: 24.7 ± 0.5 mPa.s at 5.0 ± 0.2°C, 15.3 ± 0.5 mPa.s at 15.0 ± 0.2°C, 11.4 ± 0.5 mPa.s at 25.0 ± 0.2°C or 7.2 ± 1.2 mPa.s at 40.0 ± 0.2°C.

[0198] Although the above aspects relate to a method of treatment comprising administering to the patient a formulation of omalizumab, which formulation of omalizumab is administered subcutaneously by means of a syringe, it will be understood that the syringes of the present invention may be provided alone. or in combination with a needle shield or an auto-injector. Accordingly, the present invention provides syringes containing a 150 mg / ml formulation of omalizumab that are usable with auto-injectors in that the syringes of the present invention expel the 150 mg / ml formulation of omalizumab in less time than prior art syringes when forces are applied to the stopper.

[0199] The present invention provides a syringe comprising: a reservoir filled with 1 ml of 150 mg / ml omalizumab formulation, a stopper, and a needle; and which is configured to expel 1 ml of 150 mg / ml omalizumab formulation through the needle in one or more of: less than 8 seconds when a constant force of 10 N is applied to the cap; less than 4 seconds when a constant force of 17 N is applied to the cap; and less than 2 seconds when a constant force of 30 N is applied to the cap.

[0200] In some embodiments, the syringe is configured to expel 1 ml of 150 mg / ml omalizumab formulation through the needle in one or more of: less than 8 seconds to about 4 seconds when a constant force of 10 N is applied to the stopper; less than 4 seconds to about 2 seconds when a constant force of 17 N is applied to the plug; and less than 2 seconds to about 1 second when a constant force of 30 N is applied to the cap.

[0201] In some embodiments, the syringe is configured to expel 1 ml of 150 mg / ml omalizumab formulation through the needle in less than 5 seconds, less than 4.75 seconds, less than 4.5 seconds, less than 4.25 seconds, or about 4 seconds when a constant force of 10 N is applied to the stopper.

[0202] In some embodiments, the syringe is configured to expel 1 ml of 150 mg / ml omalizumab formulation through the needle in less than 7.5 seconds to about 4 seconds, less than 5 seconds to about 4 seconds, less than 4.75 seconds to about 4 seconds, less than 4.5 seconds to about 4 seconds, less than 4.25 seconds to about 4 seconds, or about 4 seconds when a constant force of 10 N is applied to the stopper.

[0203] The present invention also provides a syringe for subcutaneous injection, the syringe comprising: a reservoir filled with 0.5 ml of 150 mg / ml omalizumab formulation, a stopper, and a needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, which syringe being configured to expel 0.5 ml of 150 mg / ml omalizumab formulation through the needle in one or more of: less than 4 seconds when a constant force of 10 N is applied to the stopper; less than 2 seconds when a constant force of 17 N is applied to the stopper; and less than 1 second when a constant force of 30 N is applied to the stopper.

[0204] In some embodiments, the syringe is configured to expel 0.5 ml of 150 mg / ml omalizumab formulation through the needle in one or more of: less than 4 seconds to about 2 seconds when a constant force of 10 N is applied to the stopper; less than 2 seconds to about 1 second when a constant force of 17 N is applied to the stopper; and less than 1 second to about 0.5 seconds when a constant force of 30 N is applied to the cap.

[0205] The present invention also provides a syringe for subcutaneous injection, the syringe comprising a reservoir filled with 2 ml of 150 mg / ml omalizumab formulation, a stopper, and a needle, the syringe being configured to expel 2 ml of the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper.

[0206] In some embodiments, the syringe is configured to expel 2 ml of 150 mg / ml omalizumab formulation from the reservoir and through the needle in one or more of: less than 16 seconds when a constant force of 10 N is applied to the cap; less than 9 seconds when a constant force of 17 N is applied to the cap; and less than 4 seconds when a constant force of 30 N is applied to the cap.

[0207] In some embodiments, the syringe is configured to expel 2 ml of 150 mg / ml omalizumab formulation from the reservoir through the needle in one or more of: less than 16 seconds to about 8 seconds when a constant force of 10 N is applied to the stopper; less than 9 seconds to about 4 seconds when a constant force of 17 N is applied to the cap; and less than 4 seconds to about 2 seconds when a constant force of 30 N is applied to the cap. Experimental results

[0208] Figures 7 to 13 show experimental results obtained with the prior art syringe (described with reference to [Fig.l]) and five syringes of the present invention (described with reference to Figures 3 to 6). Table 1 summarizes the syringes used in the experiments. [Table 1] Table 1 - Syringes used in the experiments ABCDEF Syringe Described with reference to Figure 3 Figure 5 Figure 5 Figure 6 Figure 4 Figure 1 Filling volume (150 mg / ml omalizumab) 1 ml 0.5 ml 1 ml 2 ml 1 ml 1. m]

[0209] TIME TO EXPEL A 150 MG / ML FORMULATION WITH CONSTANT FORCE ([Fig.7])

[0210] According to the present invention, the 150 mg / ml formulation of omalizumab is expelled from a syringe in less time than prior art syringes when forces are applied to the stopper. [Fig. 7] shows the measured time to expel the 150 mg / ml formulation of omalizumab from syringes that are part of the present invention (syringes A, C, D and E) and the prior art syringe (syringe F) when a constant force of 10 N, 17 N or 30 N is applied to the stopper.

[0211] A motorized test bench was used to apply a constant force to each syringe filled with the relevant volume of 150 mg / ml omalizumab formulation, and the time taken to move the stopper from its proximal position to its distal position, expelling the contents of the syringe into the air, was measured. The constant force was applied to a plunger which, in turn, applied a force to the stopper. Ten syringe samples were tested for each constant force measurement, and the average was calculated. These tests were carried out at room temperature. This test method can be used to determine the performance of syringes according to the invention.

[0212] The syringe samples were tested immediately after filling (referred to as time point 0 in the technique).

[0213] Under the experimental conditions, the prior art syringe (syringe F) is configured to expel 1 ml of 150 mg / ml omalizumab formulation through the needle in 8.53 ± 0.45 seconds when a constant force of 10 N is applied to the stopper, 4.32 ± 0.20 seconds when a constant force of 17 N is applied to the stopper, and 2.14 ± 0.09 seconds when a constant force of 30 N is applied to the stopper. In other words, the prior art syringe is configured to expel a 150 mg / ml formulation of omalizumab through the needle in 0.85 ± 0.4 seconds per ml per N of constant force applied.

[0214] Syringe A is configured to expel 1 ml of 150 mg / ml omalizumab formulation through the needle in 6.73 ± 0.51 seconds when a constant force of 10 N is applied to the stopper, 3.27 ± 0.11 seconds when a constant force of 17 N is applied to the stopper, and 1.57 ± 0.10 seconds when a constant force of 30 N is applied to the stopper. In other words, syringe A is configured to expel a 150 mg / ml omalizumab formulation through the needle in less than 0.67 ± 0.5 seconds per ml per N of constant force applied.

[0215] Syringe E is configured to expel 1 ml of 150 mg / ml omalizumab formulation through the needle in 5.40 ± 0.23 seconds when a constant force of 10 N is applied to the stopper, 2.84 ± 0.12 seconds when a constant force of 17 N is applied to the stopper, and 1.67 ± 0.15 seconds when a constant force of 30 N is applied to the stopper. In other words, syringe E is configured to expel a 150 mg / ml omalizumab formulation through the needle in less than 0.54 ± 0.2 seconds per ml per N of constant force applied.

[0216] Syringe C is configured to expel 1 ml of 150 mg / ml omalizumab formulation through the needle in 4.64 ± 0.22 seconds when a constant force of 10 N is applied to the stopper, 2.54 ± 0.11 seconds when a constant force of 17 N is applied to the stopper, and 1.39 ± 0.04 seconds when a constant force of 30 N is applied to the stopper. In other words, syringe C is configured to expel a 150 mg / ml omalizumab formulation through the needle in less than 0.4 ± 0.5 seconds per ml per N of constant force applied.

[0217] Syringe D is configured to expel 2 ml of 150 mg / ml omalizumab formulation through the needle in 15.14 ± 0.51 seconds when a constant force of 10 N is applied to the stopper, 8.30 ± 0.20 seconds when a constant force of 17 N is applied to the stopper, and 4.75 ± 0.23 seconds when a constant force of 30 N is applied to the stopper. In other words, syringe D is configured to expel a 150 mg / ml omalizumab formulation through the needle in less than 0.75 ± 0.5 seconds per ml per N of constant force applied.

[0218] [Fig. 7] demonstrates that the syringes of the present invention (syringes A, C and E) are configured to expel 1 ml of 150 mg / ml omalizumab formulation out of the reservoir and through the needle in less time than the prior art syringe (syringe F).

[0219] Accordingly, the present invention provides a method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; spontaneous urticaria chronic; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient X ml of a 150 mg / ml formulation of omalizumab, where X is 2, 1 or 0.5, and wherein X ml of 150 mg / ml formulation of omalizumab is administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, which X ml of 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a stopper, and a 25 gauge to 29 gauge needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, wherein one or more of the following options are met when a constant force of 10 N is applied to the stopper, a) when X is 2, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 16 seconds; b) when X is 1, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 5 seconds; and c) when X is 0.5, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 4 seconds.

[0220] Furthermore, [Fig. 7] demonstrates that the different components of the syringes of the present invention each contribute to a shorter injection time of the syringes of the present invention. The cap 5 of syringe F (prior art syringe) is identical to the cap of syringe A, but the reservoir 2 and needle 3 of syringe F are different from the reservoir 12 and needle 13 of syringe A. Therefore, since [Fig. 7] shows that syringe A is configured to expel 1 ml of 150 mg / ml omalizumab formulation out of the reservoir and through the needle in less time than syringe F, the features of both the needle 13 and reservoir 12 of syringe A contribute to a shorter injection time of syringe A.Similarly, the reservoir 12 and needle 13 of syringe A are identical to the reservoir 32 and needle 33 of syringe C but the stopper 15 of syringe A is different from the stopper 35 of syringe C. Therefore, as [Fig.7] shows that syringe C is configured to expel 1 ml of 150 mg / ml omalizumab formulation out of the reservoir and through the needle in less time than syringe A, the features of the stopper 35 of syringe C contribute to the . shorter injection time of syringe C. Finally, the cap 35 of syringe C is identical to the cap 25 of syringe E but the reservoir 32 and needle 33 of syringe C are different from the reservoir 22 and needle 23 of syringe E. As [Fig.7] shows that syringe E is configured to expel 1 ml of 150 mg / ml omalizumab formulation out of the reservoir and through the needle in less time than syringe C, the characteristics of the reservoir 22 and needle 23 of syringe E contribute to the shorter injection time of syringe E.

[0221] In view of this, it will be understood that the syringes of the present invention (syringes A, B, C, D and E) have been described by way of example only, and that modifications may be made while remaining within the scope of the invention. For example, it will be understood that the stopper 15 may be combined with the syringe reservoir 22 and the needle 33, 23 or 13 to form a syringe which is part of the invention.Additionally, any of the features of the syringes, needles, and stoppers of the present invention may be combined to form a syringe according to the invention, including, but not limited to, needle gauges suitable for subcutaneous injection (i.e., 23 gauge to 32 gauge), minimum inner diameter of the needle, lamination of the stopper, coating of the stopper, number of bevels on the distal surface of the needle, flange of the syringe, maximum inner diameter of the stopper, and diameter of the outer circumferential rib on the stopper.

[0222] Accordingly, the present invention provides a method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps;moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient X ml of a 150 mg / ml formulation of omalizumab, wherein X is 1, and wherein X ml of 150 mg / ml formulation of omalizumab are administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, wherein X ml of 150 mg / ml formulation of omalizumab have 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a stopper, and a 25 gauge to 29 gauge needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, into; which, when a constant force of 10 N is applied to the stopper, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 5 seconds, less than 4.75 seconds, less than 4.5 seconds, less than 4.25 seconds, or about 4 seconds.

[0223] Further, [Fig.7] demonstrates that 27 gauge needles are particularly advantageous in contributing to a shorter injection time of the syringes of the present invention as compared to the prior art because each of syringes A, C and E includes a 27 gauge needle while syringe F includes a 26 gauge needle.

[0224] Accordingly, the present invention provides a method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 2 ml of a 150 mg / ml formulation of omalizumab, wherein the omalizumab formulation is administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, which X ml of 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a stopper, and a 27 gauge needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when force is applied to the stopper.

[0225] In some embodiments, the needle has one of: (a) a minimum internal diameter of 0.277 mm; (b) a minimum internal diameter of 0.191 mm; (c) a minimum internal diameter of 0.184 mm; and (d) a minimum internal diameter of 0.241 mm.

[0226] Finally, the results for syringe D in [Fig.7] demonstrate that the syringes of the present invention can be used to administer larger volumes of omalizumab than those of the prior art syringes, i.e., greater than 0.5 ml and 1 ml of omalizumab formulation.

[0227] PEEL-OFF FORCE ([Fig.8])

[0228] As demonstrated with reference to [Fig. 8], the shorter injection times of the syringes of the present invention are due in part to the fact that the syringes of the present invention require a lower peel force than the prior art syringe. [Fig. 8] shows the measured peel force required to move the stopper of the syringes of the present invention (syringes A, C, D and E) and the prior art syringe (syringe F) from an initial fixed point at a speed of 190 mm / min.

[0229] Syringes A, C, D, E, and F were filled with 150 mg / ml omalizumab formulation as needed and stored at 5°C ± 3°C, 25°C ± 3°C, or 40°C ± 3°C. The peel strength of syringe samples stored at 5°C ± 3°C was tested 2.5 and 6 months after filling. The peel strength of syringe samples stored at 25°C ± 3°C was tested immediately after filling, and 1.5, 2.5, and 6 months after filling. The peel strength of syringe samples stored at 40°C ± 3°C was tested 1.5 and 2.5 months after filling.

[0230] A motorized test bench was used to apply force to the stopper and measure the applied force, and the instrument was adjusted to move the stopper at a speed of 190 mm / min.

[0231] Under the conditions of the experiment, the peeling force required to move the cap of the prior art syringe (syringe F) from an initial fixed point at a speed of 190 mm / min is one or more of: about 4 N to about 6 N after storage at 5°C ± 3°C for 2.5 months after filling; about 4.5 N to about 6 N after storage at 5°C ± 3°C for 6 months after filling.

[0232] Under the conditions of the experiment, the peeling force required to move the cap of the prior art syringe (syringe F) from an initial fixed point at a speed of 190 mm / min is one or more of: about 4 N to about 4.5 N at 25°C ± 3°C after filling; about 5.5 N to about 7 N after storage at 25°C ± 3°C for 1.5 months after filling; about 4.5 N to about 7.5 N after storage at 25°C ± 3°C for 2.5 months after filling; and / or about 7 N to about 10 N after storage at 25 °C ± 3 °C for 6 months after filling.

[0233] Under the conditions of the experiment, the peeling force required to move the cap of the prior art syringe (syringe F) from an initial fixed point at a speed of 190 mm / min is one or more of: about 6 N to about 10 N after storage at 40°C ± 3°C for 1.5 months after filling; and about 8 N to about ION after storage at 25°C ± 3°C for 2.5 months after filling.

[0234] [Fig.8] demonstrates that the peel force required to move the stopper of the syringes of the present invention from an initial fixed point at a speed of 190 mm / min is much lower and much less variable than that for the prior art.

[0235] The peel force required to move the stopper of the syringes of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: about 2 N to about 4 N after storage at 5°C ± 3°C for 2.5 months after filling; about 2 N to about 4 N after storage at 5°C ± 3°C for 6 months after filling.

[0236] The peel force required to move the stopper of the syringes of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: about 2 N to about 3.5 N at 25°C ± 3°C after filling; about 2 N to about 4.5 N after storage at 25°C ± 3°C for 1.5 months after filling; about 2.5 N to about 5 N after storage at 25°C ± 3°C for 2.5 months after filling; and / or about 2.5 N to about 5.5 N after storage at 25°C ± 3°C for 6 months after filling.

[0237] The peel force required to move the stopper of the syringes of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: about 3 N to about 4.5 N after storage at 40°C ± 3°C for 1.5 months after filling; and about 3 N to about 5 N after storage at 40°C ± 3°C for 2.5 months after filling.

[0238] PURITY & STABILITY MEASURED BY ION EXCHANGE CHROMATOGRAPHY (IEC) ([Fig.9])

[0239] As demonstrated with reference to [Fig.9], the syringes of the present invention preserve the purity and stability of romalizumab in a manner comparable to current syringes.

[0240] [Fig.9] shows the percentage of major charge variant of romalizumab, measured by means of ion exchange chromatography, for the syringe of the prior art (syringe F) and the syringes of the present invention (syringes A, B, C, D and E).

[0241] Syringe samples were filled with 150 mg / ml omalizumab formulation and stored at 5°C ± 3°C or 25°C ± 3°C. The percentage of romalizumab major charge variant after storage at 5°C ± 3°C was measured by IEC after filling, after 2.5 months of storage and after 6 months of storage. The percentage of romalizumab major charge variant after storage at 25°C ± 3°C was measured by IEC after 1.5 months of storage and after 2.5 months of storage. Table 2 shows the test results. [Table 2] Table 2 - By-products and degradation products by IEC, % of main variant Storage temperature Storage time (months) Syringe and A Syringe and B Syringe and C Syringe and D Syringe and E Syringe and F 5°C ± 3°C 0 76.43 76.25 76.26 76.04 76.3 75.08 2.5 77.45 77.74 77.59 77.32 77.13 76.26 6 77.47 77.97 78.12 77.57 77.96 77.27 25°C ± 3°C 1.5 69.28 68.99 69.18 69.26 69.28 68.87 2.5 68.18 68.14 68.12 68.13 68.14 68.23

[0242] As shown in Table 2 and [Fig.9], the syringes of the present invention (syringes A, B, C, D and E) preserve the purity and stability of romalizumab in a manner similar to the prior art syringe (syringe F).

[0243] The syringes of the present invention contain at least 76% of the major charge variant of omalizumab, measured by ion exchange chromatography, after filling with a 150 mg / ml solution of omalizumab stored at 5°C ± 3°C. This demonstrates that the syringes of the present invention preserve the purity of omalizumab in a manner comparable to the prior art syringe (syringe F), which contained only 75.08% of the major charge variant of omalizumab, measured by ion exchange chromatography, after filling with 1 ml of 150 mg / ml solution of omalizumab stored at 5°C ± 3°C.

[0244] The syringes of the present invention also preserve the stability of omalizumab in a manner similar to the prior art syringe. The syringes of the present invention contain at least 77% of the major charge variant of omalizumab, as measured by ion exchange chromatography, after that they were filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 3°C for 2.5 months, compared to 76% for the prior art syringe under the same conditions. In addition, the syringes of the present invention contain at least 69% of the main loading variant of romalizumab after they were filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 3°C for 1.5 months.

[0245] PURITY & STABILITY MEASURED BY HYDROPHOBIC CHROMATOGRAPHY (HIC) (Figures 10 to 12)

[0246] As demonstrated with reference to [Fig. 10], the syringes of the present invention preserve the purity and stability of romalizumab in a manner similar to prior art syringes in a manner similar to the current syringe.

[0247] [Fig. 10] shows the proportion of the first HIC peak for the prior art syringe (syringe F) and the syringes of the present invention (syringes A, B, C, D and E). [Fig.l 1] shows the proportion of the second HIC peak for the prior art syringe and the syringes of the present invention. [Fig. 12] shows the proportion of the third HIC peak for the prior art syringe and the syringes of the present invention.

[0248] Syringe samples were filled with 150 mg / ml omalizumab formulation and stored at 5°C ± 3°C or 25°C ± 3°C. The proportions of the first, second, and third HIC peaks of syringes stored at 5°C ± 3°C were measured after filling, after 2.5 months of storage, and after 6 months of storage. The proportions of the first, second, and third HIC peaks of syringes stored at 25°C ± 3°C were measured after 1.5 months of storage and after 2.5 months of storage. Tables 3, 4, and 5 show the test results. [Table 3] Table 3 - By-products and degradation products by HIC, Peak 1% Storage temperature Storage duration (months) Syringe A Syringe B Syringe C Syringe D Syringe E Syringe F 5°C ± 3°C 0 62.8 62.7 62.8 62.8 62.8 60.2 2.5 62.3 62.4 62.3 62.3 62.4 59.7 6 65.6 65.7 65.6 65.7 65.4 63.1 25°C ± 3°C 1.5 56.1 56.0 56.2 56.2 56.2 53.8 2.5 51.2 51.3 51.3 51.3 51.3 49.9 [Table 4] Table 4 - Byproducts and Degradation Products by HIC, Pic 2 % Storage temperatures Stock duration (month s) Syringe A Syringe B Syringe C Syringe D Syringe E Syringe F 5°C ± 3°C 0 27.6 27.7 27.6 27.6 27.6 28.2 20.5 27.0 27.6 6 22.5 22.7 22.5 22.6 22.9 23.5 25°C ± 3°C 1.5 24.3 24.2 24.3 24.3 24.3 25.1 23.3 [Table 5] Table 5 - Byproducts and Degradation Products by HIC, Pic 3 % Storage temperatures Stock duration (month s) Syringe A Syringe B Syringe C Syringe D Syringe E Syringe F 5°C ± 3°C 0 6.3 6.2 6.3 6.3 6.3 7.7 2.5 7.6,6.9 8.0 7.8 7.9 7.9 7.9 9.1 25°C ± 3°C 1.5 12.1 12.1 11.9 12.0 12.1 13.1 2.5 17.2 17.1

[0249] As demonstrated in Table 3 and [Fig. 10], the syringes of the present invention (syringes A, B, C, D and E) preserve the purity and stability of romalizumab in a manner comparable to the prior art syringe (syringe F).

[0250] The proportion of the first HIC peak is at least 62% for the syringes of the present invention after filling with a 150 mg / ml solution of omalizumab stored at 5°C ± 3°C. This demonstrates that the syringes of the present invention preserve the purity of romalizumab in a manner comparable to the prior art syringe (syringe F), which had a first HIC peak of 60.2% after filling with a 150 mg / ml solution of omalizumab stored at 5°C ± 3°C.

[0251] The syringes of the present invention also preserve the stability of romalizumab. The proportion of the first peak of HIC is at least 62% for the syringes of the present invention after they have been filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 3°C for 2.5 months, compared to 59% for the prior art syringe under the same conditions. The proportion of the The proportion of the first peak HIC is at least 56% for the syringes of the present invention after they have been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 3°C for 1.5 months, compared to 53.8% for the prior art syringe under the same conditions. The proportion of the first peak HIC is at least 51% for the syringes of the present invention after they have been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 3°C for 2.5 months, compared to 49.9% for the prior art syringe under the same conditions.

[0252] Therefore, in some embodiments of the invention, the proportion of the first peak of the syringe, measured by hydrophobic chromatography, is at least: a) 62% after filling with a 150 mg / ml solution of omalizumab stored at 5°C ± 3°C; and / or b) 62% after it was filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 3°C for 2.5 months.

[0253] In some embodiments of the invention, the proportion of the first peak of the syringe, measured by hydrophobic chromatography, is reduced by 0.4% or less after the syringe has been stored at 5°C ± 3°C for 2.5 months.

[0254] In certain embodiments of the invention, the proportion of the first peak of the syringe, measured by hydrophobic chromatography, is at least: (a) 56% for the syringe after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 3°C for 1.5 months; and / or b) 51% for the syringe after it was filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 3°C for 2.5 months.

[0255] POLYSORBATE 20 CONTENT ([Fig. 13])

[0256] As demonstrated with reference to [Fig. 13], the syringes of the present invention preserve the purity and stability of romalizumab in a manner similar to current syringes.

[0257] [Fig. 13] shows the polysorbate 20 (PS20) content of the prior art syringe and syringes of the present invention.

[0258] Syringe samples were filled with 150 mg / ml omalizumab formulation and stored at 5°C ± 3°C or 25°C ± 3°C. Polysorbate 20 content was measured for each sample after filling, after 2.5 months of storage, and after 6 months of storage. Table 6 shows the test results. [Table 6] Table 6 - Dosage of PS20 excipient by HPLC (mg / ml) Temperature Duration of Syringu Syringu Seringu Seringu Syringu Storage syringu u stocka eeeeee ABCDEF ge (months) 5°C ± 3°C 0 0.429 0.425 0.428 0.427 0.422 0.392 2.5 0.462 0.472 0.484 0.496 0.475 0.428 6 0.440 0.449 0.450 0.455 0.445 0.398 25°C ± 3°C 1.5 0.40- 0.404 0.413 0.402 0.401 0.360 2.5 0.420 0.414 0.421 0.432 0.423 0.363 6 0.353 0.347 0.353 0.355 0.351 0.289

[0259] As demonstrated in Table 6 and [Fig. 13], the syringes of the present invention (syringes A, B, C, D and E) preserve the purity and stability of romalizumab in a manner comparable to the prior art syringe (syringe F).

[0260] The polysorbate 20 content of the syringes of the present invention is at least 0.4 mg / ml after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 3°C. This demonstrates that the syringes of the present invention preserve the purity of the 150 mg / ml omalizumab solution in a manner comparable to the prior art syringe (syringe F), which contains a polysorbate 20 content of 0.392 mg / ml under the same conditions.

[0261] The syringes of the present invention also preserve the stability of romalizumab. The polysorbate 20 content of the syringes of the present invention is at least 0.4 mg / ml for the syringes of the present invention after they have been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 3°C for 1.5 months, compared to 0.360 mg / ml for the prior art syringe under the same conditions. The polysorbate 20 content of the syringes of the present invention is at least 0.3 mg / ml for the syringes of the present invention after they have been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 3°C for 6 months, compared to 0.289 mg / ml for the prior art syringe under the same conditions.

[0262] Therefore, in some embodiments, the syringe contains at least 0.4 mg / ml of polysorbate 20 after filling with a 150 mg / ml solution of omalizumab stored at 5°C ± 3°C.

[0263] In some embodiments, the syringe contains: a) at least 0.4 mg / ml polysorbate 20 after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 3°C for 1.5 months; and / or b) at least 0.3 mg ml polysorbate 20 after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 3°C for 6 months.

[0264] NEEDLE PROTECTIVE DEVICES

[0265] Although the present application describes a method of treatment in which a 150 mg / ml formulation of omalizumab is administered subcutaneously by means of a syringe, it will be understood that the syringes of the present invention may be provided alone, or in combination with a needle shield device.

[0266] Figures 14A and 14B show schematic diagrams of a pre-filled syringe 50 in accordance with the present invention with a needle shield device 60. [Fig. 14A] shows a configuration before use and [Fig. 14B] shows a configuration in use.

[0267] A plunger 51 is present and includes a plunger rod 53 and a plunger head 52. A user may apply manual force to the plunger head 52 in a distal direction to manually expel fluid from the reservoir through the needle. When the plunger reaches the end of its distal movement, it may unlock needle shield retaining arms 54 disposed within the needle shield device, releasing a needle sleeve 55. When the needle shield device is removed from an injection site, the needle sleeve 15 may expand under the constraint of the needle shield spring 56 to cover the needle, as shown in [Fig. 14B].

[0268] Accordingly, in some embodiments of the present invention, the syringe is provided in a needle shield device comprising a needle sleeve and a plunger; and wherein manual force can be applied to the plunger to expel the 150 mg / ml formulation of omalizumab and unlock the needle sleeve so that the needle sleeve can cover the needle after injection.

[0269] AUTO-INJECTORS

[0270] Although the present application describes a method of treatment in which a 150 mg / ml formulation of omalizumab is administered subcutaneously by means of a syringe, it will be understood that the syringes of the present invention may be provided alone, or in combination with an auto-injector. Therefore, in certain embodiments of the invention, the syringe is provided in an auto-injector.

[0271] [Fig. 15] is a schematic diagram of a pre-filled syringe 111 within an auto-injector 100. The auto-injector includes a housing 101 configured to contain the syringe 111 and a drive mechanism 102 configured to apply a force to the stopper in a distal direction and expel fluid from the syringe through the needle. A trigger mechanism 103 is arranged to actuate the drive mechanism. In the example shown in [Fig. 15], the trigger 103 is moved in the direction of the arrow, away from the pre-filled syringe.

[0272] The syringe comprises a reservoir filled with 150 mg / ml formulation of omalizumab, a stopper and a needle. As will be appreciated, the auto-injector 100 may also be combined with any of the syringes of the invention - further details of the syringes of the invention and the filling volume are described with reference to Figures 3 to 6.

[0273] The drive mechanism 102 is configured to apply a force to the stopper to drive the stopper through the reservoir toward the needle to expel the 150 mg / ml formulation of omalizumab out of the reservoir and through the needle.

[0274] A trigger mechanism 103 is present and is movable from a holding position, in which the drive mechanism is held in the rest position, to a release position, in which the drive mechanism is released, whereby the drive mechanism drives the stopper through the reservoir toward the needle to expel the 150 mg / ml formulation of omalizumab from the reservoir and through the needle in about 1 second to about 17 seconds.

[0275] In the embodiment shown in [Fig. 15], the drive mechanism is configured to expel the 150 mg / ml formulation of omalizumab from the reservoir and through the needle in about 1 second to 17 seconds by applying an average force of at least 10 N to the stopper over the period of time the 150 mg / ml formulation of omalizumab is expelled. In some embodiments, the drive mechanism is configured to apply an average force of at least 11 N to the stopper, at least 12 N, at least 13 N, at least 14 N, at least 15 N, at least 16 N, at least 17 N, at least 18 N, at least 19 N, at least 20 N, at least 21 N, at least 22 N, at least 23 N, at least 24 N, at least 25 N, at least 26 N, at least 27 N, at least 28 N, at least 29 N, at least 30 N, at least 31 N, at least 32 N, at least 33 N, at least 34 N, at least 35 N, at least 36 N, at least 37 N, at least 38 N, at least 39 N or at least 40 N.

[0276] In the embodiment shown in [Fig. 15], the drive mechanism comprises a coil spring configured to apply an average force of 25 N to the plug. The average force can be calculated by determining the force applied to the plug at the beginning of the injection (when the drive mechanism is released) and the force applied to the plug at the end of the injection (when the plug has been driven through the reservoir to its engagement with the distal end of the reservoir and can no longer be driven), and calculating the average of the two forces. As will be understood by those skilled in the art, Hooke's Law can be used to calculate the force applied by a given spring at a given extension.

[0277] Although the drive mechanism of the auto-injector shown in [Fig. 15] includes a helical drive spring, the invention is not limited to such a drive mechanism. Other types of drive mechanism may be used to apply an average force of at least 10 N to the stopper to expel the 150 mg / ml formulation of omalizumab from the reservoir and through the needle in a period of time less than 17 seconds in accordance with the present invention. For example, a drive mechanism including a torsion spring or an electromechanical drive may be used.

[0278] The auto-injector further includes an auto-injector cap (not shown). The auto-injector cap is configured to be in permanent engagement with the syringe needle shield (described in more detail with reference to Figures 3 and 6) and in releasable engagement with the auto-injector housing. When the auto-injector cap is disengaged from the housing, it removes the needle shield from the syringe, thereby allowing access to the needle.

[0279] TIME TO EXPEL THE OMALIZUMAB FORMULATION BY MEANS OF AN AUTOINJECTOR COMBINED WITH SYRINGES OF THE PRESENT INVENTION ([Fig. 16])

[0280] [Fig. 16] shows the measured time to expel the 150 mg / ml formulation of omalizumab from the reservoir and through the needle using an auto-injector when combined with syringes of the invention.

[0281] Four auto-injectors, as shown and described with reference to [Fig. 15], were tested. The first auto-injector was fitted with a syringe A. The second auto-injector was fitted with a syringe E. The third auto-injector was fitted with a syringe C. The fourth auto-injector was fitted with a syringe D. The trigger mechanism of each auto-injector was moved from the hold position to the release position and the time for the stopper to be driven through the reservoir until it engaged with the distal end of the reservoir was measured. The test was repeated 20 times for each embodiment of auto-injector.

[0282] Each auto-injector tested expelled the 150 mg / ml formulation of omalizumab out of the reservoir and through the needle in about 1 second to about 17 seconds. The drive mechanism of each auto-injector tested included a coil spring configured to apply an average force of 25 N to the stopper.

[0283] The first autoinjector expelled 1 ml of 150 mg / ml omalizumab solution out of the reservoir and through the needle in approximately 3 to 5 seconds.

[0284] The second autoinjector expelled 1 ml of 150 mg / ml omalizumab solution out of the reservoir and through the needle in approximately 4 to 6 seconds.

[0285] The third autoinjector expelled 1 mL of 150 mg / mL omalizumab solution out of the reservoir and through the needle in approximately 3 to 4 seconds. In one test, the third The auto-injector expelled 1 ml of 150 mg / ml omalizumab solution out of the reservoir and through the needle in approximately 9 seconds. - this test result turns out to be an error.

[0286] The fourth autoinjector expelled 2 ml of 150 mg / ml omalizumab solution out of the reservoir and through the needle in approximately 6 to 7 seconds.

[0287] As demonstrated in [Fig. 16], the present invention further provides an auto-injector filled with 150 mg / ml omalizumab formulation, which is configured to expel the 150 mg / ml omalizumab formulation from the reservoir and through the needle in a time period of less than 17 seconds. This time period of less than 17 seconds is acceptable to patients.

[0288] Although [Fig. 16] only shows test results for auto-injectors with syringes filled with 1 ml or 2 ml of 150 mg / ml omalizumab formulation, it will be understood that auto-injectors with syringes filled with 0.5 ml of 150 mg / ml omalizumab formulation may also be provided in accordance with the invention. In addition, [Fig. 16] does not show test results for an auto-injector provided with the prior art syringe (syringe F), because the prior art syringe is not usable with auto-injectors. The prior art syringe is not usable with auto-injectors because it cannot reliably withstand the high injection forces required for the administration of romalizumab in an acceptable period of time.

[0289] Therefore, in one aspect, there is described an auto-injector comprising: a syringe according to the invention, for example a syringe comprising a reservoir filled with 0.5 ml, 1 ml or 2 ml of 150 mg / ml formulation of omalizumab, a stopper, and a needle; a drive mechanism configured to apply a force to the stopper to drive the stopper through the reservoir toward the needle to expel the 150 mg / ml formulation of omalizumab from the reservoir and through the needle; a housing configured to contain the syringe and the drive mechanism; and a trigger mechanism movable from a holding position, in which the drive mechanism is held in a rest position in which it does not apply a force to the stopper, to a release position, in which the drive mechanism is released, whereby the drive mechanism applies a force to the stopper to drive the stopper through the reservoir toward the needle to expel the 150 mg / ml formulation of omalizumab from the reservoir and through the needle in a time period of less than 17 seconds.

[0290] The syringe may be filled with 0.5 ml of 150 mg / ml formulation of omalizumab, in which case the drive mechanism is configured to expel the 0.5 ml of 150 mg / ml formulation out of the reservoir and through the needle in a period of time from about 1 second to about 17 seconds, from about 1 second to about 16 seconds, from about 1 second to about 15 seconds, from about 1 second to about 14 seconds, from about 1 second to about 13 seconds, from about 1 second to about 12 seconds, from about 1 second to about 11 seconds, from about 1 second to about 10 seconds, from about 1 second to about 9 seconds, from about 1 second to about 8 seconds, from about 1 second to about 7 seconds, from about 1 second to about 6 seconds, from about 1 second to about 5 seconds, from about 1 second to about 4 seconds, from about 1 second to about 2 seconds; or about 1 second.

[0291] The syringe may be filled with 1 ml of 150 mg / ml formulation of omalizumab, and the drive mechanism is configured to expel the 1 ml of 150 mg / ml formulation from the reservoir and through the needle in a time period of about 3 seconds to about 17 seconds, about 3 seconds to about 16 seconds, about 3 seconds to about 15 seconds, about 3 seconds to about 14 seconds, about 3 seconds to about 13 seconds, about 3 seconds to about 12 seconds, about 3 seconds to about 11 seconds, about 3 seconds to about 10 seconds, about 3 seconds to about 9 seconds, about 3 seconds to about 8 seconds, to about 3 seconds to about 7 seconds, to about 3 seconds to about 6 seconds, to about 3 seconds to about 5 seconds, to about 3 seconds about 4 seconds; or about 3 seconds.

[0292] The syringe may be filled with 2 ml of 150 mg / ml omalizumab formulation, and the drive mechanism is configured to expel the 2 ml of 150 mg / ml omalizumab formulation from the reservoir and through the needle in a time period of about 6 seconds to 17 seconds, about 6 seconds to about 16 seconds, about 6 seconds to about 15 seconds, about 6 seconds to about 14 seconds, about 6 seconds to about 13 seconds, about 6 seconds to about 12 seconds, about 6 seconds to about 11 seconds, about 6 seconds to about 10 seconds, about 6 seconds to about 9 seconds, about 6 seconds to about 8 seconds, about 6 seconds to about 7 seconds, or about 6 seconds.

[0293] The drive mechanism may be configured to apply an average force of at least 10 N to the stopper over the period of time during which the 150 mg / ml formulation of omalizumab is expelled. It may be configured to apply an average force to the stopper over the period of time during which the 150 mg / ml formulation of omalizumab is expelled of at least 11 N, at least 12 N, at least 13 N, at least 14 N, at least 15 N, at least 16 N, at least 17 N, at least 18 N, of at least 19 N, of at least 20 N, of at least 21 N, of at least 22 N, of at least 23 N, of at least 24 N, of at least 25 N, of at least 26 N, of at least 27 N, of at least 28 N, of at least 29 N, of at least 30 N, of at least 31 N, of at least 32 N, of at least 33 N, of at least 34 N, at least 35 N, at least 36 N, at least 37 N, at least 38 N, at least 39 N or at least 40 N.

[0294] The drive mechanism may comprise a coil spring, a torsion spring and / or an electromechanical drive.

[0295] In some aspects, the syringe is filled with 0.5 ml of 150 mg / ml formulation of omalizumab and the drive is configured to expel the 0.5 ml of 150 mg / ml formulation out of the reservoir and through the needle in a time period of about 1 second to about 17 seconds, about 1 second to about 16 seconds, about 1 second to about 15 seconds, from about 1 second to about 14 seconds, from about 1 second to about 13 seconds, from about 1 second to about 12 seconds, from about 1 second to about 11 seconds, from about 1 second to about 10 seconds, from about 1 second to about 9 seconds, from about 1 second to about 8 seconds, from about 1 second to about 7 seconds, from about 1 second to about 6 seconds, from about 1 second to about 5 seconds, from about 1 second to about 4 seconds, from about 1 second to about 2 seconds; or about 1 second.

[0296] In some aspects, the syringe is filled with 1 mL of 150 mg / mL formulation of omalizumab, and the drive is configured to expel the 1 mL of 150 mg / mL formulation out of the reservoir and through the needle in a time period of about 3 seconds to about 17 seconds, about 3 seconds to about 16 seconds, about 3 seconds to about 15 seconds, about 3 seconds to about 14 seconds, about 3 seconds to about 13 seconds, about 3 seconds to about 12 seconds, about 3 seconds to about 11 seconds, about 3 seconds to about 10 seconds, about 3 seconds to about 9 seconds, about 3 seconds to about 8 seconds, to about 3 seconds to about 7 seconds, to about 3 seconds to about 6 seconds, to about 3 seconds to about 5 seconds, to about 3 seconds about 4 seconds; or about 3 seconds.

[0297] In some aspects, the syringe is filled with 2 ml of 150 mg / ml omalizumab formulation, and the drive is configured to expel the 2 ml of 150 mg / ml omalizumab formulation from the reservoir and through the needle in a time period of about 6 seconds to about 17 seconds, about 6 seconds to about 16 seconds; which time period is optionally one of: about 6 seconds to about 15 seconds, about 6 seconds to about 14 seconds, about 6 seconds to about 13 seconds, about 6 seconds to about 12 seconds, about 6 seconds to about 11 seconds, about 6 seconds to about 10 seconds, about 6 seconds to about 9 seconds, about 6 seconds to about 8 seconds, about 6 seconds to about 7 seconds, or about 6 seconds.

[0298] Also provided is a kit comprising a syringe according to the present invention and optionally: an auto-injector, a needle protection device, and / or instructions for administration.

[0299] In one aspect of the invention, there is provided for the first time the injection of a highly viscous 150 mg / ml formulation of omalizumab by means of an auto-injector. In particular, one aspect allows the injection of a highly viscous 150 mg / ml formulation of omalizumab in a time period of 1 second to 17 seconds - this time period is acceptable to patients and thus improves ease of use and patient acceptance.

[0300] Further, as shown in [Fig. 16], the auto-injectors comprise a syringe filled with 1 ml of 150 mg / ml omalizumab formulation and comprising a drive mechanism configured to expel the 1 ml of 150 mg / ml formulation out of the reservoir and through the needle in a time period of about 3 seconds to 6 seconds. This injection time is much shorter than the injection time of comparable self-administered antibody formulations such as the Fasenra 30 mg / 1 ml (benzalizumab) auto-injector (injection time period of up to 15 seconds) and the Nucala 100 mg / 1 ml (mepolizumab) auto-injector (injection time period of up to 15 seconds).

[0301] This shorter injection time facilitates the injection of high doses of omalizumab that were not previously available to patients, such as 2 ml of 300 mg / 2 ml omalizumab formulation, in a single syringe. As shown in [Fig. 16], the present invention provides an auto-injector comprising a syringe filled with 2 ml of 150 mg / ml omalizumab formulation and comprising a drive mechanism configured to expel the 2 ml of 150 mg / ml formulation from the reservoir and through the needle in a period of time of about 6 seconds to 7 seconds. This injection time is much shorter than the injection time of comparable antibody formulations of similar volume; for example, the Dupixent 300 mg / ml (dupilumab) auto-injector (injection time up to 20 seconds).

[0302] As demonstrated with reference to [Fig.7], the shorter injection times of the auto-injectors of the present invention are due in part to the fact that the syringes of the present invention expel the 150 mg / ml formulation of omalizumab more quickly than the prior art syringes when constant forces are applied to the stopper. Furthermore, as demonstrated with reference to [Fig. 8], the faster injection times of the auto-injectors of the present invention are due in part to the fact that the syringes of the present invention require a lower peel force than the prior art syringe.

[0303] Surprisingly, as demonstrated with reference to Figures 9 to 13, the syringes of the present invention better preserve the purity and stability of romalizumab. The better preserved purity and stability of romalizumab also contribute to the shorter injection time of the syringes and auto-injectors of the present invention because they reduce aggregation and thus limit increases in fluid viscosity.

[0304] BIOEQUIVALENCE DATA

[0305] New methods of treatment comprising the administration of omalizumab, described in this application, have been shown to be bioequivalent to previously approved methods of treatment comprising the administration of omalizumab, see Sangana et al. Bioequivalence between a new omalizumab prefilled syringe with an autoinjector or with a needle safety device compared with the current prefilled syringe: a randomized controlled trial in healthy volunteers, Clinical Pharmacology. 2024, 0 (0) 1-10.

[0306] Sangana et al. demonstrated the bioequivalence of omalizumab between: (1) the new 300 mg / 2 ml pre-filled syringe in an auto-injector (new PFS-AI), i.e., the auto-injector 100 described with reference to [Fig. 15] with the syringe D described with reference to [Fig. 6] and two of the current 150 mg / 1 ml pre-filled syringes in a needle shield device (current PFS-NSD), i.e., the needle shield device 60 described with reference to Figures 14A and 14B with the syringe F described with reference to [Fig. 1]; (2) the new 300 mg / 2 ml pre-filled syringe in a needle shield device (new PFS-NSD), i.e., the needle shield device 60 described with reference to Figures 14A and 14B with the syringe D described with reference to [Fig. 6] and two of the current 150 mg / 1 ml pre-filled syringes in a needle shield device (current PFS-NSD), i.e., the needle shield device 60 described with reference to Figures 14A and 14B with the syringe F described with reference to [Fig. 1]; and (3) the new 300 mg / 2 ml pre-filled syringe in an auto-injector (new PFS-AI), i.e., the auto-injector 100 described with reference to [Fig. 15] with the syringe D described with reference to [Fig. 6] and the new 300 mg / 2 ml pre-filled syringe in a needle shield device (new PFS-NSD), i.e., the needle shield device 60 described with reference to Figures 14A and 14B with the syringe D described with reference to [Fig. 6].

[0307] For bioequivalence comparison, natural log-transformed pharmacokinetic parameters (Cmax, AUCiast, AUCinf) were analyzed by an analysis of covariance (ANCOVA) model with strata of treatment group, body area of ​​injection and body weight as fixed effects, and IgE at baseline as a covariate. Cmax is the maximum observed serum concentration, AUCiast is the area under the serum concentration-time curve calculated at the last quantifiable concentration point, and AUCinf is the area under the serum concentration-time curve extrapolated to infinity. Based on the ANCOVA model, point estimates and corresponding 95% and 90% confidence limits were calculated for the difference between each new omalizumab configuration (new PSF-AI, new PFS-NSD) and the control intervention (current PFS-NSD). These point estimates and confidence limits were exponentialized to obtain point estimates with 95% and 90% confidence intervals (Cis) for the proportions of the geometric means on the original scale.Bioequivalence claims were made for each comparison if and only if Cmax, AUCiast and AUCinf were declared equivalent (i.e., the Cis for all proportions were contained between 80% and 125%) based on the Bonferroni-Holm stepwise method for multiple comparisons.

[0308] Statistical comparisons of serum pharmacokinetic parameter values ​​of romalizumab for novel PFS-AI, novel PFS-NSD and current PFS-NSD are summarized below. [Paintings?] Parameter (1) New PSF-AI vs. current PFS-NSD (2) New PFS-NSD vs. current PFS-NSD (3) New PFS-AI vs. new PFS-NSD GMR (%) [95% CI]a GMR (%) [95% CI]b GMR (%) [90% CI]c Cmax (pg / ml) 108.5 [99.6-118.1] 100.6 [92.3-109.6] 107.8 [100.4-115.8] AUClast (pg*h / ml) 109.3 [99.7-119.9] 101.6 [92.5-111.6] 107.6 [99.6-116.3] AUCinf (pg*h / ml) 110.0 [100.1-120.9] 102.7 [93.3-113.0] 107.2 [99.0-116.0] a In the comparison of each new configuration with the current configuration, bioequivalence was established on the basis of 95% Cis according to the B onferroni-Holm procedure b In the comparison of the new configurations with each other, another bioequivalence was established on the basis of 90% Cis. AUCinf, area under the curve from time 0 to infinity; AUClast, area under the curve from time 0 to the last measurable concentration sampling time; CI, confidence interval; Cmax, maximum observed (peak) drug concentration after single-dose administration; GMR, geometric mean ratio; PFS-AI, pre-filled syringe assembled with an auto-injector; PFS-NSD, pre-filled syringe with a needle safety device.

[0309] Formal bioequivalence was established between: (1) the new PFS-AI and the current PFS-NSD (95% CI or 90% CI, based on the Bonferroni-Holm procedure); (2) the new PFS-NSD and the current PFS-NSD (95% CI or 90% CI, based on the Bonferroni-Holm procedure); and (3) the new PFS-AI and the new PFS-NSD (90% CI); the CI for each treatment contrast being contained in the range of 80% to 125% for Cmax, AUCiast and AUCinf after a single dose of omalizumab.

[0310] Certain numbered examples relating to the invention are described below. Example 1

[0311] X ml of 150 mg / ml formulation of omalizumab for use in a method of treating one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, where X is 2, and which X ml of 150 mg / ml omalizumab formulation are administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of 150 mg / ml omalizumab formulation, which X ml of 150 mg / ml omalizumab formulation have 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm;and the syringe further comprising: a stopper, and a needle, the syringe being configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper.; Example 2

[0312] X ml of 150 mg / ml formulation of omalizumab for use in a method of treating one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, wherein X is 2, 1 or 0.5, and wherein X ml of 150 mg / ml formulation of omalizumab is administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, which X ml of 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a stopper, and a 27 gauge needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when force is applied to the stopper. Example 3

[0313] X ml of 150 mg / ml formulation of omalizumab for use according to Example 2, wherein the needle has one of: a) a minimum internal diameter of 0.277 mm; (b) a minimum internal diameter of 0.191 mm; (c) a minimum internal diameter of 0.184 mm; and (d) a minimum internal diameter of 0.241 mm. Example 4

[0314] X ml of 150 mg / ml formulation of omalizumab for use in a method of treating one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, wherein X is 2, 1 or 0.5, and wherein X ml of 150 mg / ml formulation of omalizumab is administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of 150 mg / ml formulation of omalizumab, wherein X ml of 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a stopper, and a needle;and the syringe being configured to expel the 150 mg / ml formulation of omalizumab contained in the reservoir through the needle when a force is applied to the stopper, the syringe being configured to expel the formulation of omalizumab through the needle in less than 0.8 seconds per ml per N of constant force applied to the stopper. ;

[0315] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 4, wherein X is 2, wherein the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 0.75 ± 0.5 seconds per ml per N of constant force applied. Example 6

[0316] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 5, wherein X is 2, wherein the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in one or more of: (a) less than 16 seconds when a constant force of 10 N is applied to the stopper; (b) less than 8.5 seconds when a constant force of 17 N is applied to the stopper; and c) less than 5 seconds when a constant force of 30 N is applied to the stopper. Example 7

[0317] X ml of 150 mg / ml omalizumab formulation for use according to Example 6, wherein the syringe is configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle in one or more of: a) about 16 seconds to about 14 seconds when a constant force of 10 N is applied to the stopper; (b) about 8.5 seconds to about 6 seconds when a constant force of 17 N is applied to the stopper; and c) about 5 seconds to about 4 seconds when a constant force of 30 N is applied to the stopper. Example 8

[0318] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 2 to 4, wherein X is 1 or 0.5, wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in less than 0.67 ± 0.5 seconds per ml per N of constant force applied, optionally less than 0.54 ± 0.2 seconds per ml per N of constant force applied, further optionally less than 0.4 ± 0.5 seconds per ml per N of constant force applied. Example 9

[0319] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 2 to 4 and 8, wherein X is 1, and wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 7.5 seconds when a constant force of 10 N is applied to the stopper; (b) less than 3 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds when a constant force of 30 N is applied to the stopper. Example 10

[0320] X ml of 150 mg / ml omalizumab formulation for use according to Example 9, wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 7.5 seconds to about 4 seconds when a constant force of 10 N is applied to the stopper; (b) less than 3.5 seconds to about 2 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30 N is applied to the stopper. Example 11

[0321] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 2 to 4 and 8, wherein X is 0.5, and wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 4 seconds when a constant force of 10 N is applied to the stopper; (b) less than 2 seconds when a constant force of 17 N is applied to the stopper; and c) less than 1 second when a constant force of 30 N is applied to the stopper. Example 12

[0322] X ml of 150 mg / ml omalizumab formulation for use according to Example 11, wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 4 seconds to about 2 seconds when a constant force of 10 N is applied to the stopper; (b) less than 2 seconds to about 1 second when a constant force of 17 N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30 N is applied to the plug. Example 13

[0323] X ml of 150 mg / ml formulation of omalizumab for use according to any one of Examples 1 to 12, wherein the syringe contains: (a) at least 76% of the major charge variant of omalizumab, measured by ion exchange chromatography, after filling with a 150 mg / ml solution of omalizumab stored at 5°C ± 1°C; and / or (b) at least 77% of the major charge variant of omalizumab, measured by ion exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 1°C for 2.5 months. Example 14

[0324] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 12, wherein the percentage of major charge variant of omalizumab in the syringe, measured by ion exchange chromatography, is reduced by 2% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months. Example 15

[0325] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 14, wherein the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is at least: a) 62% after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 1°C; and / or b) 62% after it was filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 1°C for 2.5 months. Example 16

[0326] X ml of 150 mg / ml formulation of omalizumab for use according to any one of Examples 1 to 15, wherein the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is reduced by 0.4% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months. Example 17

[0327] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 16, wherein the syringe contains at least 0.4 mg / ml polysorbate 20 after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 1°C. Example 18

[0328] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 12, wherein the syringe contains at least 69% of the major charge variant of omalizumab, as measured by ion exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 1.5 months.

[0329] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 12 and 18, wherein the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is at least: a) 56% for the syringe after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 1.5 months; and / or b) 51% after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 2.5 months. Example 20

[0330] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 12, 18 and 19, wherein the syringe contains: a) at least 0.4 mg / ml polysorbate 20 after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 1.5 months; and / or b) at least 0.3 mg / ml polysorbate 20 after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 6 months. Example 21

[0331] X ml of 150 mg / ml formulation of omalizumab for use according to any one of Examples 1 to 4 and 20 when not dependent on Example 2 or Example 3, wherein the needle is one of: 23 gauge, 24 gauge, 25 gauge, 26 gauge, 27 gauge, 28 gauge, 29 gauge, 30 gauge, 31 gauge, and 32 gauge. Example 22

[0332] X ml of 150 mg / ml formulation of omalizumab for use according to any one of Examples 1 to 4 and 20 when not dependent on Example 2 or Example 3, wherein the needle is one of: a) gauge 23 defining a minimum internal diameter of 0.370 mm; b) gauge 23 defining a minimum internal diameter of 0.317 mm; c) 24 gauge defining a minimum internal diameter of 0.343 mm; d) 24 gauge defining a minimum internal diameter of 0.280 mm; e) gauge 25 defining a minimum internal diameter of 0.292 mm; f) gauge 25 defining a minimum internal diameter of 0.232 mm; g) gauge 26 defining a minimum internal diameter of 0.292 mm; (h) gauge 26 defining a minimum internal diameter of 0.232 mm; (i) gauge 27 defining a minimum internal diameter of 0.277 mm; j) gauge 27 defining a minimum internal diameter of 0.191 mm; k) gauge 27 defining a minimum internal diameter of 0.184 mm; 1) 27 gauge defining a minimum internal diameter of 0.241 mm; m) 28 gauge defining a minimum internal diameter of 0.133 mm; n) 28 gauge defining a minimum internal diameter of 0.190 mm; o) gauge 29 defining a minimum internal diameter of 0.265 mm; p) gauge 29 defining a minimum internal diameter of 0.240 mm; q) gauge 29 defining a minimum internal diameter of 0.190 mm; r) gauge 29 defining a minimum internal diameter of 0.133 mm; s) gauge 30 defining a minimum internal diameter of 0.240 mm; t) gauge 30 defining a minimum internal diameter of 0.190 mm; u) gauge 30 defining a minimum internal diameter of 0.165 mm; (v) gauge 30 defining a minimum internal diameter of 0.133 mm; w) gauge 31 defining a minimum internal diameter of 0.176 mm; x) gauge 31 defining a minimum internal diameter of 0.146 mm; y) gauge 31 defining a minimum internal diameter of 0.125 mm; z) gauge 31 defining a minimum internal diameter of 0.114 mm; aa) gauge 32 defining a minimum internal diameter of 0.146 mm; bb) 32 gauge defining a minimum internal diameter of 0.125 mm; ce) 32 gauge defining a minimum internal diameter of 0.105 mm; and dd) 32 gauge defining a minimum internal diameter of 0.089 mm. Example 23

[0333] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 22, wherein the stopper has a fluororesin on the product contacting side or an ethylene tetrafluoroethylene (ETFE) barrier film lamination. Example 24

[0334] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 23, wherein the stopper has a UV-cured B2-40 lubricating coating or is lubricated with a 1000 cSt silicone oil. Example 25

[0335] X ml of 150 mg / ml formulation of omalizumab for use according to any one of Examples 1 to 24, wherein the syringe has an internal coating of 0.4 ± 0.2 mg of polydimethylsiloxane. Example 26

[0336] X ml of 150 mg / ml formulation of omalizumab for use according to any one of Examples 1 to 25, wherein the needle has 3 bevels on its distal surface or 5 bevels on its distal surface. Example 27

[0337] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 25, wherein the apparent viscosity of the formulation at 150 mg / ml omalizumab at a shear rate of 200 s 1 is: 24.7 ± 0.5 mPa.s at 5.0 ± 0.2°C, 15.3 ± 0.5 mPa.s at 15.0 ± 0.2°C, 11.4 ± 0.5 mPa.s at 25.0 ± 0.2°C or 7.2 ± 1.2 mPa.s at 40.0 ± 0.2°C. Example 28

[0338] X ml of 150 mg / ml formulation of omalizumab for use according to any one of Examples 1 to 27, wherein the syringe has a latex-free needle shield. Example 29

[0339] X ml of 150 mg / ml formulation of omalizumab for use according to any one of Examples 1 to 28, wherein the syringe has a round flange; optionally wherein the round flange has a maximum diameter of 11 ± 0.25 mm or 14.7 ± 0.25 mm. Example 30

[0340] X ml of 150 mg / ml formulation of omalizumab for use according to any one of Examples 2 to 4 and 8 to 29 when X is 1 or 0.5, wherein the syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 6.35 mm ± 0.05 mm. Example 31

[0341] X ml of 150 mg / ml formulation of omalizumab for use according to any one of Examples 2 to 4 and 8 to 30 when X is 1 or 0.5, wherein, when the stopper is not inserted into the reservoir, it has one of: (a) a maximum external diameter of 6.67 mm to 7.10 mm and / or a length of 7.85 ± 0.4 mm; and (b) a maximum external diameter of 6.70 ± 0.15 mm and / or a length of 7.85 ± 0.4 mm. Example 32

[0342] X ml of 150 mg / ml formulation of omalizumab for use according to any one of Examples 2 to 4 and 8 to 31 when X is 1 or 0.5, wherein the stopper has at least one rib having an outer diameter of 6.60 ± 0.15 mm. Example 33

[0343] X ml of 150 mg / ml formulation of omalizumab for use according to any one of Examples 1 to 7 and 13 to 29 when X is 2, wherein the syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 8.65 mm ± 0.05 mm. Example 34

[0344] X ml of 150 mg / ml formulation of omalizumab for use according to any one of Examples 1 to 7, 13 to 29, and 33 when X is 2, wherein the cap has a maximum external diameter of 9.05 ± 0.15 mm and / or a length of 7.70 ± 0.4 mm when not inserted into the tank. Example 35

[0345] X ml of 150 mg / ml formulation of omalizumab for use according to any one of Examples 1 to 7, 13 to 29, 33 and 34 when X is 2, wherein the stopper has at least one rib having an outer diameter of 9.00 ±0.15 mm. Example 36

[0346] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 17 and 21 to 35 when not dependent on Examples 18 to 20, wherein the peel force configured to move the plug of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: (a) about 2 N to about 4 N after storage at 5°C ± 1°C for 2.5 months; b) about 2 N to about 4 N after storage at 5°C ± 1°C for 6 months. Example 37

[0347] X ml of 150 mg / ml formulation of omalizumab for use according to any one of Examples 1 to 12 and 18 to 35 when not dependent on Examples 12 to 17, wherein the peel force configured to move the plug of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) about 2 N to about 3.5 N at 25°C ± 1°C after filling; b) about 2 N to about 4.5 N after storage at 25°C ± 1°C for 1.5 months; (c) about 2.5 N to about 5 N after storage at 25°C ± 1°C for 2.5 months; and / or (d) about 2.5 N to about 5.5 N after storage at 25°C ± 1°C for 6 months. Example 38

[0348] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 12 and 21 to 35 when not dependent on Examples 13 to 20, wherein the peel force configured to move the plug of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) about 3 N to about 4.5 N after storage at 40°C ± 1°C for 1.5 months; and b) about 3 N to about 5 N after storage at 40°C ± 1°C for 2.5 months. Example 39

[0349] X ml of 150 mg / ml formulation of omalizumab for use according to any one of Examples 1 to 38, wherein the syringe is provided in a needle shield device comprising a needle sleeve and a plunger; and wherein manual force can be applied to the plunger to expel the formulation at 150 mg / ml omalizumab and unlock the needle sleeve so that the needle sleeve can cover the needle after injection. Example 40

[0350] X ml of 150 mg / ml formulation of omalizumab for use according to any one of Examples 1 to 39, wherein the syringe is manufactured by a process comprising: aseptic filling of the reservoir with the 150 mg / ml formulation of omalizumab; and clogging the tank with the cap. Example 41

[0351] X ml of 150 mg / ml formulation of omalizumab for use according to Example 40, wherein aseptic filling is carried out using a peristaltic pump or a stainless steel piston pump. Example 42

[0352] X ml of 150 mg / ml formulation of omalizumab for use according to Example 40 or 41, wherein, prior to aseptic filling, the reservoir and needle are sterilized by treatment with ethylene oxide gas, e-beam and / or steam sterilization in an autoclave. Example 43

[0353] A syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, wherein X ml of 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a stopper, and a needle, the syringe being configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper. Example 44

[0354] A syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, which X ml of 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a stopper, and a 27 gauge needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when force is applied to the stopper. Example 45

[0355] A syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, which X ml of 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; where X is 2; and the syringe further comprising: a cork, and a needle, the syringe being configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper. Example 46

[0356] A syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, which X ml of 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; where X is 0.5, 1 or 2; and the syringe further comprising: a cork, and a 27 gauge needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when force is applied to the stopper. Example 47

[0357] The syringe of Example 46, wherein the needle has one of: (a) a minimum internal diameter of 0.277 mm; (b) a minimum internal diameter of 0.191 mm; (c) a minimum internal diameter of 0.184 mm; and (d) a minimum internal diameter of 0.241 mm. Example 48

[0358] A syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, which X ml of 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; where X is 0.5, 1 or 2; and the syringe further comprising: a cork, and a needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, the syringe being configured to expel the 150 mg / ml omalizumab formulation through the needle in less than 0.8 seconds per ml per N of constant force applied to the stopper. Example 49

[0359] The syringe according to any one of Examples 45 to 48, wherein X is 2, which syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 0.75 ± 0.5 seconds per ml per N of constant force applied. Example 50

[0360] The syringe according to any one of Examples 45 to 49, wherein X is 2, which syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in one or more of: (a) less than 16 seconds when a constant force of 10 N is applied to the stopper; (b) less than 8.5 seconds when a constant force of 17 N is applied to the stopper; and (c) less than 5 seconds when a constant force of 30 N is applied to the stopper. Example 51

[0361] The syringe according to Example 50, which syringe is configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle in one or more of: a) about 16 seconds to about 14 seconds when a constant force of 10 N is applied to the stopper; (b) about 8.5 seconds to about 6 seconds when a constant force of 17 N is applied to the plug; and c) about 5 seconds to about 4 seconds when a constant force of 30 N is applied to the stopper. Example 52

[0362] The syringe according to any one of Examples 46 to 48, wherein X is 1 or 0.5, which syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in less than 0.67 ± 0.5 seconds per ml per N of constant force applied, optionally less than 0.54 ± 0.2 seconds per ml per N of constant force applied, further optionally less than 0.4 ± 0.5 seconds per ml per N of constant force applied. Example 53

[0363] The syringe according to any one of Examples 46 to 48 and 52, wherein X is 1, which syringe is intended to expel X ml of 150 mg / ml formulation of omalizumab through the needle in one or more of: (a) less than 7.5 seconds when a constant force of 10 N is applied to the stopper; (b) less than 3 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds when a constant force of 30 N is applied to the stopper. Example 54

[0364] The syringe according to Example 53, which syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 7.5 seconds to about 4 seconds when a constant force of 10 N is applied to the stopper; (b) less than 3.5 seconds to about 2 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30 N is applied to the stopper. Example 55

[0365] The syringe according to any one of Examples 46 to 48 and 52, wherein X is 0.5, which syringe is intended to expel X ml of 150 mg / ml formulation of omalizumab through the needle in one or more of: (a) less than 4 seconds when a constant force of 10 N is applied to the stopper; (b) less than 2 seconds when a constant force of 17 N is applied to the stopper; and c) less than 1 second when a constant force of 30 N is applied to the stopper. Example 56

[0366] The syringe according to Example 55, which syringe is intended to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: a) less than 4 seconds to about 2 seconds when a constant force of 10 N is applied to the stopper; (b) less than 2 seconds to about 1 second when a constant force of 17 N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30 N is applied to the plug. Example 57

[0367] The syringe according to any one of Examples 45 to 56, which syringe contains: (a) at least 76% of the major charge variant of omalizumab, measured by ion exchange chromatography, after filling with a 150 mg / ml solution of omalizumab stored at 5°C ± 1°C; and / or (b) at least 77% of the major charge variant of omalizumab, measured by ion exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 1°C for 2.5 months. Example 58

[0368] The syringe according to any one of Examples 45 to 56, wherein the percentage of major charge variant of omalizumab in the syringe, measured by means of ion exchange chromatography, is reduced by 2% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months. Example 59

[0369] The syringe according to any one of Examples 45 to 58, wherein the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is at least: a) 62% after filling with a 150 mg / ml solution of omalizumab stored at 5°C ± 1°C; and / or b) 62% after it was filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 1°C for 2.5 months. Example 60

[0370] The syringe according to any one of Examples 45 to 59, wherein the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is reduced by 0.4% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months. Example 61

[0371] The syringe according to any one of Examples 45 to 60, which syringe contains at least 0.4 mg / ml of polysorbate 20 after filling with a 150 mg / ml solution of omalizumab stored at 5°C ± 1°C. Example 62

[0372] The syringe according to any one of Examples 45 to 56, which syringe contains at least 69% of the major charge variant of omalizumab, as measured by ion exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 1.5 months. Example 63

[0373] The syringe according to any one of Examples 45 to 56 and 62, wherein the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is at least: (a) 56% for the syringe after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 1.5 months; and / or b) 51% for the syringe after it was filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 2.5 months. Example 64

[0374] The syringe according to any one of Examples 45 to 56, 62 and 63, which syringe contains: a) at least 0.4 mg / ml polysorbate 20 after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 1.5 months; and / or b) at least 0.3 mg / ml polysorbate 20 after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 6 months. Example 65

[0375] The syringe according to any one of Examples 45 and 48 to 64 when not dependent on Example 2 or Example 3, which needle has one of: 23 gauge, 24 gauge, 25 gauge, 26 gauge, 27 gauge, 28 gauge, 29 gauge, 30 gauge, 31 gauge, and 32 gauge. Example 66

[0376] The syringe according to any one of Examples 45 and 48 to 64 when they do not depend on Example 2 or Example 3, which needle has one of: a) gauge 23 defining a minimum internal diameter of 0.370 mm; b) gauge 23 defining a minimum internal diameter of 0.317 mm; (c) gauge 24 defining a minimum internal diameter of 0.343 mm; d) gauge 24 defining a minimum internal diameter of 0.280 mm; (e) gauge 25 defining a minimum internal diameter of 0.292 mm; (f) gauge 25 defining a minimum internal diameter of 0.232 mm; (g) gauge 26 defining a minimum internal diameter of 0.292 mm; (h) gauge 27 defining a minimum internal diameter of 0.232 mm; (i) gauge 27 defining a minimum internal diameter of 0.277 mm; j) gauge 27 defining a minimum internal diameter of 0.191 mm; k) gauge 27 defining a minimum internal diameter of 0.184 mm; 1) gauge 27 defining a minimum internal diameter of 0.241 mm; m) gauge 28 defining a minimum internal diameter of 0.133 mm; n) gauge 28 defining a minimum internal diameter of 0.190 mm; o) gauge 29 defining a minimum internal diameter of 0.265 mm; p) gauge 29 defining a minimum internal diameter of 0.240 mm; q) gauge 29 defining a minimum internal diameter of 0.190 mm; r) gauge 29 defining a minimum internal diameter of 0.133 mm; s) gauge 30 defining a minimum internal diameter of 0.240 mm; t) gauge 30 defining a minimum internal diameter of 0.190 mm; u) gauge 30 defining a minimum internal diameter of 0.165 mm; (v) gauge 30 defining a minimum internal diameter of 0.133 mm; w) gauge 31 defining a minimum internal diameter of 0.176 mm; x) gauge 31 defining a minimum internal diameter of 0.146 mm; y) gauge 31 defining a minimum internal diameter of 0.125 mm; z) gauge 31 defining a minimum internal diameter of 0.114 mm; aa) gauge 32 defining a minimum internal diameter of 0.146 mm; bb) 32 gauge defining a minimum internal diameter of 0.125 mm; ce) 32 gauge defining a minimum internal diameter of 0.105 mm; and dd) 32 gauge defining a minimum internal diameter of 0.089 mm. Example 67

[0377] The syringe according to any one of Examples 45 to 66, wherein the stopper has a fluororesin on the product contacting side or an ethylene tetrafluoroethylene (ETFE) barrier film lamination. Example 68

[0378] The syringe according to any one of Examples 45 to 67, wherein the stopper has a UV-cured B2-40 lubricating coating or is lubricated with a 1000 cSt silicone oil. Example 69

[0379] The syringe according to any one of Examples 45 to 68, which syringe has an internal coating of 0.4 ± 0.2 mg of polydimethylsiloxane. Example 70

[0380] The syringe according to any one of Examples 45 to 69, wherein the needle has 3 bevels on its distal surface or 5 bevels on its distal surface. Example 71

[0381] The syringe according to any one of Examples 45 to 70, wherein the apparent viscosity of the 150 mg / ml formulation of omalizumab at a shear rate of 200 s 1 is: 24.7 ± 0.5 mPa.s at 5.0 ± 0.2°C, 15.3 ± 0.5 mPa.s at 15.0 ± 0.2°C, 11.4 ± 0.5 mPa.s at 25.0 ± 0.2°C or 7.2 ± 1.2 mPa.s at 40.0 ± 0.2°C. Example 72

[0382] The syringe according to any one of Examples 45 to 71, which syringe has a latex-free needle shield. Example 73

[0383] The syringe according to any one of Examples 45 to 72, which syringe has a round flange; optionally wherein the round flange has a maximum diameter of 11 ± 0.25 mm or 14.7 ± 0.25 mm. Example 74

[0384] The syringe according to any one of Examples 46 to 48 and 52 to 73 when X is 1 or 0.5, which syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 6.35 mm ± 0.05 mm. Example 75

[0385] The syringe according to any one of Examples 46 to 48 and 52 to 74 when X is equal to 1 or 0.5, in which, when the cap is not inserted into the tank, it has one of: (a) a maximum external diameter of 6.67 mm to 7.10 mm and / or a length of 7.85 ± 0.4 mm; and (b) a maximum external diameter of 6.70 ± 0.15 mm and / or a length of 7.85 ± 0.4 mm. Example 76

[0386] The syringe according to any one of Examples 46 to 48 and 52 to 74 when X is 1 or 0.5, wherein the stopper has at least one rib having an outside diameter of 6.60 ±0.15 mm. Example 77

[0387] The syringe according to any one of Examples 45 to 51 and 57 to 73 when X is 2, which syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 8.65 mm ± 0.05 mm. Example 78

[0388] The syringe according to any one of Examples 45 to 51, 57 to 73 and 77 when X is 2, wherein the stopper has a maximum external diameter of 9.05 ± 0.15 mm and / or a length of 7.70 ± 0.4 mm when not inserted into the reservoir. Example 79

[0389] The syringe according to any one of Examples 45 to 51, 57 to 73, 77 and 78 when X is 2, wherein the stopper has at least one rib having an outside diameter of 9.00 ±0.15 mm. Example 80

[0390] The syringe according to any one of Examples 45 to 61 and 65 to 79 when not dependent on Examples 62 to 64, wherein the peeling force configured to move the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: (a) about 2 N to about 4 N after storage at 5°C ± 1°C for 2.5 months; b) about 2 N to about 4 N after storage at 5°C ± 1°C for 6 months. Example 81

[0391] The syringe according to any one of Examples 45 to 56 and 62 to 79 when not dependent on Examples 52 to 61, wherein the peeling force configured to move the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) about 2 N to about 3.5 N at 25°C ± 1°C after filling; b) about 2 N to about 4.5 N after storage at 25°C ± 1°C for 1.5 months; (c) about 2.5 N to about 5 N after storage at 25°C ± 1°C for 2.5 months; and / or (d) about 2.5 N to about 5.5 N after storage at 25°C ± 1°C for 6 months. Example 82

[0392] The syringe according to any one of Examples 45 to 56 and 65 to 79 when not dependent on Examples 57 to 64, wherein the peeling force configured to move the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) about 3 N to about 4.5 N after storage at 40°C ± 1°C for 1.5 months; and b) about 3 N to about 5 N after storage at 40°C ± 1°C for 2.5 months. Example 83

[0393] The syringe according to any one of Examples 45 to 82, which syringe is provided in a needle shield device comprising a needle sleeve and a plunger; and wherein manual force can be applied to the plunger to expel the 150 mg / ml formulation of omalizumab and unlock the needle sleeve so that the needle sleeve can cover the needle after injection. Example 84

[0394] The syringe according to any one of Examples 45 to 83, which syringe is manufactured by a process comprising: aseptic filling of the reservoir with the 150 mg / ml formulation of omalizumab; and clogging the tank with the cap. Example 85

[0395] The syringe according to Example 84, in which the aseptic filling is carried out by means of a peristaltic pump or a stainless steel piston pump. Example 86

[0396] The syringe according to Example 84 or 85, wherein, prior to aseptic filling, the reservoir and needle are sterilized by treatment with ethylene oxide gas, e-beam and / or steam sterilization in an autoclave. Example 87

[0397] The syringe according to Examples 45 to 86, which is usable with an auto-injector. Example 88

[0398] A method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 2 ml of a 150 mg / ml formulation of omalizumab, wherein the omalizumab formulation is administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with 2 ml of a 150 mg / ml formulation of omalizumab, wherein 2 ml of the 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a stopper, and a 27 gauge needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when force is applied to the stopper. Example 89

[0399] The method according to Example 88, wherein the needle has one of: a) a minimum internal diameter of 0.277 mm; (b) a minimum internal diameter of 0.191 mm; (c) a minimum internal diameter of 0.184 mm; and (d) a minimum internal diameter of 0.241 mm. Example 90

[0400] A method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient X ml of 150 mg / ml formulation of omalizumab, where X is 2, 1 or 0.5, and wherein the X ml of 150 mg / ml formulation of omalizumab is administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, which X ml of 150 mg / ml formulation of omalizumab have 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a cork, and a 25 gauge to 29 gauge needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, wherein one of the following is satisfied when a constant force of 10 N is applied to the stopper, (a) when X is 2, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 16 seconds; (b) when X is 1, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 5 seconds; and (c) when X is 0.5, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 4 seconds. Example 91

[0401] The method of Example 88 or 90, wherein X is 2, wherein the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in one or more of: (a) less than 8.5 seconds when a constant force of 17 N is applied to the stopper; and b) less than 5 seconds when a constant force of 30 N is applied to the stopper. Example 92

[0402] The method of Example 91, wherein the syringe is configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle in one or more of: a) about 16 seconds to about 14 seconds when a constant force of 10 N is applied to the stopper; (b) about 8.5 seconds to about 6 seconds when a constant force of 17 N is applied to the plug; and c) about 5 seconds to about 4 seconds when a constant force of 30 N is applied to the stopper. Example 93

[0403] The method of Example 90, wherein X is 1, and wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 5 seconds, less than 4.75 seconds, less than 4.5 seconds, less than 4.25 seconds, or about 4 seconds when a constant force of 10 N is applied to the stopper; (b) less than 3 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds when a constant force of 30 N is applied to the stopper. Example 94

[0404] The method of Example 93, wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 5 seconds to about 4 seconds, less than 4.75 seconds to about 4 seconds, less than 4.5 seconds to about 4 seconds, less than 4.25 seconds to about 4 seconds, or about 4 seconds when a constant force of 10 N is applied to the stopper; (b) less than 3.5 seconds to about 2 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30 N is applied to the stopper. Example 95

[0405] The method of Example 90, wherein X is 0.5, and wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 2 seconds when a constant force of 17 N is applied to the stopper; and b) less than 1 second when a constant force of 30 N is applied to the stopper. Example 96

[0406] The method of Example 95, wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 4 seconds to about 2 seconds when a constant force of 10 N is applied to the stopper; (b) less than 2 seconds to about 1 second when a constant force of 17 N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30 N is applied to the plug. Example 97

[0407] The method of Example 88 or Example 90, wherein the syringe contains: (a) at least 76% of the major charge variant of omalizumab, measured by ion exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab stored at 5°C ± 1°C; and / or (b) at least 77% of the major charge variant of omalizumab, measured by ion exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 1°C for 2.5 months. Example 98

[0408] The method of Example 88 or Example 90, wherein the percentage of major charge variant of omalizumab in the syringe, measured by ion exchange chromatography, is reduced by 2% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months measured from filling. Example 99

[0409] The method of Example 88 or Example 90, wherein the proportion of the first syringe peak, measured by means of hydrophobic chromatography, is at least: a) 62% after filling with a 150 mg / ml solution of omalizumab stored at 5°C ± 1°C; and / or b) 62% after it was filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 1°C for 2.5 months. Example 100

[0410] The method of Example 88 or Example 90, wherein the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is reduced by 0.4% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months. Example 101

[0411] The method of Example 88 or Example 90, wherein the syringe contains at least 0.4 mg / ml of polysorbate 20 after filling with a 150 mg / ml solution of omalizumab stored at 5°C ± 1°C. Example 102

[0412] The method of Example 88 or Example 90, wherein the syringe contains at least 69% of the major charge variant of omalizumab, as measured by ion exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 1.5 months. Example 103

[0413] The method of Example 88 or Example 90, wherein the proportion of the first syringe peak, measured by means of hydrophobic chromatography, is at least: (a) 56% for the syringe after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 1.5 months; and / or b) 51% for the syringe after it was filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 2.5 months. Example 104

[0414] The method of Example 88 or Example 90, wherein the syringe contains: a) at least 0.4 mg / ml of polysorbate 20 after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 1.5 months; and / or b) at least 0.3 mg / ml of polysorbate 20 after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 6 months. Example 105

[0415] The method of Example 90, wherein the needle has a gauge of 26 gauge to 29 gauge, especially 27 gauge. Example 106

[0416] The method of Example 105, wherein, when the needle is 25 gauge, the needle has one of: (a) a minimum internal diameter of 0.292 mm, and (b) a minimum internal diameter of 0.232 mm. Example 107

[0417] The method of Example 105, wherein, when the needle is 26 gauge, the needle has one of: (a) a minimum internal diameter of 0.292 mm, and (b) a minimum internal diameter of 0.232 mm. Example 108

[0418] The method of Example 105, wherein, when the needle is 27 gauge, the needle has one of: (a) a minimum internal diameter of 0.277 mm; (b) a minimum internal diameter of 0.191 mm; (c) a minimum internal diameter of 0.184 mm; and (d) a minimum internal diameter of 0.241 mm. Example 109

[0419] The method of Example 105, wherein, when the needle is 28 gauge, the needle has one of: (a) a minimum internal diameter of 0.133 mm; and (b) a minimum internal diameter of 0.190 mm. Example 110

[0420] The method of Example 105, wherein, when the needle is 29 gauge, the needle has one of: (a) a minimum internal diameter of 0.265 mm; (b) a minimum internal diameter of 0.240 mm; (c) a minimum internal diameter of 0.190 mm; and (d) a minimum internal diameter of 0.133 mm; preferably the needle has a minimum internal diameter of 0.240 mm or 0.265 mm. Example 111

[0421] The method of Example 88 or Example 90, wherein the cap has a fluororesin on the product contacting side or an ethylene tetrafluoroethylene (ETFE) barrier film lamination. Example 112

[0422] The method of Example 88 or Example 90, wherein the stopper has a UV-cured B2-40 lubricating coating or is lubricated with a 1000 cSt silicone oil. Example 113

[0423] The method of Example 88 or Example 90 when X is 2, wherein the syringe has an internal coating of 0.7 ± 0.2 mg of polydimethylsiloxane. Example 114

[0424] The method of Example 90, when X is 1 or 0.5, wherein the syringe has an internal coating of 0.4 ± 0.2 mg of polydimethylsiloxane. Example 115

[0425] The method of Example 88 or Example 90, wherein the needle has 3 bevels on its distal surface or 5 bevels on its distal surface. Example 116

[0426] The method of Example 88 or Example 90, wherein the apparent viscosity of the 150 mg / ml formulation of omalizumab is 12 to 14 mPa.s or, when measured at a shear rate of 200 s 1 is: 24.7 ± 0.5 mPa.s at 5.0 ± 0.2°C, 15.3 ± 0.5 mPa.s at 15.0 ± 0.2°C, 11.4 ± 0.5 mPa.s at 25.0 ± 0.2°C or 7.2 ± 1.2 mPa.s at 40.0 ± 0.2°C. Example 117

[0427] The method of Example 88 or Example 90, wherein the syringe has a latex-free needle shield. Example 118

[0428] The method of Example 88 or Example 90, wherein the syringe has a round flange at a proximal end of the reservoir; optionally in which the round collar has a maximum diameter of 11 ± 0.25 mm or 14.7 ± 0.25 mm. Example 119

[0429] The method of Example 90 when X is 1 or 0.5, wherein the syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 6.35 mm ± 0.05 mm. Example 120

[0430] The method of Example 90 wherein, when the cap is not inserted into the reservoir, it has one of: (a) a maximum external diameter of 6.67 mm to 7.10 mm and / or a length of 7.85 ± 0.4 mm; and (b) a maximum external diameter of 6.70 ± 0.15 mm and / or a length of 7.85 ± 0.4 mm. Example 121

[0431] The method of Example 90 when X is 1 or 0.5, wherein the plug has at least one circumferential rib having an outside diameter of 6.60 ±0.15 mm. Example 122

[0432] The method of Example 88 or Example 90 when X is 2, wherein the syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 8.65 mm ± 0.05 mm. Example 123

[0433] The method of Example 88 or Example 90 when X is 2, wherein the plug has a maximum external diameter of 9.05 ± 0.15 mm and / or a length of 7.70 ± 0.4 mm when not inserted into the reservoir. Example 124

[0434] The method of Example 88 or Example 90 when X is 2, wherein the plug has at least one rib having an outside diameter of 9.00 ±0.15 mm. Example 125

[0435] The method of Example 88 or Example 90, wherein the peel force configured to move the cap of the present invention from an initial fixed point at a rate of 190 mm / min is one or more of: a) about 2 N to about 4 N after storage at 5°C ± 1°C for 2.5 months after filling; b) about 2 N to about 4 N after storage at 5°C ± 1°C for 6 months after filling. Example 126

[0436] The method of Example 88 or Example 90, wherein the peel force configured to move the cap of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) about 2 N to about 3.5 N at 25°C ± 1°C after filling; b) about 2 N to about 4.5 N after storage at 25°C ± 1°C for 1.5 months after filling; (c) about 2.5 N to about 5 N after storage at 25°C ± 1°C for 2.5 months after filling; and / or d) about 2.5 N to about 5.5 N after storage at 25°C ± 1°C for 6 months after filling. Example 127

[0437] The method of Example 88 or Example 90, wherein the peel force configured to move the cap of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) about 3 N to about 4.5 N after storage at 40°C ± 1°C for 1.5 months after filling; and b) about 3 N to about 5 N after storage at 40°C ± 1°C for 2.5 months after filling. Example 128

[0438] The method of Example 88 or Example 90, wherein the syringe is provided in a needle shield device comprising a needle sleeve and a plunger; and wherein manual force can be applied to the plunger to expel the 150 mg / ml formulation of omalizumab and unlock the needle sleeve so that the needle sleeve can cover the needle after injection. Example 129

[0439] The method of Example 88 or Example 90, wherein the syringe is manufactured by a process comprising: aseptic filling of the reservoir with the 150 mg / ml formulation of omalizumab; and clogging the tank with the cap. Example 130

[0440] The method of Example 129, wherein the aseptic filling is carried out by means of a peristaltic pump or a stainless steel piston pump. Example 131

[0441] The method of Example 129, wherein, prior to aseptic filling, the reservoir and needle are sterilized by treatment with ethylene oxide gas, electron beam, and / or steam sterilization in an autoclave. Example 132

[0442] A syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, where X is 2, 1 or 0.5, which X ml of 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a stopper, and a 25 gauge to 29 gauge needle, the syringe being configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, wherein one of the following is satisfied when a constant force of 10 N is applied to the stopper: a) when X is 2, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 16 seconds; b) when X is 1, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 5 seconds; and c) when X is 0.5, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 4 seconds. Example 133

[0443] The syringe of Example 132, wherein X is 1, which syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in less than 5 seconds to about 4 seconds, less than 4.75 seconds to about 4 seconds, less than 4.5 seconds to about 4 seconds, less than 4.25 seconds to about 4 seconds, or about 4 seconds, when a constant force of 10 N is applied to the stopper. Example 134

[0444] A syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, where X is 2, which X ml of 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a stopper, and a 27 gauge needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when force is applied to the stopper.

[0445] The method of Example 88 or Example 90, or the syringe according to Example 132 or 134, wherein the 150 mg / ml formulation of omalizumab consists of 150 mg / ml of antibody with 42.1 mg / ml of L-arginine hydrochloride, 1.37 mg / ml of L-histidine, 2.34 mg / ml of L-histidine hydrochloride monohydrate, 0.4 mg / ml of polysorbate 20 as an aqueous solution. Example 136

[0446] A method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 300 mg of an omalizumab formulation, which method comprises administering 2 ml of a 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 2 ml of a 150 mg / ml omalizumab formulation. Example 137

[0447] A method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 375 mg of an omalizumab formulation, which method comprises: administering 2 ml of a 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 2 ml of a 150 mg / ml omalizumab formulation; and administration of 0.5 ml of 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 0.5 ml of 150 mg / ml omalizumab formulation. Example 138

[0448] A method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 450 mg of an omalizumab formulation, which method comprises: administering 2 ml of a 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 2 ml of a 150 mg / ml omalizumab formulation; and administration of 1 ml of 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 1 ml of 150 mg / ml omalizumab formulation. Example 139

[0449] A method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 525 mg of an omalizumab formulation, which method comprises: administering 2 ml of a 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 2 ml of a 150 mg / ml omalizumab formulation; administration of 1 ml of 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 1 ml of 150 mg / ml omalizumab formulation; and administration of 0.5 ml of 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 0.5 ml of 150 mg / ml omalizumab formulation. Example 140

[0450] A method of treating a patient having one or more of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin prick test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 600 mg of an omalizumab formulation, which method comprises: administering 2 ml of a 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 2 ml of a 150 mg / ml omalizumab formulation; and administration of 2 ml of 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 2 ml of 150 mg / ml omalizumab formulation. Example 141

[0451] The method of any one of Examples 136 to 140, wherein any of the steps requiring administration of 2 ml of 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 2 ml of 150 mg / ml omalizumab formulation comprises carrying out the method of Example 88 or Example 90 wherein X is 2. Example 142

[0452] The method of any of Examples 137 and 139, wherein any of the steps requiring administration of 0.5 ml of 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 0.5 ml of 150 mg / ml omalizumab formulation comprises performing the method of Example 90 wherein X is 0.5. Example 143

[0453] The method of any of Examples 138 and 139, wherein any of the steps requiring administration of 1 ml of 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 1 ml of 150 mg / ml omalizumab formulation comprises performing the method of Example 90 wherein X is 1. Example 144

[0454] A syringe comprising: a reservoir filled with 2 ml of a 150 mg / ml formulation of omalizumab, wherein 2 ml of the 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a stopper, and a 27 gauge needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when force is applied to the stopper. Example 145

[0455] The syringe of Example 144, wherein the needle has one of: (a) a minimum internal diameter of 0.277 mm; (b) a minimum internal diameter of 0.191 mm; (c) a minimum internal diameter of 0.184 mm; and (d) a minimum internal diameter of 0.241 mm. Example 146

[0456] A syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, where X is 2, 1 or 0.5, which X ml of 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a stopper, and a 25 gauge to 29 gauge needle; and which syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, wherein one of the following is satisfied when a constant force of 10 N is applied to the stopper, (a) when X is 2, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 16 seconds; (b) when X is 1, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 5 seconds; and (c) when X is 0.5, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 4 seconds. Example 147

[0457] The syringe of Example 144 or 3, wherein X is 2, which syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in one or more of: (a) less than 8.5 seconds when a constant force of 17 N is applied to the stopper; and b) less than 5 seconds when a constant force of 30 N is applied to the stopper. Example 148

[0458] The syringe of Example 147, which syringe is configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle in one or more of: a) about 16 seconds to about 14 seconds when a constant force of 10 N is applied to the stopper; (b) about 8.5 seconds to about 6 seconds when a constant force of 17 N is applied to the plug; and c) about 5 seconds to about 4 seconds when a constant force of 30 N is applied to the stopper.

[0459] The syringe of Example 146, wherein X is 1, which syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 5 seconds, less than 4.75 seconds, less than 4.5 seconds, less than 4.25 seconds, or about 4 seconds when a constant force of 10 N is applied to the stopper; (b) less than 3 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds when a constant force of 30 N is applied to the stopper. Example 150

[0460] The syringe of Example 149, which syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: a) less than 5 seconds to about 4 seconds, less than 4.75 seconds to about 4 seconds, less than 4.5 seconds to about 4 seconds, less than 4.25 seconds to about 4 seconds, or about 4 seconds when a constant force of 10 N is applied to the stopper; (b) less than 3.5 seconds to about 2 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30 N is applied to the stopper. Example 151

[0461] The syringe of Example 146, wherein X is 0.5, which syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: (a) less than 2 seconds when a constant force of 17 N is applied to the stopper; and b) less than 1 second when a constant force of 30 N is applied to the stopper. Example 152

[0462] The syringe of Example 151, which syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: a) less than 4 seconds to about 2 seconds when a constant force of 10 N is applied to the stopper; (b) less than 2 seconds to about 1 second when a constant force of 17 N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30 N is applied to the plug.

[0463] The syringe of Example 144 or Example 146, which syringe contains: a) at least 76% of the major charge variant of omalizumab, as measured by ion exchange chromatography, after being filled with a 150 mg / ml solution of omalizumab stored at 5°C ± 1°C; and / or (b) at least 77% of the major charge variant of omalizumab, measured by ion exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 1°C for 2.5 months. Example 154

[0464] The syringe of Example 144 or Example 146, wherein the percentage of major charge variant of omalizumab in the syringe, as measured by ion exchange chromatography, is reduced by 2% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months measured from filling. Example 155

[0465] The syringe of Example 144 or Example 146, wherein the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is at least: a) 62% after filling with a 150 mg / ml solution of omalizumab stored at 5°C ± 1°C; and / or b) 62% after it was filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 1°C for 2.5 months. Example 156

[0466] The syringe of Example 144 or Example 146, wherein the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is reduced by 0.4% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months. Example 157

[0467] The syringe of Example 144 or Example 146, which syringe contains at least 0.4 mg / ml of polysorbate 20 after filling with a 150 mg / ml solution of omalizumab stored at 5°C ± 1°C. Example 158

[0468] The syringe of Example 144 or Example 146, which syringe contains at least 69% of the major charge variant of omalizumab, as measured by ion exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 1.5 months.

[0469] The syringe of Example 144 or Example 146, wherein the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is at least: (a) 56% for the syringe after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 1.5 months; and / or b) 51% for the syringe after it was filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 2.5 months. Example 160

[0470] The syringe of Example 144 or Example 146, which syringe contains: a) at least 0.4 mg / ml polysorbate 20 after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 1.5 months; and / or b) at least 0.3 mg / ml polysorbate 20 after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 6 months. Example 161

[0471] The syringe of Example 146, wherein the needle has a gauge of 26 gauge to 29 gauge, preferably 27 gauge. Example 162

[0472] The syringe of Example 161, wherein, when the needle is 25 gauge, the needle has one of: (a) a minimum internal diameter of 0.292 mm, and (b) a minimum internal diameter of 0.232 mm. Example 163

[0473] The syringe of Example 161, wherein, when the needle is 26 gauge, the needle has one of: (a) a minimum internal diameter of 0.292 mm, and (b) a minimum internal diameter of 0.232 mm. Example 164

[0474] The syringe of Example 161, wherein, when the needle is 27 gauge, the needle has one of: (a) a minimum internal diameter of 0.277 mm; (b) a minimum internal diameter of 0.191 mm; (c) a minimum internal diameter of 0.184 mm; and (d) a minimum internal diameter of 0.241 mm. Example 165

[0475] The syringe of Example 161, wherein, when the needle is 28 gauge, the needle has one of: (a) a minimum internal diameter of 0.133 mm; and (b) a minimum internal diameter of 0.190 mm. Example 166

[0476] The syringe of Example 161, wherein, when the needle is 29 gauge, the needle has one of: (a) a minimum internal diameter of 0.265 mm; (b) a minimum internal diameter of 0.240 mm; (c) a minimum internal diameter of 0.190 mm; and (d) a minimum internal diameter of 0.133 mm; preferably the needle has a minimum internal diameter of 0.240 mm or 0.265 mm. Example 167

[0477] The syringe of Example 144 or Example 146, wherein the stopper has a fluororesin on the product-contacting side or an ethylene-tetrafluoroethylene (ETFE) barrier film lamination. Example 168

[0478] The syringe of Example 144 or Example 146, wherein the stopper has a UV-cured B2-40 lubricating coating or is lubricated with a 1000 cSt silicone oil. Example 169

[0479] The syringe of Example 144 or Example 146 when X is 2, wherein the syringe has an internal coating of 0.7 ± 0.2 mg of polydimethylsiloxane. Example 170

[0480] The syringe of Example 146, when X is 1 or 0.5, which syringe has an internal coating of 0.4 ± 0.2 mg of polydimethylsiloxane. Example 171

[0481] The syringe of Example 144 or Example 146, wherein the needle has 3 bevels on its distal surface or 5 bevels on its distal surface. Example 172

[0482] The syringe of Example 144 or Example 146, wherein the apparent viscosity of the 150 mg / ml formulation of omalizumab is 12 to 14 mPa.s or, when measured at a shear rate of 200 s 1 is: 24.7 ± 0.5 mPa.s at 5.0 ± 0.2°C, 15.3 ± 0.5 mPa.s at 15.0 ± 0.2°C, 11.4 ± 0.5 mPa.s at 25.0 ± 0.2°C or 7.2 ± 1.2 mPa.s at 40.0 ± 0.2°C. Example 173

[0483] The syringe of Example 144 or Example 146, which syringe has a latex-free needle shield. Example 174

[0484] The syringe of Example 144 or Example 146, which syringe has a round flange at a proximal end of the reservoir; optionally wherein the round flange has a maximum diameter of 11 ± 0.25 mm or 14.7 ± 0.25 mm. Example 175

[0485] The syringe of Example 146 when X is 1 or 0.5, which syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 6.35 mm ± 0.05 mm. Example 176

[0486] The syringe of Example 146, wherein, when the stopper is not inserted into the reservoir, it has one of: (a) a maximum external diameter of 6.67 mm to 7.10 mm and / or a length of 7.85 ± 0.4 mm; and (b) a maximum external diameter of 6.70 ± 0.15 mm and / or a length of 7.85 ± 0.4 mm. Example 177

[0487] The syringe of Example 146 when X is 1 or 0.5, wherein the stopper has at least one circumferential rib having an outside diameter of 6.60 ±0.15 mm. Example 178

[0488] The syringe of Example 144 or Example 146 when X is 2, which syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 8.65 mm ± 0.05 mm. Example 179

[0489] The syringe of Example 144 or Example 146 when X is 2, wherein the stopper has a maximum external diameter of 9.05 ± 0.15 mm and / or a length of 7.70 ± 0.4 mm when not inserted into the reservoir. Example 180

[0490] The syringe of Example 144 or Example 146 when X is 2, wherein the stopper has at least one rib having an outside diameter of 9.00 ±0.15 mm. Example 181

[0491] The syringe of Example 144 or Example 146, wherein the peel force configured to move the stopper of the present invention from an initial fixed point at a rate of 190 mm / min is one or more of: a) about 2 N to about 4 N after storage at 5°C ± 1°C for 2.5 months after filling; b) about 2 N to about 4 N after storage at 5°C ± 1°C for 6 months after filling. Example 182

[0492] The syringe of Example 144 or Example 146, wherein the peel force configured to move the stopper of the present invention from an initial fixed point at a rate of 190 mm / min is one or more of: a) about 2 N to about 3.5 N at 25°C ± 1°C after filling; b) about 2 N to about 4.5 N after storage at 25°C ± 1°C for 1.5 months after filling; (c) about 2.5 N to about 5 N after storage at 25°C ± 1°C for 2.5 months after filling; and / or d) about 2.5 N to about 5.5 N after storage at 25°C ± 1°C for 6 months after filling. Example 183

[0493] The syringe of Example 144 or Example 146, wherein the peel force configured to move the stopper of the present invention from an initial fixed point at a rate of 190 mm / min is one or more of: a) about 3 N to about 4.5 N after storage at 40°C ± 1°C for 1.5 months after filling; and b) about 3 N to about 5 N after storage at 40°C ± 1°C for 2.5 months after filling. Example 184

[0494] The syringe of Example 144 or Example 146, which syringe is provided in a needle shield device comprising a needle shield and a plunger; and wherein manual force can be applied to the plunger to expel the 150 mg / ml formulation of omalizumab and unlock the needle shield so that the needle shield can cover the needle after injection. Example 185

[0495] The syringe of Example 144 or Example 146, which syringe is manufactured by a process comprising: aseptic filling of the reservoir with the 150 mg / ml formulation of omalizumab; and clogging the tank with the cap. Example 186

[0496] The syringe of Example 185, in which the aseptic filling is carried out by means of a peristaltic pump or a stainless steel piston pump. Example 187

[0497] The syringe of Example 185, wherein, prior to aseptic filling, the reservoir and needle are sterilized by treatment with ethylene oxide gas, electron beam and / or steam sterilization in an autoclave. Example 188

[0498] The syringe of Example 146, wherein X is 1, which syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in less than 5 seconds to about 4 seconds, less than 4.75 seconds to about 4 seconds, less than 4.5 seconds to about 4 seconds, less than 4.25 seconds to about 4 seconds, or about 4 seconds, when a constant force of 10 N is applied to the stopper. Example 189

[0499] The syringe of Example 144 or Example 146, wherein the 150 mg / ml formulation of omalizumab consists of 150 mg / ml of antibody with 42.1 mg / ml of L-arginine hydrochloride, 1.37 mg / ml of L-histidine, 2.34 mg / ml of L-histidine hydrochloride monohydrate, 0.4 mg / ml of polysorbate 20 as an aqueous solution.

Claims

Claims

1. A syringe comprising: a reservoir filled with 2 ml of a 150 mg / ml formulation of omalizumab, wherein the 2 ml of 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprises: a stopper, and a 27 gauge needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper.

2. The syringe of claim 1, wherein the needle has one of: a) a minimum internal diameter of 0.277 mm; b) a minimum internal diameter of 0.191 mm; c) a minimum internal diameter of 0.184 mm; and d) a minimum internal diameter of 0.241 mm.

3. A syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, wherein X is 2, 1 or 0.5, wherein the X ml of 150 mg / ml formulation of omalizumab has 6000 or fewer particles having a diameter > 10 pm and / or 600 or fewer particles having a diameter > 25 pm; and the syringe further comprises: a stopper, and a needle of gauge between 25 and 29; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, wherein one of the following is satisfied when a constant force of 10 N is applied to the stopper, a) when X is 2, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 16 seconds;(b) when X is 1, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 5 seconds; and; c) when X is 0.5, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 4 seconds.

4. A syringe according to claim 1 or 3, wherein X is 2, wherein the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in one or more of the following: a) less than 8.5 seconds when a constant force of 17 N is applied to the stopper; and b) less than 5 seconds when a constant force of 30 N is applied to the stopper.

5. The syringe of claim 4, wherein the syringe is configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle in one or more of the following: a) about 16 seconds to about 14 seconds when a constant force of 10 N is applied to the stopper; b) about 8.5 seconds to about 6 seconds when a constant force of 17 N is applied to the stopper; and c) about 5 seconds to about 4 seconds when a constant force of 30 N is applied to the stopper.

6. The syringe of claim 3, wherein X is 1, and the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 5 seconds, less than 4.75 seconds, less than 4.5 seconds, less than 4.25 seconds, or about 4 seconds when a constant force of 10 N is applied to the stopper; b) less than 3 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds when a constant force of 30 N is applied to the stopper.

7. The syringe of claim 6, wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 5 seconds to about 4 seconds, less than 4.75 seconds to about 4 seconds, less than 4.5 seconds to about 4 seconds, less than 4.25 seconds to about 4 seconds, or about 4 seconds when a constant force of 10 N is applied to the stopper; b) less than 3.5 seconds to about 2 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30 N is applied to the stopper.

8. The syringe of claim 3, wherein X is 0.5, wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 2 seconds when a constant force of 17 N is applied to the stopper; and b) less than 1 second when a constant force of 30 N is applied to the stopper.

9. The syringe of claim 8, wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 4 seconds to about 2 seconds when a constant force of 10 N is applied to the stopper; b) less than 2 seconds to about 1 second when a constant force of 17 N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30 N is applied to the stopper.

10. A syringe according to claim 1 or 3, wherein the syringe contains: a) at least 76% of the major charge variant of omalizumab, measured by ion exchange chromatography after it has been filled with a 150 mg / ml solution of omalizumab stored at 5°C ± 1°C; and / or b) at least 77% of the major charge variant of omalizumab, measured by ion exchange chromatography after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 1°C for 2.5 months.

11. A syringe according to claim 1 or claim 3, wherein the percentage of major loading variant of omalizumab in the syringe, measured by means of exchange chromatography ions, is reduced by 2% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months, measured from filling.

12. A syringe according to claim 1 or claim 3, wherein the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is at least: a) 62% after filling with a 150 mg / ml solution of omalizumab stored at 5°C ± 1°C; and / or b) 62% after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 1°C for 2.5 months.

13. A syringe according to claim 1 or claim 3, wherein the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is reduced by 0.4% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months.

14. A syringe according to claim 1 or claim 3, wherein the syringe contains at least 0.4 mg / ml of polysorbate 20 after filling with a 150 mg / ml solution of omalizumab stored at 5°C ± 1°C.

15. A syringe according to claim 1 or claim 3, wherein the syringe contains at least 69% of the major charge variant of omalizumab, as measured by ion exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 1.5 months.

16. A syringe according to claim 1 or claim 3, wherein the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is at least: a) 56% for the syringe after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 1.5 months; and / or b) 51% for the syringe after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 2.5 months.

17. A syringe according to claim 1 or 3, wherein the syringe contains: a) at least 0.4 mg / ml of polysorbate 20 after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 1.5 months; and / or (b) at least 0.3 mg ml of polysorbate 20 after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 6 months.

18. A syringe according to claim 3, wherein the needle is a 26 to 29 gauge needle, preferably a 27 gauge needle.

19. The syringe of claim 3, wherein when the needle is 25 gauge, the needle has one of: a) a minimum internal diameter of 0.292 mm, and b) a minimum internal diameter of 0.232 mm.

20. The syringe of claim 18, wherein when the needle is 26 gauge, the needle has one of: a) a minimum internal diameter of 0.292 mm, and b) a minimum internal diameter of 0.232 mm.

21. The syringe of claim 18, wherein when the needle is 27 gauge, the needle has one of: a) a minimum internal diameter of 0.277 mm; b) a minimum internal diameter of 0.191 mm; c) a minimum internal diameter of 0.184 mm; and d) a minimum internal diameter of 0.241 mm.

22. A syringe according to claim 18, wherein, when the needle is 28 gauge, the needle has one of: a) a minimum internal diameter of 0.133 mm; and b) a minimum internal diameter of 0.190 mm.

23. A syringe according to claim 18, wherein, when the needle is 29 gauge, the needle has one of: a) a minimum internal diameter of 0.265 mm; b) a minimum internal diameter of 0.240 mm; c) a minimum internal diameter of 0.190 mm; and d) a minimum internal diameter of 0.133 mm; preferably the needle has a minimum internal diameter of 0.240 mm or 0.265 mm.

24. A syringe according to claim 1 or claim 3, wherein the stopper has a fluororesin on the product contacting side or an ethylene tetrafluoroethylene (ETFE) barrier film lamination.

25. A syringe according to claim 1 or claim 3, wherein the stopper has a UV cured B2-40 lubricating coating or is lubricated with a 1000 cSt silicone oil.

26. A syringe according to claim 1 or claim 3 when X is 2, wherein the syringe has an internal coating of 0.7 ± 0.2 mg of polydimethylsiloxane.

27. ​​A syringe according to claim 3, when X is 1 or 0.5, wherein the syringe has an internal coating of 0.4 ± 0.2 mg of polydimethylsiloxane.

28. A syringe according to claim 1 or claim 3, wherein the needle has 3 bevels on its distal surface or 5 bevels on its distal surface.

29. A syringe according to claim 1 or claim 3, wherein the apparent viscosity of the 150 mg / ml formulation of omalizumab is 12 to 14 mPa.s or, when measured at a shear rate of 200 s 1 is: 24.7 ± 0.5 mPa.s at 5.0 ± 0.2°C, 15.3 ± 0.5 mPa.s at 15.0 ± 0.2°C, 11.4 ± 0.5 mPa.s at 25.0 ± 0.2°C or 7.2 ± 1.2 mPa.s at 40.0 ± 0.2°C.

30. A syringe according to claim 1 or claim 3, which syringe has a latex-free needle shield.

31. A syringe according to claim 1 or claim 3, which syringe has a round flange at a proximal end of the reservoir; optionally wherein the round flange has a maximum diameter of 11 ± 0.25 mm or 14.7 ± 0.25 mm.

32. A syringe according to claim 3 when X is 1 or 0.5, wherein the syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 6.35 mm ± 0.05 mm.

33. A syringe according to claim 3, wherein, when the stopper is not inserted into the reservoir, it has one of: a) a maximum external diameter of 6.67 mm to 7.10 mm and / or a length of 7.85 ± 0.4 mm; and b) a maximum external diameter of 6.70 ± 0.15 mm and / or a length of 7.85 ± 0.4 mm.

34. A syringe according to claim 3 when X is 1 or 0.5, wherein the stopper has at least one circumferential rib having an outer diameter of 6.60 ±0.15 mm.

35. A syringe according to claim 1 or claim 3 when X is 2, which syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 8.65 mm ± 0.05 mm.

36. A syringe according to claim 1 or claim 3 when X is 2, wherein the stopper has a maximum external diameter of 9.05 ± 0.15 mm and / or a length of 7.70 ± 0.4 mm when not inserted into the tank.

37. A syringe according to claim 1 or claim 3 when X is 2, wherein the stopper has at least one rib having an outer diameter of 9.00 ±0.15 mm.

38. A syringe according to claim 1 or claim 3, wherein the peel force configured to move the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of the following: a) about 2 N to about 4 N after storage at 5°C ± 1°C for 2.5 months after filling; b) about 2 N to about 4 N after storage at 5°C ± 1°C for 6 months after filling.

39. A syringe according to claim 1 or claim 3, wherein the peel force configured to move the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of the following: a) about 2 N to about 3.5 N at 25°C ± 1°C after filling; b) about 2 N to about 4.5 N after storage at 25°C ± 1°C for 1.5 months after filling; c) about 2.5 N to about 5 N after storage at 25°C ± 1°C for 2.5 months after filling; and / or d) about 2.5 N to about 5.5 N after storage at 25°C ± 1°C for 6 months after filling.

40. A syringe according to claim 1 or claim 3, wherein the peel force configured to move the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of the following: a) about 3 N to about 4.5 N after storage at 40°C ± 1°C for 1.5 months after filling; and b) about 3 N to about 5 N after storage at 40°C ± 1°C for 2.5 months after filling.

41. A syringe according to claim 1 or claim 3, wherein the syringe is provided in a needle shield device comprising a needle sleeve and a plunger; and wherein manual force can be applied to the plunger to expel the 150 mg / ml formulation of omalizumab and unlock the sleeve. needle so that the needle sleeve can cover the needle after injection.

42. A method of manufacturing a syringe according to claim 1 or claim 3, comprising the steps of: aseptically filling the reservoir with the 150 mg / ml formulation of omalizumab; and capping the reservoir with the stopper.

43. A manufacturing method according to claim 42, wherein the aseptic filling is carried out by means of a peristaltic pump or a stainless steel piston pump.

44. A manufacturing method according to claim 42, further comprising a step of sterilizing the reservoir and the needle by treatment with ethylene oxide gas, electron beam and / or steam sterilization in an autoclave, prior to aseptic filling.

45. The syringe of claim 3, wherein X is 1, which syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in less than 5 seconds to about 4 seconds, less than 4.75 seconds to about 4 seconds, less than 4.5 seconds to about 4 seconds, less than 4.25 seconds to about 4 seconds, or about 4 seconds, when a constant force of 10 N is applied to the stopper.

46. A syringe according to claim 1 or claim 3, wherein the 150 mg / ml formulation of omalizumab corresponds to 150 mg / ml of antibody with 42.1 mg / ml of L-arginine hydrochloride, 1.37 mg / ml of L-histidine, 2.34 mg / ml of L-histidine hydrochloride monohydrate, 0.4 mg / ml of polysorbate 20 in aqueous solution.

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